KR20020068373A - Butyne diol derivatives - Google Patents

Abstract

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

Description

Butine diol derivatives {BUTYNE DIOL DERIVATIVES}

Endothelin (ET-1, ET-2, ET-3) is a 21-amino acid peptide produced and active in almost all tissues (Yanagisawa Met al., Nature (1988) 332: 411). Endothelin is a potent vasoconstrictor and an important regulator of heart, kidney, endocrine and immune function (McMillen MA et al., J AM Coll Surg (1995) 180: 621). They participate in bronchial contraction and regulate neurotransmitter release, inflammatory cell release, fibrosis, cell proliferation, and cell differentiation (Rubanyi GM et al .: Pharmacol Rev (1994) 46: 328).

Two types of endothelin receptors (ET _A , ET _B ) have been cloned and characterized in mammals (Arai H et al., Nature (1990) 348: 730; Sakuri 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 mainly present in vascular smooth muscle cells and regulates vasoconstriction and proliferative responses (Ohlstein EH et al., Drug Dev Res (1993) 29: 108). In contrast, the ET _B receptor has equal affinity for the three endothelin isopeptides and binds to the linear endothelins tetra- alla-endotelene and sarapotoxin S6C. This receptor is located in vascular endothelial cells and smooth muscle, and is particularly abundant in the lungs and brain. Endothelial ET _B receptors regulate transient vasodilatory responses to ET-1 and ET-2 through nitric oxide and / or prostacyclin release, while smooth muscle ET _B receptors exert vasoconstrictive action (Summer MJ et al., Brit J Pharmacol (1992) 107: 858). ET _A and ET _B receptors are very similar in structure and belong to the family of G-protein coupled receptors.

In some diseases such as hypertension, sepsis, atherosclerosis, acute myocardial infarction, congestive heart failure, renal failure, migraine, and asthma, an abnormal physiological role for ET-1 has been suggested in relation to elevated plasma and tissue levels.

As a result, endothelin receptor antagonists have been extensively studied as powerful therapeutic drugs. Endothelin receptor antagonists have shown preclinical and / or clinical efficacy in a variety of diseases, such as cerebrovascular spasm, heart failure, pulmonary and systemic hypertension, neurological (inflammatory), renal failure, and myocardial infarction following subarachnoid hemorrhage.

To date, endothelin receptor antagonists are not commercially available and several are in clinical trials. However, these molecules exhibit many disadvantages such as complex synthesis, low solubility, high molecular weight, inefficient pharmacokinetics or stability problems (e.g. increased liver enzymes), as well as the differentiation of differentiated ET _A / ET _B blocks for clinical outcomes. The impact is also unknown. Thus, the selectivity profile of each antagonist for the tailoring of physicochemical and pharmacokinetic properties and any clinical signs is indispensable. We have made a new class of butyne-diol derivatives having the following formula and satisfying the above-described specific fit.

The present invention relates to novel butyne diol derivatives of formula (I) and their use as active ingredients in pharmaceutical compositions. The present invention also relates to processes for preparing the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and in particular their use as endothelin receptor antagonists.

Inhibitory activity of the compound of formula (I) on the endothelin receptor can be confirmed using the experimental procedure described below.

To assess the efficacy of the compound of formula I, the following tests are made:

1) Inhibition of Endothelin Binding to Membranes Derived from CHO Cells Carrying Human ET Receptors

In competitive binding studies, membranes of CHO cells expressing human recombinant ET _A or ET _B receptors are used. Microsome membranes are made from recombinant CHO cells and subjected to binding assays as known (Breu et al., FEBS Lett 1993; 334: 210).

The assay is performed in 200 μl 50 mM Tris / HCl buffer (pH 7.4) containing 25 mM MnCl ₂ , 1 mM EDTA, 0.5% (w / v) BSA on a polypropylene microtiter plate. Membranes containing 0.5 μg protein are incubated for 2 hours at 20 ° C. with 8 pM [ ¹²⁵ I] ET-1 (4000 cpm) and unlabeled antagonists with progressively increasing concentrations. Maximum and minimum binding is evaluated in samples with and without 100 nM ET-1, respectively. After 2 hours, the membrane is filtered on filter plates containing GF / C filters (Unifilterplates, Canberra Packard SA Zurich, Switzerland). To each well, 50 μl scintillation cocktail (MicroScint 20, Canberra Packard SA Zurich, Switzerland) is added and the filter plate is counted on a microplate counter (TopCount, Canberra Packard SA Zurich, Switzerland).

All experimental compounds are dissolved, diluted and added in DMSO. The assay is carried out in the presence of 2.5% DMSO which has been found to hardly interfere with binding. IC ₅₀ represents the concentration of antagonist that inhibits 50% of specific binding of ET-1. In the reference compound, the following IC ₅₀ values were identified: ET _A cells: 0.075 nM (n = 8) at ET-1, 118 nM (n = 8) at ET-3; ET _B cells: 0.067 nM (n = 8) in ET-1 and 0.092 nM (n = 3) in ET-3.

IC ₅₀ values obtained for compounds of Formula I are shown in Table 1.

2) Isolated rat aortic ring (ET _A Receptor) and rat tracheal ring (ET) _B Inhibition of endothelin-induced contraction)

Functional inhibition of endothelin antagonists was assessed by inhibition of endothelin-1-induced contraction in rat aortic rings (ET _A receptor) and sarapotoxin S6c-induced contraction in rat tracheal rings (ET _B receptor). do. Adult Wistar mice are anesthetized and bled. The thoracic aorta or organ is excised, incised and cut into 3-5 mm rings. The endothelium gently rubs off the vascular surface. Each ring was maintained at 37 ° C. and Krebs-Henseleit solution (mM units; Nacl 115, KCl 4.7, MgSO ₄ 1.2, KH ₂ PO ₄ 1.5, NaHCO ₃ 25, CaCl, which provided 95% O ₂ and 5% CO ₂ gas). ₂ 2.5, suspended in a 10 ml separated organ solution filled with glucose 10). The ring connects to a force transducer and records the isotonic tension (EMKA Technologies SA, Paris, France). The ring pulls to a static tension of 3 g (aorta) or 2 g (trachea). After 10 minutes of incubation with the test compound or its carrier, a cumulative dose of ET-1 (aorta) or sarapotoxin S6c (organ) is added. The functional inhibitory capacity of the test compound is assessed by calculating the concentration ratio, ie the change in the rightward direction of the EC ₅₀ induced by the different concentration of test compound. EC ₅₀ is the concentration of endothelin required to achieve anti-maximal contraction, and pA ₂ is the negative log of the antagonist concentration leading to a 2-fold change in EC ₅₀ values.

The pA ₂ values obtained for the compounds of formula (I) are shown in Table 2.

Due to their ability to inhibit endothelin binding, the aforementioned compounds can be used for the treatment of diseases associated with increased vasoconstriction, proliferation or inflammation due to endothelin. Examples of such diseases include high blood pressure, coronary artery disease, heart failure, kidney and myocardial ischemia, kidney failure, cerebral hemorrhage, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, hypertension, and pulmonary hypertension. They also include atherosclerosis, prevention of restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcers, cancer, prostate hyperplasia, erectile dysfunction, hearing loss, cataracts, chronic bronchitis, asthma, gram negative sepsis, shock, sickle cell It can be used for anemia, glomerulonephritis, renal colic, glaucoma, diabetic complications, complications after vascular or heart surgery or organ transplantation, the treatment and prevention of cyclosporine treatment and other diseases known to be related to endothelin.

The compound may be administered orally, rectally, extranasally (eg, intravenously, intramuscularly, subcutaneously, intrathecal, subcutaneously) or sublingually, in ophthalmic formulations, or in aerosols. Examples of applications are capsules, tablets, suspensions or solutions for oral administration, suppositories, injections, eye drops, ointments or aerosols / nebulizers.

Appropriate use is intravenous, intramuscular, eye drop or oral administration. Dosages used will depend on the type, age, patient needs and type of application of the particular active ingredient. Generally, a dose of 0.1-50 mg / kg body weight per day is used. Formulations containing a compound according to the invention may contain inert or pharmacodynamically active excipients. For example, tablets or granules may contain a number of binders, filler excipients, carrier materials or diluents.

In patent applications EP 743307 and EP 882719, related endothelin receptor antagonists are disclosed. However, EP 882719 only shows IC ₅₀ values for the ET _A receptor in Table 1. Corresponding levels of the compounds claimed herein are much more effective and specific in direct comparisons, as they can be distinguished between the activity of both receptors and can also produce hybrid antagonists.

The present invention relates to butene diol derivatives of the formula: pure enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, diastereomeric racemates or the like in terms of enantiomers Regarding pharmaceutically acceptable salts of:

Wherein R ¹ is phenyl; Substituted by halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkynyl, trifluoromethyl, cycloalkyl, hydroxy-cycloalkyl Single-, double- or triple-substituted phenyl; 2-pyridyl; Low-substituted alkyl, 5-substituted 2-pyridyl substituted with a pentagonal heteroaryl ring having one or two nitrogen, sulfur or oxygen atoms;

R ² is hydrogen; Lower alkyl; Phenyl; Having one or two nitrogen, sulfur or oxygen atoms that can be mono- or di-substituted with halogen, low alkyl, low alkoxy, low alkoxy-lower alkyl, trifluoromethyl, or halogen, low alkyl, low alkoxy Mono-, di-, or tri-substituted phenyl substituted with a pentagonal heteroaryl ring; benzyl; Mono- or di-substituted benzyl substituted with halogen, lower alkyl, lower alkoxy, trifluoromethyl, 2-pyrimidyl; Lower alkyl, lower alkoxy, halogen, trifluoromethyl, or ^a group of the formula -C (A) -BR ^a , wherein A is O or S; B is NH; R ^a is lower alkyl; cycloalkyl; phenyl; halogen Lower alkyl, lower alkenyl, lower alkoxy, trifluoromethyl, or a hexagonal heteroaryl ring having one or two nitrogen atoms which may be mono- or di-substituted with halogen, lower alkyl, lower alkoxy) Mono-, di-, or tri-substituted phenyl.

R ³ is single-, double- or triple-substituted phenyl substituted with lower alkyl, lower alkenyl, lower alkyloxy, trifluoromethyl, halogen, hydroxy.

R ⁴ is hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkyloxy, lower alkylthio, lower alkyl-oxy-lower alkyl; Phenyl; Halogen, lower alkyl, lower alkoxy, single- or double-substituted by lower or lower alkylene or lower alkenylene or lower alkyleneoxy or lower alkylenedioxy or heteroaryl forming a pentagonal or hexagonal phenyl ring with a phenyl ring; Substituted phenyl; Heterocyclyl.

X is the hand of oxygen, sulfur or atom.

Unless otherwise specified, the low cost in the definition of formula (I) refers to a straight and branched chain group having 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. Examples of lower alkyl and lower alkoxy groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, hexyl, heptyl, methoxy, ethoxy, pro Foxy, butoxy, iso-butoxy, sec.-butoxy, tert.-butoxy are mentioned. The lower alkylenedioxy-group is preferably the methylene-dioxy, ethylene-dioxy, propylene-dioxy, butylene-dioxy-group. Examples of low cost alkanoyl-groups include acetyl, propanoyl, butanoyl. Lower alkenylene means, for example, vinylene, propenylene, butenylene. Low alkenyl and low alkynyl mean ethylene, propylene, butylene, tert.-butylene (2-methyl-propenyl), acetylenyl, propynylene, butynylene, petynylene, 2-methyl-pentynylene, etc. do. Lower alkenyloxy means alkyloxy, vinyloxy, propenyloxy and the like. Cycloalkyl means a saturated cyclic hydrocarbon ring having 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., which are lower alkyl, hydroxy-lower alkyl, amino- Low alkyl, low alkoxy-lower alkyl, lower alkenylene groups. Heterocyclyl is a saturated or unsaturated (excluding aromatic) pentagonal, hexagonal or octagonal ring having one or two nitrogen, oxygen or sulfur atoms, wherein the ring is a lower alkyl, amino, halogen , Nitro, hydroxy, low alkoxy (e.g. piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, Dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, pyrazolidinyl, etc.) and derivatives of such rings substituted with the aforementioned substituents. Heteroaryl is a hexagonal aromatic ring having 1 to 4 nitrogen atoms; Benzo-fused hexagonal aromatic rings having 1 to 3 nitrogen atoms; Pentagonal aromatic rings having one oxygen, nitrogen or sulfur atom; Benzo-fused pentagonal aromatic rings having one oxygen, nitrogen or sulfur atom; Pentagonal aromatic rings having one oxygen and nitrogen atom and their benzo-fused derivatives; Pentagonal aromatic rings having one sulfur, nitrogen or oxygen atom and their benzo-fused derivatives; Pentagonal aromatic rings having two nitrogen atoms and their benzo-fused derivatives; Pentagonal aromatic rings having three nitrogen atoms and their benzo-fused derivatives; Or tetrazolyl rings (e.g. furanyl, thienyl, pyrrolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, pyridazinyl, oxazolyl, etc.) Wherein such rings may be substituted with lower alkyl, amino, amino-lower alkyl, halogen, hydroxy, lower alkoxy or trifluoromethyl. Aryl means an aromatic ring mono-, di- or tri-substituted with 6 to 10 carbon atoms, such as a phenyl or naphthyl ring, which are phenyl, halogen, hydroxy, low alkoxy, low alkyl, trifluoromethyl, It may be substituted with lower alkenyloxy, trifluoromethoxy, cyclopropyl, hydroxy-cyclopropyl, lower alkenyl or lower alkylenedioxy.

Pharmaceutically acceptable salts include hydrohalonic acid, such as hydrochloric acid or bromic acid; Alkali or earth alkaline bases when inorganic and organic acids such as sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methylsulfonic acid, p-tolusulfonic acid, and compounds of formula I are acidic Salts with inorganic bases such as, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.

Formula I compounds may have one or more asymmetric carbon atoms, and are optically pure enantiomers or diastereomers, enantiomers or mixtures of diastereomers, diastereomeric racemates, diastereomeric racemates It can be prepared in the form of a mixture. The present invention includes all of these forms. The mixture can be separated by methods known in the art, for example chromatography, thin layer chromatography, HPLC, crystallization.

Due to the ability to inhibit endothelin binding, the above-mentioned formulas (I) compounds and pharmaceutically acceptable salts thereof can be used for the treatment of vasoconstriction, proliferation or inflammation due to endothelin. Examples of such diseases include high blood pressure, coronary artery disease, heart failure, kidney and myocardial ischemia, kidney failure, cerebral hemorrhage, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, hypertension, and pulmonary hypertension. They also include atherosclerosis, prevention of restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcers, cancer, prostate hyperplasia, erectile dysfunction, hearing loss, cataracts, chronic bronchitis, asthma, gram negative sepsis, shock, sickle cell It can be used for the treatment and prevention of anemia, glomerulonephritis, renal colic, glaucoma, diabetic complications, complications after vascular or cardiac surgery or organ transplantation, and complications of cyclosporine treatment and other diseases known to be related to endothelin.

These compositions can be administered in the form of enteric or oral forms (eg tablets, dragees, gelatin capsules, emulsions, solutions or suspensions), nasal forms (eg sprays) or suppositories. These compounds may also be administered in intramuscular, intestinal or intravenous form, for example by injection solution.

These pharmaceutical compositions are of formula (I) or pharmaceutically acceptable, together with inorganic and / or organic excipients commonly used in the pharmaceutical industry, such as lactose, corn or derivatives thereof, talc, stearic acid or salts thereof. These salts can be contained.

For gelatin capsules, vegetable oils, waxes, fats, lipids or semi-lipid polyols can be used. In the case of solutions and syrups, water, polyols, saccharose, glucose and the like are used. Injections are prepared using water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes, and the like. Suppositories are prepared using natural or hydrogenated oils, waxes, fatty acids (fats), liquids or semi-liquid polyols.

The composition may further contain preservatives, stabilization improving substances, viscosity improving or controlling substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts that change the osmotic pressure, buffers, antioxidants and the like.

Formula I compounds also include one or a plurality of other therapeutically active substances, for example α- and β-blockers (pentolamin, phenoxybenzamine, atenolol, propranolol, timolol, metoprolol, carteolol, and the like); Vasodilators (hydralazine, minoxidil, diazoxide, flosequinan, etc.); Calcium-antagonists (diltiazem, nicardipine, minodipine, verapamil, nifedipine, etc.); ACE-inhibitors (clazapril, captopril, enalapril, lisinopril, etc.); Calcium activators (such as pinassidyl); Angiotensin II antagonists; Diuretics (hydrochlorothiazide, chlorothiazide, acetolamide, bumetanide, furosemide, metolazone, crotalidone and the like); Sympatholitics (methyldopa, clonidine, guanabenz, reserpin, etc.); It can be used in combination with other therapeutic agents that can be used to treat hypertension or any heart disease.

Dosages can vary but must be adjusted to the specific situation. In general, the dosage administered daily in oral form is 3 mg to 3 g, preferably 10 mg to 1 g, more preferably 5 mg to 300 mg in adults weighing 70 kg. The dosage is preferably administered in one to three portions of equivalent weight per day. In general, children should eat less than this according to their weight and age.

Suitable groups of compounds are compounds of formula I and pharmaceutically acceptable salts thereof: wherein R ¹ , R ² , R ⁴ are as defined above and R ³ is phenyl; Lower alkyl, lower alkoxy, trifluoromethyl, monosubstituted phenyl substituted with halogen, X is oxygen or atom hand.

Another suitable group of compounds are compounds of Formula II and pharmaceutically acceptable salts thereof:

Wherein R ² , R ³ , R ⁴ , X are the same as defined in Formula I above, and R ⁵ is lower alkyl.

Another suitable group of compounds are compounds of Formula III and pharmaceutically acceptable salts thereof:

Wherein R ¹ , R ³ , R ⁴ , X are the same as defined in formula (I), and R ⁶ , R ⁷ , R ⁸ are each independently hydrogen, lower alkyl, lower alkyloxy, halogen, trifluoromethyl.

Another suitable group of compounds are Formula IV compounds and pharmaceutically acceptable salts thereof:

Here, R ¹ , R ³ , R ⁴ , R ^a , X are the same as defined in formula (I).

Another suitable group of compounds are compounds of formula I and pharmaceutically acceptable salts thereof: wherein R ¹ , R ³ , R ⁴ , X are as defined in formula I above and R ² is lower alkyl.

Another suitable group of compounds are the compounds shown below and pharmaceutically acceptable salts thereof:

5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl]- 2-pyridine sulfonamide;

4-tert.-Butyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl ] -Benzene sulfonamide;

5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2 -Pyridine sulfonamides;

5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfonamide;

4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] benzene sulfonamide;

5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide;

5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (p-tolyl) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine Sulfonamides;

5-isopropyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- ( 4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide;

4-tert.-Butyl-N- [6- (4- (2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -benzene sulfonamide;

4-tert.-Butyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2 -(4-pyridyl) -4-pyrimidinyl] -benzene sulfonamide;

2-Pyrimidinyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2-pyridin-4-yl-pyrimidine -4-yloxy] -but-2-ynyl ester;

Phenyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2-methyl-pyrimidin-4-yloxy] -but 2-ynyl esters;

Phenyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidine-4- Iloxy] -but-2-ynyl ester;

2-Pyridinyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (N-morpholino) -pyri Midin-4-yloxy-but-2-ynyl ester;

2-Pyridinyl-carbamic acid 4- [6- (5-methyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (4-morpholino) -pyrimidine -4-yloxy] -but-2-ynyl ester;

4-Pyrazinyl-carbamic acid 4- [6- (5-methyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (4-morpholino) -pyrimidine -4-yloxy] -but-2-ynyl ester;

4-tert.-Butyl-N- [6- (4-methoxy-2-butynyloxy) -5- (o-methoxy-phenoxy) -2- (2-pyrimidinyl) -4-pyri Midinyl] benzene sulfonamide;

5-isopropyl-N- [6- (4-methoxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide;

The compound of formula (I) is prepared from compound of formula (V) via one of two routes given below. Compound VI is compound R ² -Y, wherein Y is a reactive leaving group such as chlorine, bromine, sulfone, sulfate, and the like; Or when R ² is 1 group of the formula C (A) -NH-R ^a, the compound R ^a -N = C = A, wherein R ^a and A are as defined in formula (I).

Compound VII is a 2-butyne-1,4-diol in the presence of a base (e.g., alkali metal hydroxide, alkali metal hydroxide, sodium hydroxide, etc.) in a solvent such as DMSO, DMF, THF, pyridine, water and the like. By reaction with R ² -Y (Tetrahedron Letters 38 (1997), 7887-7890; Bull. Chem. Soc. Jpn. 28 (1995), 80-82; J. Org. Chem. 18 (1953), 1601-1606). In addition, the compound of formula VII can be made by reacting an alkoxide with hydroxy-protected 1-chloro-4-hydroxy-2-butynin as appropriate, followed by removal of the protecting group (Bull. Chim. Soc. 1955, 502; J. Org. Chem. 63 (1998), 4291-4298).

Compound V is prepared from the corresponding dichloro compound VIII (Bioorg, Med. Chem. Letters 7 (1997), 2223-2228, Chimia 50 (1996), 519-524).

Compound VIII is treated with excess sulfonamide potassium salt in the presence of a base (eg triethylamine, diisopropylethylamine) on a solvent (eg DMF, DMSO) at room temperature to afford the desired compound V. Sulfonamide potassium salts are described, for example, in Bioorg. Med. Chem. It may be prepared according to Letters 7 (1997), 2223-2228.

Compound VIII is a chlorinating agent such as POCl ³ , PCl ⁵ or these at elevated temperatures (30-120 ° C.) in the presence of a base such as N, N-dialkylaniline or benzyltriethyl ammonium chloride. Can be prepared by treatment of the corresponding compound IX (or tautomeric forms thereof) (Bioorg. Med. Chem. Letters 7 (1997), 2223-2228; J. Med. Chem., 41 (1998). ), 3793-3803; J. Chem. Soc. 1959, 2214; Bull. Soc. Chim. Fr. 1959, 741-742).

In the standard method described by Pinner (The Pyrimidines, by DJ Brown, Wiley Interscience, New York 1970), Compound IX is amidine X (corresponding to the presence of sodium alkoxide in a solvent (e.g. methanol, ethanol, etc.) at room temperature. Hydrochloride) is made by condensation with the appropriate malonic ester derivative XI (Bull. Soc. Chim. Fr. 1960, 1648).

Amidine X is made from the corresponding nitrile XII by treating nitrile XII with sodium methylate in methanol and then adding ammonium chloride or by treating nitrile XII with litum hexamethyldisilazane in isopropanol and then adding hydrochloric acid ( Advanced Organic Chemistry, by J. March, 3 ^rd edition, Wiley 1985, p. 803).

The malonic ester derivative XI is either purchased commercially or made according to the procedures disclosed in the literature (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).

In general, compounds having at least one optically active carbon atom are pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, or diastereomers by methods known in the art. The compound of formula (I) synthesized and, if desired, synthesized into a mixture of sex racemates, are converted into pharmaceutically acceptable salts by methods known in the art.

The following examples illustrate the invention. All temperatures are expressed in degrees Celsius.

The compounds shown below are synthesized according to the procedure described above. All compounds have ¹ H-NMR (300 MHz) and in special cases ¹³ C-NMR (75 MHz) (Varian Oxford, 300 MHz; chemical variations are expressed in ppm relative to the solvent used; multiplicity: s = single, d = doublet , t = triple), LC-MS (Waters Micromass; ZMD-Platform with ESI-probe of Alliance 2790 HT; Column: 2 × 30 mm, Gromsil ODS4, 3 μm, 120 μs; Gradient: 0-100% aceto in water Nitrile, 6 min, 0.05% formic acid, flow rate: 0.45 ml / min; t _R represents the molecular weight of the aliquot in minutes from t _r ), TLC (TLC-plate, Merck, silica gel 60 F ₂₅₄ ) and in special cases melting point Let's do it. Abbreviations: DCM = dichloromethane, MeOH = methanol, DMF = N, N-dimethylformamide, THF = tetrahydrofuran, DMSO = dimethyl sulfoxide, DMPU = 1,3-dimethyl-3,4,5,6-tetra Hydro-2 (1H) -pyrimidinone, DMAP = 4-dimethylaminopyridine, DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene, min = minute, h = hour.

Example 1

a) To 0.23 g sodium solution dissolved in 40 mL methanol is added 10.62 g 4-cyanopyridine at room temperature. Stirring is continued for 6 hours after addition of 5.9 g ammonium chloride and for an additional 10 hours. 120 ml diethyl ether is then added, and the precipitate is filtered after 30 minutes and washed once more with 20 ml diethyl ether. The product is dried under high vacuum. White powder gives 14.95 g 4-amino-pyridine hydrochloride.

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

c) To a stirred solution of 9.7 g sodium methylate dissolved in 100 ml methanol, 21.7 g dimethyl- (o-methoxyphenoxy) malonate dissolved in 50 ml methanol was added within 15 minutes and stirred for 30 minutes, followed by 15.0 g. 4-Amidine-pyridine hydrochloride is added and stirred at room temperature for 20 hours. The reaction mixture is concentrated in vacuo. The solid residue is stirred with ether. The powder obtained is filtered and dissolved in 300 ml water. The pH is adjusted to 4 by adding acetic acid. The precipitated product is filtered off, washed with water and dried in vacuo at 50 ° C. 20.1 g 5- (o-methoxyphenoxy) -4,6-dihydroxy-2- (4-pyridyl) -pyrimidine (or tautomer 5- (o-methoxyphenoxy)-as a white powder 2- (4-pyridyl) -tetrahydropyrimidine-4,6-dione) is obtained.

d) 10 g 5- (o-methoxyphenoxy) -4,6-dihydroxy-2 (4-pyridyl) -pyrimidine, 11.2 g N-ethyldiisopropylamine, 11 g tetraethylammonium chloride, 13.8 g Phosphorus pentachloride is dissolved in 25 ml phosphorus oxychloride and heated to reflux for 3 hours. The mixture is evaporated in vacuo, toluene is added and the mixture is evaporated once more. The residue is taken up in DCM and poured into ice / water. The layers are separated and the organic layer is washed with water, dried over sodium sulfate and evaporated. After recrystallization from acetone, 6.52 g 4,6-dichloro-5- (o-methoxyphenoxy) -2 (4-pyridyl) -pyrimidine is obtained.

e) 5-isopropyl pyridine-2-sulfonamide potassium salt is prepared according to the procedures disclosed in EP 0713875 A1 and Bioorganic & Medical Chemistr Letters, 7 (1997), 2223-2228.

f) 20 ml dry 1 g 4,6-dichloro-5- (o-methoxyphenoxy) -2- (4-pyridyl) -pyrimidine and 1.43 g 5-isopropyl pyridine-2-sulfonamide potassium salt Suspend in DMF. The mixture is stirred under argon at room temperature, which becomes clear in a few hours. After 16 hours at room temperature, most solvents are removed by evaporation under reduced pressure. The residue is taken up in 20 ml water and the pH adjusted to 4-5 by addition of 1 ml acetic acid. A precipitate is formed. The precipitate is filtered off, washed with water and dried. The yellow powder is further purified by column chromatography on silica gel, eluting in the order of 1: 1 hexanes: ethyl acetate and 10: 1 DCM: MeOH. 1.43 g 5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfone in slightly yellow powder Obtain an amide. LC-MS: t _R = 5.00 min, [M + 1] ⁺ = 512.19, [M-1] ^- = 510.26.

g) At 0-5 ° C., 5.04 g 2-butyne-1,4-diol is added in portions to a stirred slurry of 0.7 g sodium hydroxide dissolved in 30 ml dry DMF and 5 ml DMPU. Stirring is continued until gas evolution stops. In the resulting suspension at room temperature 1.5 g 5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine Sulfonamide is added and the mixture is stirred at 95 ° C. for 24 hours. Finally, the slurry is cooled to room temperature, poured into 100 ml 10% aqueous citric acid solution and extracted twice with 150 ml ethyl acetate. The combined organic layers are washed twice with 50 ml water, dried over MgSO ₄ and evaporated. The remaining dark brown oil is purified by column chromatography on 80 g silica gel and eluted with DCM containing 0-5% methanol. 0.82 g 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) as a light yellow solid here -4-pyrimidinyl] -2-pyridine sulfonamide is made. LC-MS: t _R = 4.39 min, [M + 1] ⁺ = 562.29, [M-1] ^- = 560.41.

Example 2

a) A 15.2 g 4-tert.-butylbenzene sulfonyl chloride solution dissolved in 150 mL THF is cooled with an ice solution. Add 15.2 ml 25% aqueous ammonium hydroxide solution drop by drop. After the addition is complete, the solution is stirred at room temperature for 15 minutes. The solvent is removed under vacuum. The residue is dissolved in ethyl acetate once more and washed twice with water. The organic phase is dried over Na ₂ SO ₄ , evaporated and dried. The resulting 14.8 g white powder was dissolved in 75 mL methanol and 7.5 g potassium tert. Butylate is added. The solution is stirred briefly at room temperature and evaporated. The resulting residue is carefully dried to give 16.3 g 4-tert.-butylbenzene sulfonamide potassium salt as a white solid.

b) 6.1 g 4,6-dichloro-5- (o-methoxyphenoxy) -2- (4-pyridyl) -pyrimidine (Example 1, sections a) to d) dissolved in 100 ml dry DMF) To the solution is added 8.8 g 4-tert.-butyl benzene sulfonamide potassium salt at room temperature. The solution is stirred overnight at room temperature. The solution is added to a mixture of 150 ml water and 100 ml diethyl ether. The pH is adjusted to 5 by adding acetic acid. The resulting precipitate is collected and washed with water and diethyl ether. The resulting powder is suspended in boil ethyl acetate. The mixture is cooled in an ice solution. Finally, the solid material was collected and dried to give 6.6 g 4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (4-pyridyl) as beige crystals. 4-pyrimidinyl] -benzene sulfonamide is obtained. LC-MS: t _R = 5.80 min, [M + 1] ⁺ = 525.31, [M-1] ^- = 523.48.

c) At room temperature, 6.9 g 2-butyne-1,4-diol is added in portions to a stirred slurry of 0.96 g sodium hydroxide dissolved in 25 ml dry DMF and 5 ml dry DMPU. Stirring is continued until gas evolution stops. To the resulting suspension 2.1 g 4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -benzene sulfonamide Is added at room temperature and the mixture is stirred at 90 ° C. for 48 hours. Finally, the solvent is removed under reduced pressure and the resulting oil is treated with 150 ml of 10% aqueous acetic acid. The black solution is extracted with 150 ml DCM. The organic layer is washed with water, dried over MgSO ₄ and evaporated. The resulting dark brown oil is further purified by column chromatography on silica gel and eluted with 4: 1 to 1: 4 toluene: ethyl acetate. 1.28 g 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridine as a beige solid Dill) -4-pyrimidinyl] -benzene sulfonamide. LC-MS: t _R = 4.87 min, [M + 1] ⁺ = 575.32, [M-1] ^- = 573.45.

Example 3

To a 70 g 2-bromo-5-methyl pyridine suspension in 500 ml water is added 200 ml 25% aqueous hydrochloric acid at room temperature. To the clear solution is added 68 g thiourea and the mixture is heated to reflux. 34 g after 4 h and 17 g after 20 h are further added. After 24 hours, the solution is cooled with an ice solution and 360 ml of 4N sodium hydroxide solution are added. The resulting precipitate is dissolved by adding 600 ml DCM. The organic layer is separated and washed with 500 ml water. The aqueous phase is acidified to pH 3 with hydrochloric acid and extracted repeatedly with DCM. The combined organic layers are dried over MgSO ₄ , evaporated and dried under reduced pressure. Here 46.9 g yellow solid is made, which is recrystallized from boil ethanol to give 37.6 g 5-methyl-2-thio-pyridine in the form of a pale yellow plate which is soaked at 168 ° C. and gradually dissolved at 179 to 190 ° C. do. ¹ H-NMR (CDCl ₃ , 300 MHz): 2.17 (s, 3H); 7.24 (dd, J = 2.0, 8.8, 1 H); 7.41 (t, J = 1.0, 1 H); 7.47 (d, J = 8.8, 1 H); 14.03 (s br, 1 H).

b) 18 g 5-methyl-2-thio-pyridine is added to a mixture of 100 ml 25% aqueous hydrochloric acid and 250 ml DCM. While the mixture is vigorously stirred and maintained at -10 ° C, 250 ml aqueous solution containing 13% sodium hypochlorite is carefully added. Immediately after addition is complete, stir for 10 minutes. The organic layer is separated. 250 ml DCM is added to the aqueous layer and the mixture is treated once more with 250 ml sodium hypochlorite. Immediately after completion of the addition, the organic layer is separated. The aqueous layer is extracted five times with 200 ml DCM. The organic layers are combined, dried over MgSO ₄ and evaporated. The resulting oil is taken up in 125 mL THF and cooled to -20 ° C. 25 ml saturated aqueous ammonium hydroxide solution is added slowly. The mixture is stirred overnight at room temperature. Excess ammonia is neutralized by addition of hydrochloric acid and THF is removed in vacuo. The remaining aqueous solution is extracted three times with 150 ml ethyl acetate. The combined organic layers are dried over MgSO ₄ and the solvent is evaporated. The remaining solid is recrystallized from boil ethyl acetate to give 13.35 g 5-methyl-2-pyridine sulfonamide in the form of beige crystals. ¹ H-NMR (D ₆ -DMSO, 300 MHz): 2.37 (s, 3H); 7.36 (s, 2 H); 7.78-7. 85 (m, 2 H); 8.53 (s, 1 H); LC-MS: t _R = 2.32 min, [M + 1] ⁺ = 173.04, [M-1] ^- = 171.10.

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

d) 40 g of 4 g 4,6-dichloro-5- (o-methoxyphenoxy) -2- (4-pyridyl) -pyrimidine (Example 1, sections a) to d)) under argon Dissolve in DMF and add 3.62 g 5-methylpyridine-2-sulfonamide potassium salt followed by 2.95 mL diisopropyl ethylamine. The black solution is stirred for 22 hours at room temperature. 0.75 g 5-methylpyridine-2-sulfonamide potassium salt is further added and it stirred for 18 hours. The reaction mixture is poured into 150 ml 10% citric acid dissolved in water and extracted four times with 150 ml ethyl acetate. The combined organic phases are washed with water, dried over MgSO ₄ and evaporated. The resulting residue is suspended in 20 ml methanol and 20 ml acetone. The precipitate is collected, washed with 1: 1 methanol: diethyl ether and dried. 4.56 g 5-methyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfone as beige powder here Amide is made. LC-MS: t _R = 4.38 min, [M + 1] ⁺ = 484.58, [M-1] ^- = 482.51.

e) At room temperature, 8.0 g 2-butyne-1,4-diol is added in portions to a stirred slurry of 0.99 g sodium hydroxide dissolved in 25 ml dry DMF and 5 ml dry DMPU. Stirring is continued until gas evolution stops. To the resulting suspension was added 2.0 g 4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -benzene sulfonamide Is added at room temperature and the mixture is stirred at 90 ° C. for 16 h. Finally, the slurry is cooled to room temperature and then poured into a mixture of 200 mL 10% citric acid aqueous solution and 200 mL ethyl acetate. Fine precipitates are formed. The precipitate is filtered off and washed with water and ethyl acetate. The organic layer is separated and the aqueous layer is extracted twice more with ethyl acetate. The combined organic layers are dried over MgSO ₄ and the solvent is removed to a volume of 10 ml. The resulting final precipitate is collected, washed with ethyl acetate and combined with the precipitate separated from the aqueous layer. 1.65 g 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl)-as a beige powder here 4-pyrimidinyl] -2-pyridine sulfonamide is made. LC-MS: t _R = 3.81 min, [M + 1] ⁺ = 534.63, [M-1] ^- = 532.54.

Example 4

a) 4,6-dihydroxy-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidine [or its tautomer 5- (o-methoxyphenoxy) -2 -(2-pyrimidinyl) -tetrahydropyrimidine-4,6-dione] is disclosed in EP 0 526 708 A1 from 2-amidino-pyrimidine and dimethyl- (o-methoxyphenoxy) -malonate Prepared according to the procedure.

b) 4,6-dichloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidine is 4,6-dihydroxy-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidine (or tautomer 5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -tetrahydro-pyrimidine-4,6-dione thereof) ) According to the procedure disclosed in EP 0 526 708 A1.

c) 3.5 g 4,6-dichloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidine and 4.98 g 5-isopropyl-2-pyridine sulfone dissolved in 40 mL DMSO The solution of amide potassium salt (Example 1, section e)) is stirred at room temperature for 4 hours. The mixture is poured into water and extracted twice with diethyl ether. The aqueous layer is acidified with acetic acid. The resulting precipitate was collected, washed with water and diethyl ether and dried to give 5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (2-pyrimidy) as a white powder. Niyl) -4-pyrimidinyl] -2-pyridine sulfonamide. LC-MS: t _R = 4.87 min, [M + 1] ⁺ = 513.32, [M-1] ^- = 511.26.

d) 273 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4- Pyrimidinyl] -2-pyridine sulfonamide was prepared using 600 mg 5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (2-pyridine according to the procedure given in Example 1g. Midinyl) -4-pyrimidinyl] -2-pyridine sulfonamide as starting material is obtained as a beige foam. LC-MS: t _R = 4.31 min, [M + 1] ⁺ = 563.71, [M-1] ^- = 561.59.

Example 5

a) 4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] benzene sulfonamide is 4,6 Prepared according to the procedure disclosed in EP 0 526 708 A1 from -dichloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidine and p-tert.-butyl benzene sulfonamide potassium salt do. LC-MS: t _R = 5.50 min, [M + 1] ⁺ = 526.29, [M-1] ^- = 524.43.

b) 295 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (2-pyrimidinyl)- 4-pyrimidinyl] benzene sulfonamide was prepared according to the procedure given in Example 1g, 1.4 g 4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (2- Obtained as a beige foam using pyrimidinyl) -4-pyrimidinyl] benzene sulfonamide as starting material. LC-MS: t _R = 5.06 min, [M + 1] ⁺ = 576.33, [M-1] ^- = 574.45.

Example 6

a) 2.0 g 4,6-dichloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidine (Example 4b) and 2.65 g 5-methyl- dissolved in 40 mL DMF 10 ml DMSO is added to a solution of 2-pyridine sulfonamide potassium salt (Example 3c). The mixture becomes clear and stirring is continued for 16 hours at room temperature. As soon as the mixture is poured into 50 ml 10% citric acid dissolved in water, a white precipitate is formed. The precipitate is collected, washed with water and ethyl acetate and dried. 2.67 g 5-methyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfone as white powder here Amide is made. LC-MS: t _R = 4.23 min, [M + 1] ⁺ = 485.56, [M-1] ^- = 483.48.

b) 347 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyri Midinyl] -2-pyridine sulfonamide was prepared using 1 g 5-methyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) according to the procedure given in Example 1g. 4-pyrimidinyl] -2-pyridine sulfonamide as starting material is obtained as a pale yellow foam. LC-MS: t _R = 3.90 min, [M + 1] ⁺ = 535.66, [M-1] ^- = 533.55.

Example 7

a) The solution of 10 g dimethyl- (o-methoxyphenoxy) malonate (Example 1b) dissolved in 80 ml dry methanol is cooled to 0 ° C. Add 6.71 g sodium methylate in small portions. 2.84 g acetamidine hydrochloride is added to the suspension and the mixture is stirred overnight at room temperature. The solvent is removed under reduced pressure and the residue is suspended in 100 ml diethyl ether. The solid is filtered off, washed with additional 100 ml diethyl ether and dissolved in 50 ml water. The pH is adjusted to 4 by addition of 25 ml cold acetic acid. The resulting white precipitate is filtered, washed with water and dried to give 5.17 g 5- (o-methoxyphenoxy) -4,6-dihydroxy-2-methyl-pyrimidine (or tautomer) as a white powder. do.

b) 10.9 g 5- (o-methoxyphenoxy) -4,6-dihydroxy-2-methyl-pyrimidine (or tautomer) solution in 150 mL POCl ₃ is stirred at 50 ° C. for 72 hours. . Excess POCl ₃ is evaporated and toluene is added to assist in evaporating trace amounts of POCl ₃ . Finally, the ice: water mixture is carefully added to the residue and the pH is adjusted to 8 using 3N sodium hydroxide solution. The mixture is further diluted with 300 ml water and extracted with 500 ml DCM. The organic layer is separated, washed with 300 ml water, dried over Na ₂ SO ₄ and evaporated. The residue is dissolved in DCM once more, filtered through silica gel and eluted with DCM. The solvent is removed under vacuum. The resulting residue is dried to give 8.7 g 4,6-dichloro-5- (o-methoxyphenoxy) -2-methyl-pyrimidine as beige powder.

c) 3.59 g 5-isopropyl-2-pyridine sulfonamide potassium salt is added to a 2.15 g 4,6-dichloro-5- (o-methoxyphenoxy) -2-methyl-pyrimidine solution dissolved in 40 ml DMSO. do. The mixture is stirred at rt for 72 h. The solution is diluted with 350 ml water and extracted twice with 200 ml diethyl ether. The organic layer is extracted twice with water. The combined aqueous layers are acidified to pH 4 with 5 ml acetic acid and extracted twice with DCM. The organic layer is washed with water and dried over Na ₂ SO ₄ . The solution is treated with activated charcoal, filtered and evaporated in Celite. The residue was suspended in 30 ml diethyl ether and filtered to give 3.15 g 5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -2-methyl-4- as a light beige powder. Pyrimidinyl] -2-pyridine sulfonamide is obtained. LC-MS: t _R = 5.18 min, [M + 1] ⁺ = 449.25, [M-1] ^- = 447.31.

d) 440 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -2 -Pyridine sulfonamide follows the procedure set forth in Example 1 g, except that the reaction mixture was stirred at 95 ° C. for 48 hours, 600 mg 5-isopropyl-N- [6-chloro-5- (o-meth Toxic phenoxy) -2-methyl-4-pyrimidinyl] -2-pyridine sulfonamide as starting material is obtained as a beige foam. LC-MS: t _R = 4.74 min, [M + 1] ⁺ = 499.25, [M-1] ^- = 497.33.

Example 8

a) At room temperature, 2.95 g 5-methyl-2-pyridine sulfonamide potassium salt (Example 3c) was dissolved in 2 g 4,6-dichloro-5- (o-methoxyphenoxy) -2-methyl dissolved in 30 ml DMSO. Add to the suspension of pyrimidine (Example 7b). The mixture is stirred at rt for 48 h and then poured into 300 ml water. The aqueous solution is extracted twice with 200 ml diethyl ether. The organic layer is extracted with water, the aqueous layers are combined and acidified to pH 4 with 3 ml acetic acid. Precipitation of the product is improved by adding 100 ml saturated aqueous sodium chloride and cooling the mixture to 0 ° C. Finally, the precipitate was filtered off, washed with cold water and dried in high vacuum to yield 2.26 g 5-methyl-N- [6-chloro-5- (o-methoxyphenoxy) -2-methyl-4 as a beige powder. -Pyrimidinyl] -2-pyridine sulfonamide. LC-MS: t _R = 4.79 min, [M + 1] ⁺ = 421.42, [M-1] ^- = 419.46.

b) 584 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -2- Pyridine sulfonamide follows the procedure given in Example 1 g, except that the reaction mixture was stirred at 95 ° C. for 72 hours, 950 mg 5-methyl-N- [6-chloro-5 (o-methoxyphenoxy ) -2-methyl-4-pyrimidinyl] -2-pyridine sulfonamide as starting material is obtained as a beige foam. LC-MS: t _R = 4.32 min, [M + 1] ⁺ = 471.57, [M-1] ^- = 469.40.

Example 9

a) The solution of 32.75 g dimethyl- (o-methoxyphenoxy) malonate (Example 1b) dissolved in 250 ml methanol is cooled to 0 ° C. 20.0 g sodium methylate are added in portions and the mixture is stirred for 6 hours at room temperature immediately after the addition is complete. 25.0 g morpholinoformamidine hydrobromide is then added and stirred for 72 hours. The solvent in the beige suspension is evaporated and the residue is washed twice with 150 ml diethyl ether. The remaining powder is dissolved in 200 ml water. Immediately after adjusting the pH to 4 with 500 ml acetic acid, a precipitate is formed. The precipitate was collected, washed with water and dried under high vacuum to give 17.01 g 5- (o-methoxyphenoxy) -4,6-dihydroxy-2- (N-morpholino) as a slightly beige powder. Pyrimidine (or tautomer) is obtained.

b) At 0 ° C., 50 ml POCl ₃ is carefully added to 27.5 ml diisopropyl ethylamine. To the mixture is added 17g 5- (o-methoxyphenoxy) -4,6-dihydroxy-2- (N-morpholino) -pyrimidine in small portions. The resulting mixture is stirred at 130 ° C. overnight. Excess reagent is evaporated and traces of POCl ₃ are removed by co-evaporation with toluene. The black residue is treated with 50 ml DCM and 50 ml water: ice mixture. After stirring for 15 minutes, the mixture is diluted with 400 ml water and 400 ml DCM. The organic layer is separated and washed with 300 ml water. The aqueous layer is extracted with 400 ml DCM. The combined DCM layers are dried over Na ₂ SO ₄ and the solvent is removed to 100 ml volume. The remaining solution is filtered over 50 g silica gel and eluted with DCM. The filtrate is evaporated. The resulting residue is suspended in 50 ml diethyl ether. The solid is filtered and dried to afford 13.85 g 4,6-dichloro-5- (o-methoxyphenoxy) -2- (N-morpholino) -pyrimidine as a white crystalline powder.

c) 5.32 g 5-isopropyl-2-pyridine sulfone in 4 g 4,6-dichloro-5- (o-methoxyphenoxy) -2- (N-morpholino) -pyrimidine suspension in 60 ml DMSO Amide potassium salt (Example 3c) and 0.98 mL diisopropyl ethylamine are added. The mixture is stirred at 65 ° C. for 72 hours. The black solution is poured into 500 ml water and quickly filtered through Celite. The filtrate is extracted with 500 ml and 250 ml diethyl ether. The organic layer is extracted with 100 ml water. The aqueous layers are combined, acidified with 3.5 ml acetic acid and cooled to 0 ° C. The resulting precipitate was collected, washed with cold water and dried under high vacuum, and 4.94 g 5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (N-mor) as a brown powder. Polyno) -4-pyrimidinyl] -2-pyridine sulfonamide is obtained. LC-MS: t _R = 5.46 min, [M + 1] ⁺ = 520.22, [M-1] ^- = 518.36.

d) At 0-5 ° C. 3.97 g 2-butyne-1,4-diol are added in portions to a stirred slurry of 0.55 g sodium hydroxide dissolved in 30 ml dry DMF and 7 ml DMPU. Stirring is continued until gas evolution stops. To the resulting suspension was added 1.2 g 5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2- at room temperature. Pyridine sulfonamide is added and the mixture is stirred at 95 ° C. for 6 days. Finally, the slurry is cooled to room temperature and then poured into 100 ml 10% aqueous citric acid solution and extracted twice with 150 ml ethyl acetate. The combined organic layers are washed twice with 75 ml water, dried over MgSO ₄ and evaporated. The remaining brown oil is purified by column chromatography on 120 g silica gel and eluted with DCM containing 0-2% methanol. Aliquots containing the required compounds are collected and evaporated and the residue is further purified by recrystallization from diethyl ether: hexane. Here, 327 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (colorless crystal having a melting point of 196.0-197.5 ° C was obtained. N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide is made. LC-MS: t _R = 4.89 min, [M + 1] ⁺ = 570.30, [M-1] ^- = 568.43. In addition, 494 mg starting material is recovered in beige foam.

Example 10

a) At 5 ° C., 12.7 g sodium methylate is added in portions to a 18.9 g dimethyl- (o-methoxyphenoxy) malonate (Example 1b) solution dissolved in 450 ml methanol. Immediately after addition is complete, further stirring at room temperature for 30 minutes is followed by the addition of 6 g formamidine hydrochloride. The mixture is stirred at rt for 72 h. Finally, the solvent is removed under reduced pressure and the remaining residue is suspended in dietel ether. The solid material is filtered and dissolved in 100 ml water. The solution is conc. Acidify with hydrochloric acid. White precipitate is formed. The precipitate is collected, washed with water and dried to give 15.1 g 5- (o-methoxyphenoxy) -4,6-dihydroxy-pyrimidine (or tautomer) as a white powder.

b) 90㎖ ₃ 7.5g 5- (o- methoxyphenoxy dissolved in POCl) -4,6- dihydroxy-pyrimidine was added to the 24㎖ N, N- dimethyl aniline. The mixture is heated to 160 ° C. and stirred for 2.5 h. Excess POCl ₃ is distilled off under reduced pressure. Traces of POCl ₃ are co-evaporated with toluene. The remaining oil is treated with a water: ice mixture. The mixture is acidified with 1N hydrochloric acid and extracted twice with diethyl ether. The combined organic layers are washed twice with diluted aqueous hydrochloric acid, dried over MgSO ₄ and evaporated. The remaining solid is washed with methanol and dried. 4.75 g 4,6-dichloro-5- (o-methoxyphenoxy) -pyrimidine is made from light yellow powder.

c) To 2 g 4,6-dichloro-5- (o-methoxyphenoxy) -pyrimidine solution dissolved in 40 ml DMSO is added 3.7 g 4-tert.butylbenzene sulfonamide potassium salt. The resulting solution is stirred at room temperature for 20 hours. Finally, the mixture is poured into 400 ml water and washed twice with 200 ml diethyl ether. The organic layer is extracted with 200 ml water. The combined water layers are conc. Acidify with hydrochloric acid. The mixture is cooled to 0 ° C. and 100 ml brine are added. The resulting precipitate was collected and dried to give 2.7 g 4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -4-pyrimidinyl] -benzene sulfonamide as a white powder. To obtain. LC-MS: t _R = 5.80 min, [M + 1] ⁺ = 448.17, [M-1] ^- = 446.21.

d) To 0.79 g sodium hydroxide slurry dissolved in 45 mL DMF and 15 mL DMPU is added 5.68 g 2-butyne-1,4-diol at 10 ° C. The mixture is stirred until no more gas is generated. Then 1.48 g 4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -4-pyrimidinyl] -benzene sulfonamide is added and the mixture is 72 hours at 90 ° C. Stir while. The solvent is removed in vacuo and the residue is taken up in 150 ml 10% aqueous acetic acid. The mixture is extracted three times with 150 ml ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO ₄ and evaporated. The resulting brown oil is purified by column chromatography on silica gel and eluted with 3: 1 to 1: 1 hexanes: ethyl acetate. 320 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl ] -Benzene sulfonamide is made. LC-MS: t _R = 5.21 min, [M + 1] ⁺ = 498.35, [M-1] ^- = 496.49.

Example 11

a) 6.8 g sodium methylate solution in 200 mL methanol is cooled to 0 ° C. Slowly add 10.3 g diethyl 2- (p-tolyl) -malonate solution in 50 mL methanol. Immediately after completion of the addition, the solution is allowed to room temperature and 7.57 g 4-amidino-pyridine hydrochloride (Example 1a) is added. The mixture is stirred at rt for 16 h. Finally, the solvent is removed under reduced pressure and the remaining residue is dissolved in 2M hydrochloric acid. The solution is extracted with diethyl ether and then adjusted to pH 5 with 10M sodium hydroxide solution. A precipitate is formed. The precipitate is collected, washed with cold water and dried at 60 ° C. under high vacuum. Orange crystals form 8.77 g 4,6-dihydroxy-2- (4-pyridyl) -5- (p-tolyl) -pyrimidine (or tautomer).

b) 25 ml diethylamine are added to a mixture of 8.0 g 5- (p-tolyl) -4,6-dihydroxy-pyrimidine and 100 ml POCl ₃ at room temperature. The mixture is stirred at 60 ° C. for 16 h. Excess POCl ₃ is distilled off under reduced pressure. The remaining oil is dissolved in 300 ml DCM and treated with 300 ml water. The aqueous layer is separated and extracted three times with DCM. The combined organic layers are washed with water and brine, dried over MgSO ₄ and evaporated. The resulting residue is suspended in isopropanol. The solid material is collected, washed with isopropanol and diethyl ether and dried to give 7.2 g 4,6-dichloro-2- (4-pyridyl) -5- (p-tolyl) -pyrimidine as a white crystalline powder. .

c) 654 mg 4,6-dichloro-2- (4-pyridyl) -5- (p-tolyl) -pyrimidine and 1051 mg 5-isopropyl-2-pyridine sulfonamide potassium salt dissolved in 20 ml DMF ( The mixture of Example 1e) is stirred for 16 hours at room temperature. Finally, the solvent is distilled off under reduced pressure and the resulting residue is treated with 100 ml 10% aqueous acetic acid and 100 ml DCM. The layers separate. The aqueous layer is extracted twice with DCM. The combined organic layers are washed once with water, dried over MgSO ₄ and evaporated. The remaining residue is crystallized from isopropanol: diethyl ether. The yellow crystals were collected, washed with cold isopropanol and diethyl ether and dried under high vacuum to give 870 mg 5-isopropyl-N- [6-chloro-5- (p-tolyl) -2- (4-pyridyl) 4-pyrimidinyl] -2-pyridine sulfonamide is obtained. LC-MS: t _R = 5.06 min, [M + 1] ⁺ = 480.40, [M-1] ^- = 478.48.

d) 2.4 g 2-butyne-1,4-diol is added to a 0.34 g sodium hydroxide slurry dissolved in 15 ml DMF and 4 ml DMPU at room temperature. The mixture is stirred until no more gas is generated. Then 0.67 g 5-isopropyl-N- [6-chloro-5- (p-tolyl) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide is added and the mixture Is stirred at 90 ° C. for 48 h. The solvent is removed in vacuo and the residue is taken up in 100 ml 10% aqueous acetic acid. The mixture is extracted three times with 100 ml ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO ₄ and evaporated. The resulting brown oil is purified by column chromatography on silica gel and eluted with DCM containing 4-10% methanol. This yields an aliquot, which is 43 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (p as light yellow crystals after recrystallization from DCM: ethyl acetate. -Tolyl) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide. The second aliquot is brown oil, about 90% pure, 456mg5-isopropyl-N- [6- (4-hydroxy-2-bunnityloxy) -5- (p-tolyl) -2- (4 -Pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide. LC-MS: t _R = 4.53 min, [M + 1] ⁺ = 530.23, [M-1] ^- = 528.21.

Example 12

a) At 0 ° C., a 14.2 g diethyl 2- (p-tolyl) -malonate solution dissolved in 50 mL methanol is slowly added to a 9.4 g sodium methylate solution dissolved in 300 mL methanol. Immediately after completion of the addition, the reaction mixture is warmed and 5.4 g formamidine hydrochloride is added. The mixture is stirred at rt for 16 h. The solvent is removed under reduced pressure and the remaining residue is treated with 150 ml 2N hydrochloric acid. The suspension is stirred for 0.5 h. At 0-5 ° C., the pH is carefully adjusted to 4 using 10N sodium hydroxide solution. The precipitate is collected, washed with cold water, isopropanol, diethyl ether and dried at 65 ° C. under high vacuum to give 11.2 g 4,6-dihydroxy-5- (p-tolyl) -pyrimidine (or tautomer) as a white powder. ).

b) At room temperature, 10 ml N, N-dimethylaniline is added to a mixture of 5.1 g 4,6-dihydroxy-5- (p-tolyl) -pyrimidine and 75 ml POCl ₃ . The reaction mixture is stirred at 70 ° C. for 16 hours. Excess POCl ₃ is distilled off and the remaining oil is treated with an ice: water mixture and extracted three times with diethyl ether. The combined organic layers are washed in 1N aqueous hydrochloric acid and brine sequence, dried over MgSO ₄ and evaporated. The remaining brown oil crystallizes from isopropanol. The pale yellow crystals are collected, washed with cold isopropanol and dried under high vacuum to yield 4.1 g 4,6-dichloro-5- (p-tolyl) -pyrimidine.

c) A mixture of 0.8 g 4,6-dichloro-5- (p-tolyl) -pyrimidine and 1.68 g 4-tert.-butylbenzene sulfonamide potassium salt (Example 2a) dissolved in 20 ml DMSO Stir for time. The mixture is poured into 200 ml water and extracted twice with 100 ml diethyl ether. The organic layer is extracted twice with 50 ml water. The combined aqueous layers are acidified with hydrochloric acid. The resulting fine suspension is extracted twice with ethyl acetate. The combined organic layers are dried over Na ₂ SO ₄ and evaporated. The residue is dried under high vacuum to afford 1.34 g 4-tert.-butyl-N- [6-chloro-5- (p-tolyl) -4-pyrimidinyl] -benzene sulfonamide as a white powder. LC-MS: t _R = 5.92 min, [M + 1] ⁺ = 416.20, [M-1] ^- = 414.24.

d) 700 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (p-tolyl) -4-pyrimidinyl] -benzene sulfonamide Obtained as a brown glassy material using 4-tert.-butyl-N- [6-chloro-5- (p-tolyl) -4-pyrimidinyl] -benzene sulfonamide as starting material according to the procedure given in 10d. . LC-MS: t _R = 5.38 min, [M + 1] ⁺ = 466.24, [M-1] ^- = 464.32.

Example 13

a) 2.71 g 4,6-dichloro-5- (o-methoxyphenoxy) -pyrimidine (Example 10b) and 5.0 g 5-isopropyl pyridine-2-sulfonamide potassium salt dissolved in 50 ml DMF The solution of Example 1e) is stirred at room temperature for 20 hours. The solvent is removed in vacuo and the residue is taken up in 200 ml 10% aqueous acetic acid and extracted three times with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO ₄ and evaporated. The crude product is crystallized from 2-propanol and diethyl ether. The crystals were collected, washed with cold 2-propanol and diethyl ether and dried to give 2.8 g 5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -4-pyrimidy as white crystals. Nil] -2-pyridine sulfonamide. LC-MS: t _R = 4.99 min, [M + 1] ⁺ = 435.25, [M-1] ^- = 433.28.

b) To a 11.02 g 2-butyne-1,4-diol solution dissolved in 100 ml DMF and 30 ml DMPU, add 2.8 g sodium hydroxide in small portions. Immediately after addition was complete, stirred for 1.5 hours, followed by addition of 2.78 g 5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -4-pyrimidinyl] -2-pyridine sulfonamide do. The mixture is heated to 90 ° C. and stirred for 65 h. The solvent is removed in vacuo and the residue is taken up in 250 ml 10% aqueous citric acid and extracted twice with 250 ml ethyl acetate. The organic phase is washed with water and brine, dried over MgSO ₄ and evaporated. The crude product was purified by column chromatography on silica gel and eluted with 1: 1 to 1: 4 hexanes: ethyl acetate to give 1.27 g 5-isopropyl-N- [6- (4-hydroxy-2) as a brown solid. -Butynyloxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl] -2-pyridine sulfonamide is obtained. After some of the separated product is crystallized from 2-propanol, beige crystals are obtained for the purpose of analysis. LC-MS: t _R = 4.50 min, [M + 1] ⁺ = 485.27, [M-1] ^- = 483.41.

Example 14

a) A solution of 15.2 g 4-tert.-butylbenzene sulfonyl chloride dissolved in 150 ml THF is cooled in an ice solution. Add 15.2 ml 25% aqueous ammonium hydroxide solution drop by drop. After complete addition, the solution is stirred at room temperature for 15 minutes. The solvent is removed under vacuum. The residue is dissolved in ethyl acetate once more and washed twice with water. The organic phase is dried over Na ₂ SO ₄ , evaporated and dried. The resulting 14.8 g white powder was dissolved in 75 ml methanol and 7.5 g potassium tert. Butylate is added. The solution is stirred briefly at room temperature and evaporated. The resulting residue is carefully dried to give 16.3 g 4-tert.-butylbenzene sulfonamide potassium salt as a white solid.

b) 2.0 g 4,6-dichloro-5- (2-methoxyphenoxy) -2- (N-morpholino) -pyrimidine (Example 9b) and 2.96 g 4-tert dissolved in 30 mL DMSO. The solution of butylbenzene sulfonamide potassium is stirred at room temperature for 24 hours. After addition of 1 g 4-tert.-butylbenzene sulfonamide potassium salt, it is stirred for an additional 24 hours at room temperature and for 16 hours at 55 ° C. Finally, the mixture is poured into 350 ml water and 350 ml ether. The mixture is acidified by addition of acetic acid. A white sticky precipitate is formed. The mixture is stirred at 0 ° C. for 1 hour. The precipitate is filtered off, washed with water and ether and dissolved in ethyl acetate once more. The solvent is removed in vacuo and the remaining solid is suspended in 100 ml diethyl ether. The solid was filtered, washed with additional diethyl ether and dried to give 2.57 g 4-tert.-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2-morpholine- as white powder. 4-yl-pyrimidin-4-yl] -benzene sulfonamide is obtained. LC-MS: t _R = 5.98 min, [M + 1] ⁺ = 533.29, [M-1] ^- = 531.41.

c) 4.85 g 2-butyne-1,4-diol is added to a 675 mg NaH suspension in 45 ml DMF and 5 ml DMPU. The mixture is stirred at room temperature until gas evolution ceases. Then 1.5 g 4-tert.-butyl-N- [6-chloro-5- (2-methoxy-phenoxy) -2-morpholin-4-yl-]-benzene sulfonamide was added and the resultant The mixture is heated to 95 ° C. and stirred for 5 days. Finally, the mixture is poured into 150 ml 10% aqueous citric acid and extracted three times with 150 ml ethyl acetate. The organic layer is washed with water and brine, dried over MgSO ₄ and evaporated. The resulting residue was purified by column chromatography on silica gel and eluted with 1: 1 hexanes: ethyl acetate to give 265 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-) in beige foam. Butynyloxy) -5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-yl] -benzene sulfonamide and 1.13 g of starting material 4-tert.-butyl- N- [6-Chloro-5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-yl] -benzene sulfonamide is obtained. LC-MS: t _R = 5.39 min, [M + 1] ⁺ = 583.41, [M-1] ^- = 581.35.

Example 15

a) 4.72 g 5-methyl- in a suspension of 4 g 4,6-dichloro-5- (2-methoxyphenoxy) -2- (N-morpholino) -pyrimidine (Example 9b) dissolved in 20 mL DMSO 2-pyridine sulfonamide potassium salt (Example 3c) is added. The mixture is stirred at 55 ° C. for 17 h. The black solution is poured into 500 ml water and quickly filtered through Celite. The filtrate is extracted with 500 ml and 250 ml diethyl ether. The organic layer is extracted with 100 ml water. The aqueous layers are combined, acidified with 3.5 ml acetic acid and cooled to 0 ° C. The resulting precipitate was collected, washed with cold water and dried under high vacuum to give 4.42 g 5-methyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (N-morpholi) as a brown powder. No) -4-pyrimidinyl] -2-pyridine sulfonamide. LC-MS: t _R = 4.80 min, [M + 1] ⁺ = 492.31, [M-1] ^- = 490.37.

b) To a 712 mg NaH suspension in 30 ml DMF and 7 ml DMPU add 5.11 g 2-butyne-1,4-diol. The mixture is stirred at room temperature until gas evolution ceases. Then, 1.45 g 5-methyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide is added The resulting mixture is heated to 95 ° C. and stirred for 4 days. Finally, the mixture is poured into 200 ml 10% aqueous citric acid and extracted three times with 200 ml ethyl acetate. The organic layer is washed with water and brine, dried over MgSO ₄ and evaporated. The resulting residue was purified by column chromatography on silica gel and eluted with 1: 1 hexanes: ethyl acetate to give 470 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) as a beige powder. ) -5- (2-methoxy-phenoxy) -2- (N-morpholino) -4-pyrimidine] -2-pyridine sulfonamide and 660 mg of starting material 5-methyl-N- [6- Chloro-5- (2-methoxyphenoxy) -2- (N-morpholino) -4-yl-pyrimidinyl] -2-pyridine sulfonamide is obtained. LC-MS: t _R = 4.33 min, [M + 1] ⁺ = 542.35, [M-1] ^- = 540.32.

Example 16

a) 10 g 4,6-dichloro-5- (p-tolyl) -pyrimidine (Example 12b) dissolved in 100 ml DMF and 4.8 g 5-isopropyl pyridine-2-sulfonamide potassium salt (Example 1e) The mixture is stirred at rt for 72 h. Prior to treating the mixture with 50 ml diethyl ether, the solvent is partially removed in vacuo. Under vigorous stirring, the pH of the aqueous phase is adjusted to 3 by addition of 10% aqueous citric acid solution. Stirring is continued at 10 ° C. for 15 hours. The resulting precipitate is collected, washed with water and diethyl ether and dried at 50 ° C. under high vacuum. 7.67 g 5-isopropyl-N- [6-chloro-5- (p-tolyl) -4-pyrimidinyl] -2-pyridine sulfonamide is produced here as white powder. LC-MS: t _R = 5.13 min, [M + 1] ⁺ = 403.24, [M-1] ^- = 401.28.

b) 5.5 g NaH 55% dissolved in mineral oil is added in small portions to a 21.5 g 2-butyne-1,4-diol solution dissolved in 200 ml DMF and 50 ml DMPU. After gas evolution ceased, 5.04 g 5-isopropyl-N- [6-chloro-5- (p-tolyl) -4-pyrimidinyl] -2-pyridine sulfonamide was added and the resulting mixture was 90 Stir at 80 ° C. for 80 hours. The solvent is removed in vacuo and the residue is partitioned between 300 ml 10% aqueous citric acid and 300 ml ethyl acetate. The aqueous phase is extracted twice more with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO ₄ and evaporated. The crude product was purified by column chromatography on silica gel and eluted with 1: 1 to 1: 4 hexanes: ethyl acetate to give 2.0 g 5-isopropyl-N- [6-4-hydroxy-2- as a brown solid. Butynyloxy) -5- (p-tolyl) -4-pyrimidinyl] -2-pyridine sulfonamide is obtained. LC-MS: t _R = 4.64 min, [M + 1] ⁺ = 453.28, [M-1] ^- = 451.40.

Example 17

80 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5 in 14 mg 55% sodium hydroxide suspension dispersed in mineral oil dissolved in 2 ml dry DMF and 2 ml dry THF -(o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl) -2-pyridine sulfonamide (Example 1g) is added. After stirring for 10 minutes, 41 mg 2-chloro-pyrimidine is added. Stirring is continued at 70 ° C. for 1 hour. The reaction mixture is poured into 50 ml 10% aqueous citric acid. The solution is extracted twice with 50 ml ethyl acetate. The combined organic layers are washed twice with water, dried over MgSO ₄ and evaporated. The remaining residue is purified by column chromatography on silica gel and eluted with 0-2% gradient methanol in DCM. 72 mg 5-isopropyl-N- [6- (4- (2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- ( 4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide is made. LC-MS: t _R = 4.74 min, [M + 1] ⁺ = 640.35, [M-1] ^- = 638.49.

Example 18

88 mg 5-isopropyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2 -(4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide was prepared in 80 mg 5-isopropyl-N- [6- (4-hydroxy-2-buty) following the procedure set forth in Example 17. Nyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyridinyl) -2-pyridine sulfonamide (Example 1g) and 78 mg 4,6-dimethoxy 2-Methyl-sulfonylpyrimidine as starting material is obtained as a pale yellow solid. LC-MS: t _R = 5.34 min, [M + 1] ⁺ = 700.42, [M-1] ^- = 698.52.

Example 19

In 76 mg 55% sodium hydroxide suspension dispersed in 15 ml dry THF mineral oil 403 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o -Methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -benzene sulfonamide (Example 2c) is added. After stirring for 2 hours, 91 mg 2-chloropyrimidine is added. Stirring is continued for 42 hours at room temperature. The solvent is evaporated and the remaining residue is partitioned between 50 ml 10% aqueous acetic acid and 50 ml ethyl acetate. The organic layer is separated and the aqueous layer is extracted twice more with 50 ml ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO ₄ and evaporated. The remaining residue is purified by column chromatography on silica gel and eluted with 5-10% gradient methanol dissolved in DCM. 256 mg 4-tert.-butyl-N- [6- (4- (2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2 -(4-pyridyl) -4-pyrimidinyl] -benzene sulfonamide is made. LC-MS: t _R = 5.21 min, [M + 1] ⁺ = 653.69, [M-1] ^- = 651.78.

Example 20

200 mg 4-tert.-butyl-N- [6- (4- (5-bromo-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2 -(4-Pyridyl) -4-pyrimidinyl] -benzene sulfonamide was prepared in accordance with the procedure set forth in Example 19. Nyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -benzene sulfonamide (Example 2c) with 73 mg 5-bromo-2-chloro Pyridine as a starting material is obtained as beige crystals. LC-MS: t _R = 5.63 min, [M + 1] ⁺ = 731.65, [M-1] ^- = 729.66.

Example 21

400 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) dissolved in 15 ml DMF ) 4-pyrimidinyl] -benzene sulfonamide (Example 2c), 116 mg 4,6-dimethoxy-2-methyl-sulfonylpyrimidine, a suspension of 147 mg potassium carbonate was stirred at 90 ° C. for 16 hours. do. Further 42 mg 4,6-dimethoxy-2-methyl-sulfonylpyrimidine is added and stirring is continued at 90 ° C. for 24 hours. Finally, the solvent is removed in vacuo and the resulting residue is partitioned between 50 ml 5% aqueous acetic acid and 50 ml DCM. The organic layer is separated and the aqueous layer is extracted twice more with 50 ml DCM. The combined organic layers are washed with water, dried over MgSO ₄ and evaporated. The remaining oil is purified by column chromatography on silica gel and eluted with 4: 1 to 1: 1 toluene: ethyl acetate. The product obtained was recrystallized from ethyl acetate: diethyl ether to give 76 mg 4-tert.-butyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) as white crystals. 2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -benzene sulfonamide is obtained. LC-MS: t _R = 5.84 min, [M + 1] ⁺ = 713.35, [M-1] ^- = 711.45.

Example 22

200 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- in a 41 mg 55% sodium hydroxide suspension dispersed in mineral oil dissolved in 5 ml dry DMF and 5 ml dry THF. (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 3e) is added. After stirring for 10 minutes, 47 mg 2-chloropyridine is added. Stirring is continued for 20 hours at room temperature. Thereafter, additional 20 mg 2-chloropyrimidine is added and stirred for a further 24 hours. Finally, the reaction mixture is poured into 50 ml 10% aqueous citric acid. The solution is extracted twice with 50 ml ethyl acetate. The combined organic layers are washed twice with water, dried over MgSO ₄ and evaporated. The remaining residue is purified by column chromatography on silica gel and eluted with a 0-3% gradient of methanol dissolved in DCM. Here as a pale yellow powder, 147 mg 5-methyl-N- [6- (4- (2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- ( 4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide is made. LC-MS: t _R = 4.26 min, [M + 1] ⁺ = 612.29, [M-1] ^- = 610.43.

Example 23

65 mg 5-methyl-N- [6- (4- (5-bromo-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4 -Pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide was 100 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy)-according to the procedure set forth in Example 22. 5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 3e) and 44 mg 5-bromo-2-chloropyridine As starting material it is obtained as a pale yellow solid. LC-MS: t _R = 4.77 min, [M + 1] ⁺ = 690.22, [M-1] ^- = 688.36.

Example 24

91 mg 5-methyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-Pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide was prepared in 100 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy according to the procedure given in Example 22. ) -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 3e) and 82 mg 4,6-dimethoxy-2 Obtained as a pale yellow solid with -methylsulfonylpyrimidine as a starting material. LC-MS: t _R = 4.80 min, [M + 1] ⁺ = 672.32, [M-1] ^- = 670.46.

Example 25

72 mg 5-methyl-N- [6- (4- (4,6-dimethyl-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- ( 4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide was prepared in 80 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) according to the procedure set forth in Example 22. -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 3e) and 70 mg 4,6-dimethyl-2-methyl As a starting material, sulfonylpyrimidine is obtained as a pale yellow solid. LC-MS: t _R = 4.68 min, [M + 1] ⁺ = 640.32, [M-1] ^- = 638.39.

Example 26

59 mg 5-isopropyl-N- [6- (4- (2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- (2-pyrimidinyl ) -4-pyrimidinyl] -2-pyridine sulfonamide was prepared in 80 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- according to the procedure set forth in Example 22. (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 4d) and 33 mg 2-chloropyrimidine as starting material Obtained as color foam. LC-MS: t _R = 4.55 min, [M + 1] ⁺ = 641.63, [M-1] ^- = 639.47.

Example 27

78 mg 5-isopropyl-N- [6- (4- (5-bromo-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- ( 2-pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfonamide was prepared in 80 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyl) according to the procedure set forth in Example 22. Oxy) -5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 4d) and 55 mg 5-bromo-2 Chloropyrimidine as starting material is obtained as a beige foam. LC-MS: t _R = 4.99 min, [M + 1] ⁺ = 719.56, [M-1] ^- = 717.28.

Example 28

65 mg 4-tert.-Butyl-N- [6- (4- (5-bromo-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2 -(2-pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide was prepared in 75 mg 4-tert.-butyl-N- [6- (4-hydroxy-2- according to the procedure given in Example 22). Butynyloxy) -5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide (Example 5b) with 103 mg 5-bromo-2 Chloropyrimidine as starting material is obtained as a beige foam. LC-MS: t _R = 5.83 min, [M + 1] ⁺ = 732.31, [M-1] ^- = 730.36.

Example 29

71 mg 4-tert.-butyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide was prepared in 75 mg 4-tert.-butyl-N- [6- (4-hydroxy-) according to the procedure set forth in Example 22. 2-butynyloxy) -5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide (Example 5b) with 140 mg 4,6- Dimethoxy-2-methylsulfonylpyrimidine as starting material is obtained as a colorless foam. LC-MS: t _R = 5.92 min, [M + 1] ⁺ = 714.42, [M-1] ^- = 712.50.

Example 30

20 mg 5-methyl-N- [6- (4- (2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfonamide was prepared using 60 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o according to the procedure set forth in Example 22). -Methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 6b) and 36 mg 2-chloropyrimidine as starting materials. Obtained. LC-MS: t _R = 4.37 min, [M + 1] ⁺ = 613.29, [M-1] ^- = 611.45.

Example 31

75 mg 5-methyl-N- [6- (4- (5-bromo-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- (2 -Pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfonamide was prepared in 80 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) according to the procedure set forth in Example 22. -5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 6b) and 120 mg 5-bromo-2-chloro It is obtained as a colorless powder using pyrimidine as a starting material. LC-MS: t _R = 4.64 min, [M + 1] ⁺ = 691.64, [M-1] ^- = 689.45.

Example 32

84 mg 5-methyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfonamide was prepared in 80 mg 5-methyl-N- [6- (4-hydroxy-2-butynyl) according to the procedure set forth in Example 22. Oxy) -5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 6b) and 65 mg 4,6-dimethoxy It is obtained as a colorless powder using 2-methylsulfonylpyrimidine as a starting material. LC-MS: t _R = 4.72 min, [M + 1] ⁺ = 673.70, [M-1] ^- = 671.53.

Example 33

73 mg 5-isopropyl-N- [6- (4- (2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidy Nyl] -2-pyridine sulfonamide was prepared using 80 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) according to the procedure set forth in Example 17. C) -2-methyl-4-pyrimidinyl] -2-pyridine sulfonamide (Example 7d) and 46 mg 2-chloropyrimidine as starting materials are obtained as colorless foams. LC-MS: t _R = 5.18 min, [M + 1] ⁺ = 577.27, [M-1] ^- = 575.36.

Example 34

75 mg 5-isopropyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2 -Methyl-4-pyrimidinyl] -2-pyridine sulfonamide was prepared in 80 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5 according to the procedure set forth in Example 17. -(o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -2-pyridine sulfonamide (Example 7d) with 88 mg 4,6-dimethoxy-2-methylsulfonylpyrimidine It is obtained as a colorless foam as a substance. LC-MS: t _R = 5.80 min, [M + 1] ⁺ = 637.31, [M-1] ^- = 635.40.

Example 35

76 mg 5-isopropyl-N- [6- (4- (4,6-dimethyl-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- Methyl-4-pyrimidinyl] -2-pyridine sulfonamide was prepared in 80 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- according to the procedure set forth in Example 17. (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -2-pyridine sulfonamide (Example 7d) and 75 mg 4,6-dimethyl-2-methylsulfonylpyrimidine as starting material To give a colorless foam. LC-MS: t _R = 5.51 min, [M + 1] ⁺ = 605.35, [M-1] ^- = 603.43.

Example 36

98 mg 5-methyl-N- [6- (4- (5-bromo-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2-methyl- 4-pyrimidinyl] -2-pyridine sulfonamide was prepared using 80 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-) according to the procedure set forth in Example 22. Obtained as a colorless foam using methoxyphenoxy) -2-methyl-4-pyrimidinyl] -2-pyridine sulfonamide (Example 8b) and 96 mg 5-bromo-2-chloropyrimidine as starting material. . LC-MS: t _R = 5.33 min, [M + 1] ⁺ = 627.20, [M-1] ^- = 625.27.

Example 37

80 mg 5-methyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- Methyl-4-pyrimidinyl] -2-pyridine sulfonamide was prepared by 80 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- ( o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -2-pyridine sulfonamide (Example 8b) and 74 mg 4,6-dimethoxy-2-methylsulfonylpyrimidine as starting material To give a colorless foam. LC-MS: t _R = 5.46 min, [M + 1] ⁺ = 609.31, [M-1] ^- = 607.38.

Example 38

80 mg 5-methyl-N- [6- (4- (4,6-dimethyl-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2-methyl 4-Pyrimidinyl] -2-pyridine sulfonamide was prepared using 80 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o according to the procedure set forth in Example 22). -Methoxyphenoxy) -2-methyl-4-pyrimidinyl] -2-pyridine sulfonamide (Example 8b) and 79 mg 4,6-dimethyl-2-methylsulfonylpyrimidine as colorless starting materials Obtained as a foam. LC-MS: t _R = 5.10 min, [M + 1] ⁺ = 577.30, [M-1] ^- = 575.41.

Example 39

280 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (p) in 58 mg 55% sodium hydroxide suspension dispersed in 15 ml dry THF mineral oil. -Tolyl) -4-pyrimidinyl] -benzene sulfonamide (Example 12) is added. After stirring for 1 hour, 144 mg 4,6-dimethoxy-2-methylsulfonylpyrimidine is added. Stirring is continued for 12 hours at reflux. Finally, the solvent is evaporated and the remaining residue is partitioned between 50 ml 10% aqueous citric acid and 50 ml ethyl acetate. The organic layer is separated and the aqueous layer is extracted twice more with 50 ml ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO ₄ and evaporated. The remaining residue is purified by column chromatography on silica gel and eluted with 10-20% gradient ethyl acetate dissolved in toluene. The separated yellow foam is further purified on a preliminary silica gel plate. 91 mg 4-tert.-butyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -butynyloxy) -5- (p-tolyl) 4-pyrimidinyl] -benzene sulfonamide is made. LC-MS: t _R = 6.32 min, [M + 1] ⁺ = 604.31, [M-1] ^- = 602.43.

Example 40

375 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (p in 88 mg 55% sodium hydroxide suspension dispersed in mineral oil dissolved in 15 ml dry THF -Tolyl) -4-pyrimidinyl] -benzene sulfonamide (Example 12) is added. After stirring for 1 hour, 170 mg 5-bromo-2-chloropyrimidine is added. Stirring is continued at 40 ° C. for 60 hours. Finally, the solvent is evaporated and the remaining residue is partitioned between 50 ml 10% aqueous citric acid and 50 ml ethyl acetate. The organic layer is separated and the aqueous layer is extracted twice more with 50 ml ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO ₄ and evaporated. The crude product was crystallized from 2-propanol containing a small amount of diethyl ether to give 168 mg 4-tert.-butyl-N- [6- (4- (5-bromo-2-pyri) as beige crystals. Midinyloxy) -butynyloxy) -5- (p-tolyl) -4-pyrimidinyl] -benzene sulfonamide is obtained. LC-MS: t _R = 6.22 min, [M + 1] ⁺ = 624.28.

Example 41

150 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o in 29 mg 55% sodium hydroxide suspension dispersed in mineral oil dissolved in 15 ml dry THF) -Methoxyphenoxy) -4-pyrimidinyl] -benzene sulfonamide (Example 10) is added. After stirring for 0.5 h, 64 mg 5-bromo-2-chloropyrimidine is added. Stirring is continued for 40 hours at 40 ° C. Finally, the solvent is evaporated and the remaining residue is partitioned between 50 ml 10% aqueous citric acid and 50 ml ethyl acetate. The organic layer is separated and the aqueous layer is extracted twice more with 50 ml ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO ₄ and evaporated. The crude product was crystallized from 2-propanol to give 126 mg 4-tert.-butyl-N- [6- (4- (5-bromo-2-pyrimidinyloxy) -2-buty as beige crystals. Nyloxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl] -benzene sulfonamide is obtained. LC-MS: t _R = 6.07 min, [M + 1] ⁺ = 656.24, [M-1] ^- = 654.34.

Example 42

126 mg 4-tert.-butyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) 4-pyrimidinyl] -benzene sulfonamide was prepared in 150 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy) -5- ( Obtained as a colorless foam using o-methoxyphenoxy) -4-pyrimidinyl] -benzene sulfonamide (Example 10) and 72 mg 4,6-dimethoxy-2-methylsulfonylpyrimidine as starting materials. . LC-MS: t _R = 6.13 min, [M + 1] ⁺ = 635.81, [M-1] ^- = 633.77.

Example 43

450 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (p-tolyl) -2- (4 in a 243 mg K ₂ CO ₃ suspension dissolved in 15 ml DMF. -Pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 11) is added. After 0.5 hour stirring at 90 ° C., 192 mg 4,6-dimethoxy-2-methylsulfonylpyrimidine is added and stirring is continued at 90 ° C. for 16 hours. Finally, the solvent is evaporated and the remaining residue is partitioned between 50 ml 10% aqueous citric acid and 50 ml DCM. The organic layer is separated and the aqueous layer is extracted twice more with 50 ml DCM. The combined organic layers are washed with water and brine, dried over MgSO ₄ and evaporated. The crude product was purified by column chromatography on silica gel and eluted with 20: 1 DCM methanol to give 88 mg 5-isopropyl-N- [6- (4- (4,6-dimethoxy-2) as beige foam. Pyrimidinyloxy) -2-butynyloxy) -5- (p-tolyl) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide is obtained. LC-MS: t _R = 5.54 min, [M + 1] ⁺ = 668.38, [M-1] ^- = 666.39.

Example 44

186 mg 5-isopropyl-N- [6- (4- (5-bromo-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -4-pyri Midinyl] -2-pyridine sulfonamide was prepared in 250 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxy) according to the procedure set forth in Example 41. Phenoxy) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 13) and 194 mg 5-bromo-2-chloropyrimidine as starting materials were obtained as beige crystals. LC-MS: t _R = 5.43 min, [M + 1] ⁺ = 643.18, [M-1] ^- = 641.29.

Example 45

250 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl] -2- dissolved in 15 mL THF To the pyridine sulfonamide (Example 13) solution 48 mg NaH is added. The mixture is stirred at room temperature for 2 hours, after which 120 mg 4,6-dimethoxy-2-methylsulfonylpyrimidine is added. Stirring is continued for 16 hours at reflux. Finally, the solvent is evaporated and the remaining residue is partitioned between 50 ml 10% aqueous citric acid and 50 ml ethyl acetate. The organic layer is separated and the aqueous layer is extracted twice more with 50 ml ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO ₄ and evaporated. The crude product was 8: 2: 1 ethyl acetate: methanol: sat. Prep. Coated with silica gel containing aqueous ammonia. Purification by column chromatography on tlc-plates gave 71 mg 5-isopropyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyl as beige foam. Oxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl] -2-pyridine sulfonamide is obtained. LC-MS: t _R = 5.50 min, [M + 1] ⁺ = 623.29, [M-1] ^- = 621.40.

Example 46

50 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy) -5 in a 9 mg NaH 55% suspension dispersed in mineral oil dissolved in 4 ml 1: 1 DMF: THF. -(2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-yl] -benzene sulfonamide (Example 14) is added. After gas evolution has ceased, 42 mg 5-bromo-2-chloropyrimidine is added and the mixture is stirred at 65 ° C. for 1 h, then diluted with 50 ml 10% aqueous citric acid and 50 ml ethyl acetate. The organic layer is separated, washed with 50 ml water, dried over MgSO ₄ and evaporated. The crude product was purified by column chromatography on silica gel and eluted with 3: 2 hexanes: ethyl acetate to give 60 mg 4-tert.-butyl-N- [6- (4- (5-bromo-) as a colorless foam. 2-pyrimidinyloxy) -2-butynyloxy) -5- (2-methoxyphenoxy) -2-morpholin-4-yl-pyrimidin-4-yl] -benzene sulfonamide is obtained. LC-MS: t _R = 6.14 min, [M + 1] ⁺ = 739.18, [M-1] ^- = 741.32.

Example 47

48 mg 4-tert.-butyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (2-methoxyphenoxy) -2-morpholin-4-yl-pyrimidin-4-yl] -benzene sulfonamide was prepared in 50 mg 4-tert.-butyl-N- [6- (4-hydroxy-) according to the procedure set forth in Example 46. 2-butynyloxy) -5- (2-methoxyphenoxy) -2-morpholin-4-yl-pyrimidin-4-yl] -benzene sulfonamide (Example 14) with 47 mg 4,6- Dimethoxy-2-methylsulfonylpyrimidine as starting material is obtained as a colorless foam. LC-MS: t _R = 6.21 min, [M + 1] ⁺ = 721.44, [M-1] ^- = 719.35.

Example 48

37 mg 5-methyl-N- [6- (4- (5-bromo-2-pyrimidinyloxy) -2-butynyloxy) -5- (2-methoxyphenoxy) -2- (N -Morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide was prepared in 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) according to the procedure set forth in Example 46. -5- (2-methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 15) and 45 mg 5-bromo-2-chloro Pyrimidine as starting material is obtained as a beige powder. LC-MS: t _R = 5.31 min, [M + 1] ⁺ = 700.34, [M-1] ^- = 698.24.

Example 49

48 mg 5-methyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (2-methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide was prepared in 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyl) according to the procedure given in Example 46. Oxy) -5- (2-methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 15) with 50 mg 4,6-dimethoxy As a starting material, 2-methylsulfonylpyrimidine is obtained as a colorless solid. LC-MS: t _R = 5.42 min, [M + 1] ⁺ = 680.43, [M-1] ^- = 678.36.

Example 50

128 mg 5-isopropyl-N- [6- (4- (5-bromo-2-pyrimidinyloxy) -2-butynyloxy) -5- (p-tolyl) -4-pyrimidinyl] 2-pyridine sulfonamide was prepared in 230 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (p-tolyl) -4- according to the procedure set forth in Example 45. Pyrimidinyl] -2-pyridine sulfonamide (Example 16) and 194 mg 5-bromo-2-chloropyridine as starting material are obtained as a beige foam. LC-MS: t _R = 5.49 min, [M + 1] ⁺ = 611.25, [M-1] ^- = 609.39.

Example 51

68mg5-isopropyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (p-tolyl) -4-pyrimidy Nyl] -2-pyridine sulfonamide was prepared in 230 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (p-tolyl)-according to the procedure set forth in Example 45. 4-pyrimidinyl] -2-pyridine sulfonamide (Example 16) and 120 mg 4,6-dimethoxy-2-methylsulfonylpyridine as starting material were obtained as a beige foam. LC-MS: t _R = 5.60 min, [M + 1] ⁺ = 591.21, [M-1] ^- = 589.24.

Example 52

50 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) dissolved in 5 ml dry chloroform To a solution of -4-pyrimidinyl] -2-pyridine sulfonamide (Example 1 g) and 10 mg 4-dimethylaminopyridine is added 25 [mu] l n-butyl isocyanate at room temperature. The mixture is heated to 65 ° C. and stirred for 42 hours. After 6 hours, 18 hours, 28 hours, an additional 25 μl n-butyl isocyanate is added. Finally, the mixture is diluted with 50 ml ethyl acetate. The solution is washed twice with 20 ml water. The aqueous layer is extracted once with ethyl acetate. The combined organic layers are dried over MgSO ₄ and evaporated. The residue is purified by column chromatography on silica gel and eluted in the order of DCM containing 1: 1 hexanes: ethyl acetate and 4% methanol. 39 mg n-butyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxyphenoxy) -2-pyridine-4 -Yl-pyrimidin-4-yloxy] -but-2-ynyl ester is made. LC-MS: t _R = 5.17 min, [M + 1] ⁺ = 661.37, [M-1] ^- = 659.51.

Example 53

50 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) dissolved in 5 ml dry chloroform To a solution of -4-pyrimidinyl] -2-pyridine sulfonamide (Example 1 g) and 10 mg 4-dimethylaminopyridine is added 25 [mu] l phenyl isocyanate at room temperature. The mixture is heated to 65 ° C. and stirred for 4 hours. Finally, the mixture is diluted with 50 ml ethyl acetate. The solution is washed twice with 20 ml water. The aqueous layer is extracted once with ethyl acetate. The combined organic layers are dried over MgSO ₄ and evaporated. The residue is purified by column chromatography on silica gel and eluted in the order of DCM containing 1: 1 hexanes: ethyl acetate and 4% methanol. 40 mg phenyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxyphenoxy) -2-pyridine-4 as a grayish white solid -Yl-pyrimidin-4-yloxy] -but-2-ynyl ester is made, which dissolves at 163-164 ° C. LC-MS: t _R = 5.15 min, [M + 1] ⁺ = 681.36, [M-1] ^- = 679.51.

Example 54

39 mg m-tolyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxyphenoxy) -2-pyridin-4-yl-pyrimidine- 4-yloxy] -but-2-ynyl ester was prepared using 50 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o according to the procedure set forth in Example 53. -Methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 1g) and a grayish white solid starting with 25 [mu] l m-tolyl isocyanate Is obtained. Melting point: 163-165 ° C. LC-MS: t _R = 5.33 min, [M + 1] ⁺ = 695.39, [M-1] ^- = 693.53.

Example 55

45 mg (4-methoxyphenyl) -carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxyphenoxy) -2-pyridin-4-yl -Pyrimidin-4-yloxy] -but-2-ynyl ester was prepared in 50 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy)-according to the procedure set forth in Example 53. 5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 1g) and 25 [mu] l 4-methoxyphenyl isocyanate as starting materials To a pale yellow foam. LC-MS: t _R = 5.06 min, [M + 1] ⁺ = 711.35, [M-1] ^- = 709.48.

Example 56

27 mg (2-methoxyphenyl) -carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxyphenoxy) -2-pyridin-4-yl -Pyrimidin-4-yloxy] -but-2-ynyl ester was prepared in 50 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy)-according to the procedure set forth in Example 53. 5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 1g) and 25 μl 2-methoxyphenyl isocyanate as starting materials To a pale yellow foam. LC-MS: t _R = 5.30 min, [M + 1] ⁺ = 711.36, [M-1] ^- = 709.49.

Example 57

36 mg (2-Fluorophenyl) -carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2-pyridin-4-yl -Pyrimidin-4-yloxy] -but-2-ynyl ester was prepared in 50 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy)-according to the procedure set forth in Example 53. 5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 1g) and 12 mg 2-fluorophenyl isocyanate as starting materials Obtained as a white solid. LC-MS: t _R = 5.16 min, [M + 1] ⁺ = 699.36, [M-1] ^- = 697.28.

Example 58

A solution of 50 mg 2-picolinic acid azide (prepared from 2-picolinic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657) and 10 mg DMAP dissolved in 8 ml chloroform for 1 hour at 75 ° C Stir while. 50 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl ] -2-pyridine sulfonamide (Example 1 g) and 3 ml DMF are added in sequence, and the resulting clear solution is stirred at 75 ° C. for 16 hours. The mixture is diluted with 75 ml ethyl acetate and washed in the order of 50 ml 10% aqueous citric acid and 50 ml water. The organic layer was evaporated and the crude product was prep. Containing 10: 1 dichloromethane: methanol. Purification by chromatography on tlc-plate gives 41 mg 2-pyridinyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy- as a white solid. Phenoxy) -2-pyridin-4-yl-pyrimidin-4-yloxy] -but-2-ynyl ester. LC-MS: t _R = 4.74 min, [M + 1] ⁺ = 682.47, [M-1] ^- = 680.41.

Example 59

271 mg 2-pyrazinyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2-pyridin-4-yl-pyri Midin-4-yloxy] -but-2-ynyl ester was prepared in 300 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- according to the procedure set forth in Example 58. (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 1g) and 199 mg pyrazine-2-carbonyl azide (Chem. Pharm A white powder is obtained, starting from Pyrazine-2-carboxylic acid according to Bull.25 (1977) 1651-1657. LC-MS: t _R = 4.73 min, [M + 1] ⁺ = 683.44, [M-1] ^- = 681.37.

Example 60

Under argon, 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- () dissolved in 4 ml chloroform and 3 ml DMF. A suspension of 4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 3), 10 mg DMAP, 25 μl cyclohexyl isocyanate is stirred at 70 ° C. for 72 hours. The mixture is diluted with 50 ml ethyl acetate and washed with 50 ml 10% aqueous citric acid and 2x25 ml water. The organic phase is dried over MgSO ₄ and evaporated. The crude product was purified by column chromatography on silica gel and eluted with DCM containing 1: 1 gradient hexane: ethyl acetate and then 4% methanol to give 38 mg cyclohexylcarbamic acid 4- [6- in beige foam. (5-Methylpyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2-pyridin-4-yl-pyrimidin-4-yloxy] -but-2-ynyl ester do. LC-MS: t _R = 4.89 min, [M + 1] ⁺ = 659.33, [M-1] ^- = 657.25.

Example 61

50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4 in 5 ml chloroform A suspension of -pyrimidinyl] -2-pyridine sulfonamide (Example 3), 10 mg DMAP, 25 μl phenylisocyanate, was refluxed under argon for 15 minutes. 1.5 ml DMF is added, stirring and heating are continued for 16 hours. The clear solution is diluted with 50 mL ethyl acetate and washed with 50 mL 10% aqueous citric acid and 2 × 50 mL water. The organic phase is dried over MgSO ₄ and evaporated. The crude product was purified by column chromatography on silica gel and eluted with DCM containing 1: 1 gradient hexane: ethyl acetate and then 4% methanol to give 47 mg phenylcarbamic acid 4- [6- as a slightly yellow solid. (5-Methylpyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2-pyridin-4-yl-pyrimidin-4-yloxy] -but-2-ynyl ester do. LC-MS: t _R = 4.80 min, [M + 1] ⁺ = 653.37, [M-1] ^- = 651.33.

Example 62

37 mg (3-methylphenyl) -carbamic acid 4- [6- (5-methylpyridine-2-sulfonylamino) -5- (2-methoxyphenoxy) -2-pyridin-4-yl-pyrimidine- 4-yloxy] -but-2-ynyl ester was prepared using 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-) according to the procedure set forth in Example 61. Obtained as a yellow solid using methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 3) and 25 [mu] l 3-methylphenylisocyanate as starting materials. LC-MS: t _R = 4.95 min, [M + 1] ⁺ = 667.42, [M-1] ^- = 665.30.

Example 63

38 mg (2-Fluorophenyl) -carbamic acid 4- [6- (5-methylpyridine-2-sulfonylamino) -5- (2-methoxyphenoxy) -2-pyridin-4-yl-pyrimidine The 4-yloxy] -but-2-ynyl ester was prepared in 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o according to the procedure set forth in Example 61. -Methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 3) and 25 µl 2-fluorophenylisocyanate as starting materials. Obtained as a foam. LC-MS: t _R = 4.79 min, [M + 1] ⁺ = 671.34, [M-1] ^- = 669.28.

Example 64

42 mg (4-fluorophenyl) -carbamic acid 4- [6- (5-methylpyridine-2-sulfonylamino) -5- (2-methoxyphenoxy) -2-pyridin-4-yl-pyrimidine The 4-yloxy] -but-2-ynyl ester was prepared in 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o according to the procedure set forth in Example 61. -Methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 3) and 25 µl 4-fluorophenylisocyanate as starting materials Obtained as a foam. LC-MS: t _R = 4.89 min, [M + 1] ⁺ = 671.34, [M-1] ^- = 669.28.

Example 65

38 mg 2-pyridinyl-carbamic acid 4- [6- (5-methylpyridine-2-sulfonylamino) -5- (2-methoxyphenoxy) -2-pyridin-4-yl-pyrimidine-4 -Yloxy] -but-2-ynyl ester was prepared using 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-meth) according to the procedure set forth in Example 58. Toxiphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 3) and 50 mg 2-picolinic acid azide (Chem. Pharm. Bull. 25 ( 1977) 1651-1657, obtained from 2-picolinic acid) as a starting material, to obtain a white powder. LC-MS: t _R = 4.32 min, [M + 1] ⁺ = 654.39, [M-1] ^- = 652.33.

Example 66

18 mg 2-pyridinyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxyphenoxy) -2- (2-pyrimidinyl)- Pyrimidin-4-yloxy] -but-2-ynyl ester was obtained in 50 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5 according to the procedure set forth in Example 58. -(o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 4) and 28 mg 2-picolinic acid azide (Chem. Obtained as a starting material according to Pharm. Bull. 25 (1977) 1651-1657) as a starting material. LC-MS: t _R = 4.84 min, [M + 1] ⁺ = 684.41.

Example 67

28 mg 2-pyrazinyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (2-pyrimidinyl) -Pyrimidin-4-yloxy] -but-2-ynyl ester was prepared in 50 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy)-according to the procedure set forth in Example 58. 5- (o-methoxy-phenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 4) and 50 mg pyrazine-2-carbonyl azide (A preparation from pyrazine-2-carboxylic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657) is obtained as a slightly yellow solid as a starting material. LC-MS: t _R = 4.67 min, [M + 1] ⁺ = 684.42, [M-1] ^- = 682.39.

Example 68

24 mg 2-pyridinyl-carbamic acid 4- [6- (4-tert.-butylbenzenesulfonylamino) -5- (2-methoxy-phenoxy) -2- (2-pyrimidinyl) -pyri Midin-4-yloxy] -but-2-ynyl ester was prepared in 50 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy)-according to the procedure set forth in Example 58. 5- (o-methoxy-phenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide (Example 5) and 50 mg 2-picolinic acid azide (Chem. Obtained as a starting material according to Pharm. Bull. 25 (1977) 1651-1657) as a starting material. LC-MS: t _R = 5.44 min, [M + 1] ⁺ = 696.43, [M-1] ^- = 694.35.

Example 69

39 mg 2-pyridinyl-carbamic acid 4- [6- (4-tert.-butylbenzenesulfonylamino) -5- (2-methoxy-phenoxy) -2- (2-pyrimidinyl) -pyri Midin-4-yloxy] -but-2-ynyl ester was prepared in 50 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy)-according to the procedure set forth in Example 58. 5- (o-methoxy-phenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide (Example 5) and 50 mg pyrazine-2-carbonyl azide (Chem Starting from pyrazine-2-carboxylic acid according to Pharm.Bull. 25 (1977) 1651-1657) as a starting material is obtained as a slightly yellow solid. LC-MS: t _R = 5.25 min, [M + 1] ⁺ = 697.44, [M-1] ^- = 695.35.

Example 70

50 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidy dissolved in 5 ml dry chloroform To the solution of [Nyl] -2-pyridine sulfonamide (Example 7d), 25 [mu] l phenyl isocyanate and 20 mg DMAP are added in sequence. The solution is stirred at 65 ° C. for 3 hours. The solvent is partially removed under reduced pressure, and the remaining solution is purified by column chromatography on 20 g silica gel and eluted with 2: 1 hexanes: ethyl acetate. 35 mg phenyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2-methyl-pyrimidine- 4-yloxy] -but-2-ynyl ester is made. LC-MS: t _R = 5.62 min, [M + 1] ⁺ = 618.33, [M-1] ^- = 618.45.

Example 71

43 mg Phenyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidine- 4-yloxy] -but-2-ynyl ester was prepared using 50 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o according to the procedure set forth in Example 53. -Methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 9) and 30 µl phenylisocyanate as starting materials are obtained as a white foam. LC-MS: t _R = 5.57 min, [M + 1] ⁺ = 689.38, [M-1] ^- = 687.49.

Example 72

142 mg 2-pyridinyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (N-morpholino) -Pyrimidin-4-yloxy] -but-2-ynyl ester was 150 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy)-according to the procedure set forth in Example 58. 5- (o-methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 9) and 100 mg 2-picolinic acid azide (Chem Obtained as a starting material according to Pharm.Bull. 25 (1977) 1651-1657) as a starting material. LC-MS: t _R = 5.37 min, [M + 1] ⁺ = 690.53, [M-1] ^- = 688.38.

Example 73

570 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (N-morpholino) dissolved in 15 ml DCM To the solution of 4-pyrimidinyl] -2-pyridine sulfonamide (Example 9) is added 0.37 mL DBU, catalytic amount of DMAP, 70 μl morpholine-4-carbonyl chloride. The mixture is stirred at reflux for 16 h and then evaporated. The residue is partitioned between 75 ml 10% aqueous citric acid and 75 ml ethyl acetate. The aqueous phase is extracted two more times with ethyl acetate and the combined organic layers are washed with water and brine, dried over MgSO ₄ and evaporated. The crude product was prep. Containing 1: 1 toluene: ethyl acetate. Purified on tlc-plate, 152 mg morpholine-4-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy in beige foam ) -2- (N-morpholino) -pyrimidin-4-yloxy] -but-2-ynyl ester is obtained. LC-MS: t _R = 5.26 min, [M + 1] ⁺ = 683.43, [M-1] ^- = 681.57.

Example 74

170 mg dimethyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (N-morpholino) -pyrimidine -4-yloxy] -but-2-ynyl ester was prepared using 570 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- ( white crystals (o-methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 9) and 52 µl dimethylcarbamic acid chloride as starting materials From 2-propanol / methanol). LC-MS: t _R = 5.29 min, [M + 1] ⁺ = 641.41, [M-1] ^- = 639.56.

Example 75

39 mg phenyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -pyrimidin-4-yloxy] -but-2 The -ynyl ester was 40 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -4- according to the procedure set forth in Example 53. Pyrimidinyl] -2-pyridine sulfonamide (Example 13) and 50 μl phenylisocyanate as starting materials are obtained as colorless foam. LC-MS: t _R = 5.38 min, [M + 1] ⁺ = 604.32, [M-1] ^- = 602.25.

Example 76

50 mg phenyl-carbamic acid 4- [6- (4-tert.-butyl-benzene-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyri Midin-4-yloxy] -but-2-ynyl ester was prepared in 50 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-butynyloxy)-according to the procedure set forth in Example 53. 5- (2-Methoxy-phenoxy) -2-morpholin-4-yl-pyrimidin-4-yl] -benzene sulfonamide (Example 14) and 50 µl phenylisocyanate as starting materials were used as colorless foams. Obtained. LC-MS: t _R = 6.07 min, [M + 1] ⁺ = 702.50, [M-1] ^- = 700.40.

Example 77

39 mg 2-pyridinyl-carbamic acid 4- [6- (4-tert.-butyl-benzene-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (N-morpholi No) -pyrimidin-4-yloxy] -but-2-ynyl ester was obtained in 50 mg 4-tert.-butyl-N- [6- (4-hydroxy-2-buty) according to the procedure set forth in Example 58. Nyloxy) -5- (2-methoxy-phenoxy) -2- (N-morpholine) -pyrimidin-4-yl] -benzene sulfonamide (Example 14) and 50 mg 2-picolinic acid Zide (prepared from 2-picolinic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657) as a starting material is obtained as a colorless foam. LC-MS: t _R = 5.63 min, [M + 1] ⁺ = 703.46, [M-1] ^- = 701.38.

Example 78

44 mg n-butyl-carbamic acid 4- [6- (5-methyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (N-morpholino) -pyri Midin-4-yloxy] -but-2-ynyl ester was prepared in 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (following the procedure set forth in Example 53). 2-Methoxy-phenoxy) -2- (N-morpholino) -4-pyrimidyl] -2-pyridine sulfonamide (Example 15) and 50 μl n-butylisocyanate as starting materials Obtained. LC-MS: t _R = 5.24 min, [M + 1] ⁺ = 641.47, [M-1] ^- = 639.39.

Example 79

53 mg cyclohexyl-carbamic acid 4- [6- (5-methyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (4-morpholino) -pyrimidine The 4-yloxy] -but-2-ynyl ester was prepared in 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (2 according to the procedure set forth in Example 53. -Methoxy-phenoxy) -2- (4-morpholino) -4-pyrimidyl] -2-pyridine sulfonamide (Example 15) and 100 μl cyclohexyl isocyanate as starting materials are obtained as colorless foam. . LC-MS: t _R = 5.32 min, [M + 1] ⁺ = 667.48, [M-1] ^- = 665.41.

Example 80

54 mg phenyl-carbamic acid 4- [6- (5-methyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (4-morpholino) -pyrimidine- 4-yloxy] -but-2-ynyl ester was prepared in 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (2- according to the procedure set forth in Example 53. Obtained as a colorless foam using methoxy-phenoxy) -2- (4-morpholino) -4-pyrimidyl] -2-pyridine sulfonamide (Example 15) as a starting material and 50 μl phenylisocyanate. LC-MS: t _R = 5.32 min, [M + 1] ⁺ = 661.43, [M-1] ^- = 659.38.

Example 81

36 mg 2-pyridinyl-carbamic acid 4- [6- (5-methyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (4-morpholino)- Pyrimidin-4-yloxy] -but-2-ynyl ester was prepared in 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- according to the procedure set forth in Example 58. (2-methoxy-phenoxy) -2- (4-morpholino) -4-pyrimidyl] -2-pyridine sulfonamide (Example 15) and 50 mg 2-picolinic acid azide (Chem. Pharm A white powder is obtained, starting from 2-picolinic acid according to Bull.25 (1977) 1651-1657). LC-MS: t _R = 4.90 min, [M + 1] ⁺ = 662.17, [M-1] ^- = 660.12.

Example 82

40 mg 3-pyridinyl-carbamic acid 4- [6- (5-methyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (4-morpholino)- Pyrimidin-4-yloxy] -but-2-ynyl ester was prepared in 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- according to the procedure set forth in Example 58. (2-methoxy-phenoxy) -2- (4-morpholino) -4-pyrimidyl] -2-pyridine sulfonamide (Example 15) and 50 mg nicotinic acid azide (Chem. Pharm. Bull. 25 (1977) 161-1657 prepared from nicotinic acid) as a starting material, a white powder is obtained. LC-MS: t _R = 4.19 min, [M + 1] ⁺ = 662.39, [M-1] ^- = 660.59.

Example 83

7 mg 4-pyridinyl-carbamic acid 4- [6- (5-methyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (4-morpholino)- Pyrimidin-4-yloxy] -but-2-ynyl ester was prepared in 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- according to the procedure set forth in Example 58. (2-Methoxy-phenoxy) -2- (4-morpholino) -4-pyrimidyl] -2-pyridine sulfonamide (Example 15) and 50 mg isonicotinic acid azide (Chem. Pharm. Bull. 25 (1977) 1651-1657, prepared from isnicotinic acid), is obtained as a white solid. LC-MS: t _R = 3.89 min, [M + 1] ⁺ = 662.39, [M-1] ^- = 660.33.

Example 84

204 mg 4-pyrazinyl-carbamic acid 4- [6- (5-methyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (4-morpholino)- Pyrimidin-4-yloxy] -but-2-ynyl ester was prepared in 50 mg 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- according to the procedure set forth in Example 58. (2-methoxy-phenoxy) -2- (4-morpholino) -4-pyrimidyl] -2-pyridine sulfonamide (Example 15) and 50 mg pyrazine-2-carbonyl azide (Chem. From Pyrazine-2-carboxylic acid according to Pharm. Bull. 25 (1977) 1651-1657) is obtained as a white solid. LC-MS: t _R = 4.80 min, [M + 1] ⁺ = 663.43, [M-1] ^- = 661.36.

Example 85

36 mg phenyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (p-tolyl) -pyrimidin-4-yloxy] -but-2-ynyl ester 60 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (p-tolyl) -4-pyrimidyl] -2-pyridine according to the procedure set forth in Example 53 Obtained as a grayish white foam starting with sulfonamide (Example 16) and 50 μl phenylisocyanate. LC-MS: t _R = 5.50 min, [M + 1] ⁺ = 572.36, [M-1] ^- = 570.30.

Example 86

79 mg N-methyl-N-phenyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (p-tolyl) -pyrimidin-4-yloxy] -buty The 2-ynyl ester was 230 mg 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (p-tolyl) -4-pyridine according to the procedure set forth in Example 72. Midiyl] -2-pyridine sulfonamide (Example 16) and 95 mg N-methyl-N-phenyl-carbamic acid chloride as starting material are obtained as a beige foam. LC-MS: t _R = 5.44 min, [M + 1] ⁺ = 586.33, [M-1] ^- = 584.50.

Example 87

300 mg 5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfone in 15 mL DMF Amide (Example 1f) and 1.47 g 4-methoxy-2-butynol (Bull. Chem. Soc. Japan 28 (1955), 80-83, according to the procedure set forth in 2-butyne-1,4-diol and dimethyl) 234 mg 55% NaH dissolved in mineral oil is carefully added to the solution of sulphate as a starting material). The brown solution is stirred at room temperature for 24 hours, after which additional 120 mg 55% NaH dissolved in mineral oil is added. Stirring lasts for 24 hours. The mixture is diluted with 100 ml 10% aqueous citric acid and extracted four times with 50 ml ethyl acetate. The combined organic phases are washed twice with 50 ml water, dried over MgSO ₄ and evaporated. The crude product was purified by column chromatography on silica gel and eluted with ethyl acetate to give 154 mg 5-isopropyl-N- [6- (4-methoxy-but-2-ynyloxy) -5- as a yellow solid. (2-methoxy-phenoxy) -2-pyridin-4-yl-pyrimidin-4-yl] -2-pyridine sulfonamide is obtained. LC-MS: t _R = 4.84 min, [M + 1] ⁺ = 576.42, [M-1] ^- = 574.37.

Example 88

300 mg 5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfone in 15 mL THF Amide (Example 1f) and 502 mg 4-phenoxy-2-butyn-1-ol (Phenylpropargylether according to the procedure set forth in J. Chem. Soc. Perkin Trans. 1, 1991, 1721-1727). To a solution of para-formaldehyde as a starting material), 228 mg 55% NaH dissolved in mineral oil is added. The orange suspension is stirred for 1 hour at room temperature and then diluted with 100 ml 10% aqueous citric acid. The mixture is extracted three times with 50 ml ethyl acetate. The combined organic phases are washed with 50 ml water, dried over MgSO ₄ and evaporated. The crude product was 8: 2: 1 ethyl acetate: methanol: sat. Prep containing aqueous ammonia. Purification by chromatography on tlc-plate gave 241 mg 5-isopropyl-N- [6- (4-phenoxy-but-2-ynyloxy) -5- (2-methoxy-phenoxy in a slightly yellow foam. C) -2-pyridin-4-yl-pyrimidin-4-yl] -2-pyridine sulfonamide. LC-MS: t _R = 5.95 min, [M + 1] ⁺ = 666.58, [M-1] ^- = 664.62.

Example 89

250 mg 4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -benzene in 15 mL THF Sulfonamide (Example 5a) and 1.11g 4-methoxy-2-butynol (Bull. Chem. Soc. Japan 28 (1955), 80-83, according to the procedure described in 2-butyne-1,4-diol) 177 mg 55% NaH dissolved in mineral oil is added to the mixture of dimethylsulfate as a starting material. The suspension is stirred at reflux for 16 h. The reaction mixture is cooled, diluted with 100 ml 10% aqueous citric acid and extracted four times with 50 ml ethyl acetate. The combined organic phases are washed with water, dried over MgSO ₄ and evaporated. The crude product was 8: 2: 1 ethyl acetate: methanol: sat. Prep containing aqueous ammonia. Purification by chromatography on tlc-plate gave 116 mg 4-tert.-butyl-N- [6- (4-methoxy-2-butynyloxy) -5- (o-methoxy-) as a slightly yellow foam. Phenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide. LC-MS: t _R = 5.19 min, [M + 1] ⁺ = 590.40, [M-1] ^- = 588.39.

Example 90

260 mg 4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -benzene in 15 mL THF Sulfonamide (Example 5a) and 1.50 g 4-phenoxy-2-butyn-1-ol (phenyl-propargylether according to the procedure set forth in J. Chem. Soc. Perkin Trans. 1, 1991, 1721-1727). And 184 mg 55% NaH dissolved in mineral oil are added to the mixture of and para-formaldehyde as a starting material. The suspension is stirred at reflux for 1 hour. The reaction mixture is cooled, diluted with 100 ml 10% aqueous citric acid and extracted four times with 50 ml ethyl acetate. The combined organic phases are washed with water, dried over MgSO ₄ and evaporated. The crude product was 8: 2: 1 ethyl acetate: methanol: sat. Prep containing aqueous ammonia. Purification by chromatography on tlc-plate gave 82 mg 4-tert.-butyl-N- [6- (4-phenoxy-2-butynyloxy) -5- (o-methoxy-) as a slightly yellow foam. Phenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide. LC-MS: t _R = 5.60 min, [M + 1] ⁺ = 652.63, [M-1] ^- = 650.58.

Example 91

390 mg 4-benzyloxy-2-butyn-1-ol dissolved in 5 ml 1: 1 DMF: THF (Tetrahedron Lett. 38 (1997), 7887-7890), similar to the procedure described in 2-butyne-1,4- To a solution of diol and benzyl bromide as starting materials) is added 97 mg 55% NaH dissolved in mineral oil. 250 mg 4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] after gas evolution ceased Benzene sulfonamide (Example 5a) is added and the mixture is stirred at 50 ° C. for 20 hours and then diluted with 75 ml ethyl acetate. The mixture is washed with 75 ml 10% aqueous citric acid and 75 ml water and evaporated. The crude product was 10: 2: 1 ethyl acetate: methanol: sat. Prep containing aqueous ammonia. Purification by chromatography on tlc-plate gave 125 mg 4-tert.-butyl-N- [6- (4-benzyloxy-2-butynyloxy) -5- (o-methoxy-phenoxy) as a yellow foam. ) -2- (2-pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide. LC-MS: t _R = 5.93 min, [M + 1] ⁺ = 666.47, [M-1] ^- = 664.63.

Example 92

184 mg 4-tert.-butyl-N- [6- (4- (4-methoxybenzyloxy) -2-butynyloxy) -5- (o-methoxy-phenoxy) -2- (2- Pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide was prepared in 250 mg 4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) according to the procedure set forth in Example 91. -2- (2-pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide (Example 5a) and 421 mg 4- (4-methylbenzyloxy) -2-butyn-1-ol (Tetrahedron Lett. Similar to the procedure shown in 38 (1997), 7887-7890, a starting product of 2-butyne-1,4-diol and 4-methylbenzylbromide) is obtained as a yellow foam. LC-MS: t _R = 6.11 min, [M + 1] ⁺ = 680.51, [M-1] ^- = 678.61.

Example 93

Crude 4-tert.-butyl-N- [6- (4- (3-methoxybenzyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- (2- Pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide was prepared in 300 mg 4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) according to the procedure set forth in Example 91. -2- (2-pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide (Example 5a) and 1096 mg 4- (3-methoxybenzyloxy) -2-butyn-1-ol (Tetrahedron Lett 38 (1997), prepared in the same manner as 7887-7890 with 2-butyne-1,4-diol and 3-methoxybenzylbromide as starting materials). The compound was purified by column chromatography on silica gel, eluting with DCM containing 0-2.5% methanol, then prep. With DCM containing 5% methanol. Purify by chromatography on tlc-plate. The resulting oil is covered with 10 ml diethyl ether and treated with pentane. The precipitate was collected and dried to give 102 mg 4-tert.-butyl-N- [6- (4- (3-methoxybenzyloxy) -2-butynyloxy) -5- (o-) as an almost white powder. Methoxy-phenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -benzene sulfonamide. LC-MS: t _R = 5.74 min, [M + 1] ⁺ = 696.40, [M-1] ^- = 694.32.

Example 94

250 mg 5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide (Example 9c) and 1.2 g 4-methoxy-2-butyn-1-ol (Bull. Chem. Soc. Japan 28 (1955), 80-83, according to the procedure set forth in 2-butyne-1,4-diol and dimethylsulfate) To 192 mg 55% NaH dissolved in mineral oil is added to the mixture. After gas evolution ceased, the brown suspension was refluxed for 16 hours. An additional 96 mg 55% NaH dissolved in mineral oil is added and heating and stirring is continued for an additional 3 hours. The mixture is cooled, diluted with 50 ml 10% aqueous citric acid and extracted four times with 50 ml ethyl acetate. The combined organic phases are washed with water, dried over MgSO ₄ and evaporated. The crude product was purified by column chromatography on silica gel, eluted with 1: 3 hexanes: ethyl acetate and precipitated from diethyl ether to give 114 mg 5-isopropyl-N- [6- (4-methoxy) as a white powder. 2-butynyloxy) -5- (o-methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide is obtained. LC-MS: t _R = 5.19 min, [M + 1] ⁺ = 584.46, [M-1] ^- = 582.38.

Example 95

300 mg 4-tert.-butyl-N- [6-chloro-5- (p-tolyl) -4-pyrimidinyl] -benzene sulfonamide (Example 12c) and 1.8 g 4-methoxy-2-butyne To a mineral oil in a mixture of -1-ol (prepared with 2-butyne-1,4-diol and dimethylsulfate as starting material according to the procedure given in Bull. Chem. Dissolve 288 mg 55% NaH. After gas evolution has ceased, the brown suspension is stirred for 24 hours at room temperature. An additional 288 mg 55% NaH dissolved in mineral oil is added and the mixture is stirred at 60 ° C. for 18 hours. The mixture is cooled, diluted with 50 ml 10% aqueous citric acid and extracted four times with 50 ml ethyl acetate. The combined organic phases are washed with water, dried over MgSO ₄ and evaporated. The crude product was purified by column chromatography on silica gel, eluted with 1: 1 hexanes: ethyl acetate and precipitated from diethyl ether to give 213 mg 4-tert.-butyl-N- [6- (4- Methoxy-2-butynyloxy) -5- (p-tolyl) -4-pyrimidinyl] -benzene sulfonamide is obtained. LC-MS: t _R = 5.61 min, [M + 1] ⁺ = 480.30, [M-1] ^- = 478.39.

Example 96

282 mg 4-tert.-butyl-N- [6-chloro-5- (p-tolyl) -4-pyrimidinyl] -benzene sulfonamide (Example 12c) dissolved in 15 ml THF and 1.10 g 4-phenoxy Cy-2-butyn-1-ol (prepared with phenyl-propargylether and para-formaldehyde as starting materials according to the procedure set forth in J. Chem. Soc. Perkin Trans. 1, 1991, 1721-1727). To the mixture is added 271 mg 55% NaH dissolved in mineral oil. The suspension is stirred at reflux for 4 hours. The reaction mixture is cooled, diluted with 100 ml 10% aqueous citric acid and extracted four times with 50 ml ethyl acetate. The combined organic phases are washed with water, dried over MgSO ₄ and evaporated. The crude product was purified by column chromatography on silica gel, eluted with 1: 1 heptane: ethyl acetate and precipitated from diethyl ether to give 151 mg 4-tert.-butyl-N- [6- (4- as white powder). Phenoxy-2-butynyloxy) -5- (p-tolyl) -4-pyrimidinyl] -benzene sulfonamide is obtained. LC-MS: t _R = 6.34 min, [M + 1] ⁺ = 542.48, [M-1] ^- = 540.15.

Claims (16)

Compounds of formula (I), pure enantiomers, pure diastereomers in terms of enantiomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, pharmaceutically acceptable Possible salts: Formula I Wherein R ¹ is phenyl; Substituted by halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkynyl, trifluoromethyl, cycloalkyl, hydroxy-cycloalkyl Single-, double- or triple-substituted phenyl; 2-pyridyl; Low-substituted alkyl, 5-substituted 2-pyridyl substituted with a pentagonal heteroaryl ring having one or two nitrogen, sulfur or oxygen atoms; R ² is hydrogen; Lower alkyl; Phenyl; Having one or two nitrogen, sulfur or oxygen atoms that can be mono- or di-substituted with halogen, low alkyl, low alkoxy, low alkoxy-lower alkyl, trifluoromethyl, or halogen, low alkyl, low alkoxy Mono-, di-, or tri-substituted phenyl substituted with a pentagonal heteroaryl ring; benzyl; Mono- or di-substituted benzyl substituted with halogen, lower alkyl, lower alkoxy, trifluoromethyl, 2-pyrimidyl; Lower alkyl, lower alkoxy, halogen, trifluoromethyl, or ^a group of the formula -C (A) -BR ^a , wherein A is O or S; B is NH; R ^a is lower alkyl; cycloalkyl; phenyl; halogen Lower alkyl, lower alkenyl, lower alkoxy, trifluoromethyl, or a hexagonal heteroaryl ring having one or two nitrogen atoms which may be mono- or di-substituted with halogen, lower alkyl, lower alkoxy) Mono-, di-, or tri-substituted phenyl; R ³ is mono-, bi- or tri-substituted phenyl substituted with lower alkyl, lower alkenyl, lower alkyloxy, trifluoromethyl, halogen, hydroxy; R ⁴ is hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkyloxy, lower alkylthio, lower alkyl-oxy-lower alkyl; Phenyl; Halogen, lower alkyl, lower alkoxy, single- or double-substituted by lower or lower alkylene or lower alkenylene or lower alkyleneoxy or lower alkylenedioxy or heteroaryl forming a pentagonal or hexagonal phenyl ring with a phenyl ring; Substituted phenyl; Heterocyclyl; X is the hand of oxygen, sulfur or atom. The method according to claim ¹ , wherein R ¹ , R ² , R ⁴ are the same as defined in claim 1, R ³ is phenyl; Phenyl monosubstituted with lower alkyl, lower alkoxy, trifluoromethyl or halogen; X is oxygen or a hand of an atom. Compounds II and pharmaceutically acceptable salts thereof: Formula II Wherein R ² , R ³ , R ⁴ , X are the same as defined in claim 1, and R ⁵ is lower alkyl. Compounds III and pharmaceutically acceptable salts thereof: Formula III Here, R ¹ , R ³ , R ⁴ , X are the same as defined in claim 1, and R ⁶ , R ⁷ , R ⁸ are each independently hydrogen, lower alkyl, lower alkyloxy, halogen, trifluoromethyl. Compounds IV and pharmaceutically acceptable salts thereof: Formula IV ^{Wherein, R 1, R 3, R} 4, R a, X are the same as defined in claim 1. R ¹ , R ³ , R ⁴ , X are the same as defined in claim 1 and R ² is lower alkyl and pharmaceutically acceptable salts thereof. A compound according to any one of claims 1 to 6 and pharmaceutically acceptable salts thereof, selected from: 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl]- 2-pyridine sulfonamide; 4-tert.-Butyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl ] -Benzene sulfonamide; 5-methyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (4-pyridyl) -4-pyrimidinyl] -2 -Pyridine sulfonamides; 5-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -2-pyridine sulfonamide; 4-tert.-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] benzene sulfonamide; 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide; 5-isopropyl-N- [6- (4-hydroxy-2-butynyloxy) -5- (p-tolyl) -2- (4-pyridyl) -4-pyrimidinyl] -2-pyridine Sulfonamides; 5-isopropyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2- ( 4-pyridyl) -4-pyrimidinyl] -2-pyridine sulfonamide; 4-tert.-Butyl-N- [6- (4- (2-pyrimidinyloxy) -2-butynyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2 -(4-pyridyl) -4-pyrimidinyl] -benzene sulfonamide; 4-tert.-Butyl-N- [6- (4- (4,6-dimethoxy-2-pyrimidinyloxy) -2-butynyloxy) -5- (o-methoxyphenoxy) -2 -(4-pyridyl) -4-pyrimidinyl] -benzene sulfonamide; 2-Pyrimidinyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2-pyridin-4-yl-pyrimidine -4-yloxy] -but-2-ynyl ester; Phenyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2-methyl-pyrimidin-4-yloxy] -but 2-ynyl esters; Phenyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2-morpholin-4-yl-pyrimidine-4- Iloxy] -but-2-ynyl ester; 2-Pyridinyl-carbamic acid 4- [6- (5-isopropyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (N-morpholino) -pyri Midin-4-yloxy-but-2-ynyl ester; 2-Pyridinyl-carbamic acid 4- [6- (5-methyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (4-morpholino) -pyrimidine -4-yloxy] -but-2-ynyl ester; 4-Pyrazinyl-carbamic acid 4- [6- (5-methyl-pyridine-2-sulfonylamino) -5- (2-methoxy-phenoxy) -2- (4-morpholino) -pyrimidine -4-yloxy] -but-2-ynyl ester; 4-tert.-Butyl-N- [6- (4-methoxy-2-butynyloxy) -5- (o-methoxy-phenoxy) -2- (2-pyrimidinyl) -4-pyri Midinyl] benzene sulfonamide; 5-isopropyl-N- [6- (4-methoxy-2-butynyloxy) -5- (o-methoxyphenoxy) -2- (N-morpholino) -4-pyrimidinyl] -2-pyridine sulfonamide. In pharmaceutical compositions for the treatment of diseases associated with the role of endothelin, in particular circulatory diseases such as hypertension, ischemia, angina and metastatic diseases such as cancer, the compounds of any one of claims 1 to 7 A pharmaceutical composition comprising an adjuvant. A pharmaceutical composition for treating diseases associated with the role of endothelin, such as migraine, asthma or inflammatory diseases, comprising the compound of any one of claims 1 to 7 and a conventional carrier material and adjuvant Pharmaceutical compositions. 8. A compound according to any one of claims 1 to 7, which is used as a drug for the treatment of diseases related to the role of endothelin, in particular circulatory diseases such as hypertension, ischemia, angina and metastatic diseases such as cancer. 8. _A compound according to any one of claims 1 to 7, characterized in that it is used as a drug for treating diseases associated with the role of endothelin and requiring ET _A and ET _B hybridization for treatment. 8. _A compound according to any one of claims 1 to 7, characterized in that it is used as a drug for treating diseases associated with the role of endothelin and requiring selective ET _A blockage for treatment. 8. A compound according to any one of claims 1 to 7, characterized in that it is used as a drug for treating diseases associated with the role of endothelin and requiring selective ET _B blockade for treatment. Any one of claims 1 to 7, characterized in that it is used as an active ingredient in the production of pharmaceutical compositions for treating diseases related to the role of endothelin, in particular circulatory diseases such as hypertension, ischemia, angina and metastatic diseases such as cancer. Use of one or more compounds according to claim. Use of at least one compound according to any one of claims 1 to 7, characterized in that it is used as an active ingredient in the production of a pharmaceutical composition for the treatment of diseases associated with endothelin activity such as migraine, asthma or inflammatory diseases. A process for preparing a pharmaceutical composition containing at least one compound according to any one of claims 1 to 7 as an active ingredient and used for the treatment of diseases associated with the role of endothelin, A process comprising mixing an acceptable excipient and one or more active ingredients.