TWI303245B - Novel sulfamides - Google Patents

Description

1303245 A7 B7 V. INSTRUCTION DESCRIPTION OF THE INVENTION (1) The present invention relates to the use of the novel Formula I VI-dense-thiosulphonamide and its use as an active ingredient in the preparation of pharmaceutical compositions. The invention also relates to related aspects, including methods of preparing the compounds, pharmaceutical compositions containing one or more compounds of formula I, and especially their use as endothelin receptor antagonists. Endothelin (ET-1, ET-2 and ET-3) is a 21-amino acid peptide which is produced and active in almost all tissues (Yanagisawa M et al.: Nature (1988) 332: 411). Endothelin is an important mediator of effective vasoconstrictors and functions of heart, kidney, endocrine and immunity (McMillen MA et al.: J Am Coll Surg (1995) 180:621). It is involved in branch tracheal contraction and regulation of neurotransmitter release, activation of inflammatory cells, fibrosis, cell proliferation and cell differentiation (Rubanyi GM et al.: Pharmacol Rev (1994) 46: 328). Two endothelin receptors have been vegetatively propagated and characterized in mammals (ETA, ETB) (Arai H et al: Nature (1990) 348: 730; Sakurai T et al: Nature (1990) 348: 732 ). The ETA receptor is characterized by a higher affinity for ET-1 than for ET-2. It is mainly present in vascular smooth muscle cells and mediates vasoconstriction and proliferative responses (Ohlstein EH et al.: Drug Dev Res (1993) 29 · 108). In contrast, the ETB receptor has equal affinity for peptides such as three endothelial peptides, and binds linear form of endothelin, tetra-alanine-endothelin and sarafotoxin S6C (Ogawa Y et al.: BBRC (1991) 178: 248). This receptor system is located in the vascular endothelium and smooth muscle, and is also particularly large in the lungs and brain. ETB from endothelial cells is mediated by transient vasodilation of ET-1 and ET-3 via release of nitric oxide and/or prostacyclin, whereas vasoconstriction is applied to ETB receptors from smooth muscle cells (Sumner MJ) Etc.: 81^1?1^〇1^〇1(1992) 107: * 4 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (2 858) ETA and ETB receptors are structurally highly similar and belong to the superfamily of protein-coupled receptors. ΕΤ-1 has pointed out a pathophysiological role, given the status of several diseases, such as 咼Blood pressure, pulmonary hypertension, septicemia, atherosclerosis, acute myocardial infarction, septic heart failure, renal failure, migraine, and asthma increase plasma and tissue levels. Therefore, endothelin receptor antagonists have been Widely studied as a possible therapeutic agent. Endothelin receptor antagonists have been confirmed in various diseases such as cerebral vasospasm after subarachnoid hemorrhage, heart failure, lung and systemic hypertension, neurological inflammation, renal failure and myocardial infarction In, there is Pre-certification and/or clinical efficacy. Today, only one endothelin receptor antagonist (TracleerTM) is marketed and several are in clinical trials. However, some of these molecules have many weaknesses, such as complex synthesis, low solubility, High molecular weight, poor pharmacokinetics or safety issues (eg increased liver enzymes). Furthermore, the contribution of different eta/etb receptor blockers to clinical outcomes is unknown. Therefore, physical and pharmacokinetic properties are tailored. And the selective form of each antagonist for a given clinical indication is mandatory. Until now, endothelin receptor antagonists with a pyrimidine core structure containing thiopurine units have not been reported [2, 3, 5 , 6, 8]. We have found that the novel species of the underlying structure have been substituted for pyrimidines and have been found to permit the specific customizations described above, and have been shown to exhibit compounds in the mixed and ETA-selective binding modalities. The inhibitory activity of the endothelin receptor can be confirmed using the test procedure described later: To evaluate the efficacy and efficacy of the compound of formula I, the following test is used: L-----5-ben Paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (3) 1) Inhibition of endothelin binding to cell membranes of CHO cells bearing human ET receptors·· About competition In conjunction with the study, cell membranes of CHO cells expressing human recombinant ETA or ETB receptors were used. Microsomal membranes taken from recombinant CHO cells were prepared and tested for binding as previously described (Breu V. et al., FEBS Lett 1993; 334: 210). The assay was performed in a polypropylene microtiter plate in 200 μl of 50 mM Tris/HCl buffer in ρΗ7·4 containing 25 mM MnCl2, 1 mM EDTA and 0.5. . (w/v) BSA. The cell membrane containing 0.5 μg of protein was incubated with 8 Pm p 25I]ET-1 (4000 cpm) at an increasing concentration of unlabeled antagonist for 2 hours at 20 ° C. The maximum and minimum binding lines were 100 and 100, respectively. Sample estimation of nM ET-1. After 2 hours, the cell membrane was filtered on a filter plate containing GF/C filters (Unifilterplates, available from Canberra Packard S. A. Zurich, Switzerland). Add 50 μl of scintillation solution (MicroScint 20, Canberra Packard SA·Zurich, Switzerland) to each well and count the plates in a microplate counter (TopCount, Canberra Packard SA Zurich, Switzerland) 0 Dissolve all test compounds Dilute and add to DMSO. The test system was operated in the presence of 2.5% DMSO. which was found to not significantly interfere with binding. The IC50 is calculated to suppress 50°/. Antagonist concentration of ET-1 specific binding. Regarding the reference compound, the following IC5 0値: ETA cells: ET-1 was 0.075 nM (n=8) and ET-3 was 118 nM (n=8); ETb cells··ET-1 was 0.067 nM (n =8) and ET-3 is 0·092 nM (11= 3). The IC5{) oxime obtained by the compound of the formula I is shown in Table 1. -6 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Invention description (4) Table 1: Example compound Eta IC5 〇[nM] ΕΤβ Example 1 721 8429 Example 2 2190 8743 Example 3 1384 744 Example 4 96 680 Example 5 28 1280 Example 6 286 7240 Example 7 1237 9467 Example 8 1160 > 10000 Example 9 3629 > 10000 Example 10 2866 193 Example 12 59 > 10000 Example 14 5.6 1033 Example 15 18.5 2161 Example 16 45 8452 Example 18 8.5 3333 Example 19 25 3414 Example 20 4.9 1723 Example 21 7 1001 Example 22 12 434 Example 23 3.6 1585 Example 24 2.2 2496 Example 26 54 > 10000 Example 29 13.5 4230 Example 32 3.5 864 Example 33 3.7 609 Example 34 23 3267 Example 37 16 822 Example 38 14.5 One 290 Example 39 32.7 524 Example 41 3.2 41.6 Example 42 3.5 146 Wood Paper Scale Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) 1303245 A7 B7 V. INSTRUCTIONS (5) Example 43 6.8 214 Example 48 1.46 46.6 Example 49 0.82 25.4 Example 50 0.87 7.5 Example 51 13.4 306 Example 55 5.2 80 Example 56 6.9 164 Example 57 4.9 35.8 Example 59 5.6 124 Example 60 3.4 232 Example 61 1.6 200 Example 66 11 487 Example 71 23.6 635 Example 73 1.9 567 Example 74 1.8 164 Example 75 14 895 Example 80 10 > 1000 Example 81 3.6 274 Example 84 37 574 Example 88 16 1251 Example 89 19 621 Example 90 7.4 433 Example 91 2.5 79 Example 96 6.3 585 Example 97 1.55 92 Example 98 2.1 159 Example 100 0.76 283 Example 101 1.24 335 Example 102 0.46 65 Example 104 0.88 601 Example 105 0.69 203 Example 107 0.25 96 Example 108 0.28 56 Example 109 1.94 >1000 Example 110 2.3 >1000 -8- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (6) Example 111 12.3 3750 Example 112 0.52 257 Example 113 4.26 581 Example 114 8.3 > 1000 Example 115 2.2 > 1000 Example 116 1.3 567 Example 117 0.45 518 Example 118 0.34 611 Example 119 4.2 > 1000 Example 123 2.9 124 Example 124 7.3 102 Example 127 7.3 87 Example 130 3.7 347 Example 131 3.2 233 Example 133 1.7 212 Example 134 2.4 187 Example 137 2.7 173 Example 138 0.9 40 Example 142 2.6 108 Example 143 3.1 35 Example 145 1.64 > 1000 Example 146 5 514 Example 147 1.2 408 Example 149 15 1315 Example 151 0.77 57 Example 152 1.1 79 Example 155 5.8 173 Example 156 18 409 Example 157 42.2 954 Example 158 10 80 Example 160 11 3221 Example 161 6,2 > 1000 Example 163 0.44 80 Example 164 1 81 Example 166 1 3 -9 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. DESCRIPTION OF THE INVENTION (Example 167 5.2 6.4 Example 168 2.7 1.6 Example 170 1.7 42 Example m 11 61 Example 172 3 16 Example 174 3.7 93 Example 175 22 62 Example 176 2.5 22 Example 181 14.3 224 Example 182 29 1867 Example 184 29.5 3777 Example 187 9.8 532 Instance 188 11 290 Instance 193 3.6 > 1000 Instance 194 9.5 > 1000 Instance 196 4.4 > 1000 Instance 197 1.16 418 Example 198 38.4 667 Instance 199 12 205 Instance 200 23 310 Instance 201 133 682 Instance 202 9.6 351 Instance 204 390 1047 Example 205 135 623 Example 206 1.03 209 Example 207 17 > 1000 Example 208 17 342 Example 209 733 > 1000 Example 210 23 936 Example 211 290 722 Example 212 3.1 >1000 Example 213 1.32 347 Example 214 0.76 241 2) For the isolated rat aortic ring (ETA receptor) and the rat tracheal ring (ETB subject to -10- paper scale applicable to China) Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (

Inhibition of contraction induced by endothelin on the body) Functional inhibition of endothelin antagonists, inhibition of contraction induced by endothelin on Wang Dongyue, and for large The inhibition of contraction induced by salbutazone S6c on the tracheal ring (ΕΤβ receptor) in white rats was evaluated. Adult Wi coffee rats are anesthetized and devascularized. The thoracic aorta or trachea was excised, dissected, and cut into a 3.5 mm ring. The endothelium/epithelial system is removed by gentle rubbing of the intima surface. Each ring was suspended in a bath containing Krebs-Hensdeit solution (expressed in mM; NaC1U5, κα47, MgS%i 2 , ΚΗ2Ρ041·5 v NaHC0325, CaCl22.5, glucose ίο) in a separate organ bath, which was maintained At 37. It is treated with 95% and 5% c〇2 gas. Connect the ring to the force sensor and note the green isometric tension (EMKA Techn〇l〇gies SA, Paris, France). The ring was stretched to a static tension of 3 grams (aorta) or 2 grams (trache). The cumulative dose of ET-1 (aorta) or savory toxin S6C (trache) is added after 1 minute of incubation with the test compound or its vehicle. The functional inhibitory efficacy of the test compound is assessed by calculating the concentration ratio, ie to the ε (: 5 〇 right displacement 値 expressed by the test compound at different concentrations. ECS 0 is required for half-maximal contraction The endopeptide concentration, ρΑ2 is the negative logarithm of the antagonist concentration that causes twice the change in ECS 0. The pa2 oxime obtained from the compound of formula ί is shown in Table 2. This paper scale is applicable to the SS sample (CNS) A4. Specifications (21QX 297 mm)

Binding

1303245 A7 B7 V. INSTRUCTIONS (9) TABLE 2:

Because of its ability to inhibit endothelin binding, the compounds are useful in the treatment of diseases associated with increased vasoconstriction, hyperplasia or inflammation caused by endothelin. Examples of such diseases are hypertension, pulmonary hypertension, coronary disease, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral heliorrhea, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, and portal vein. Sexual hypertension. It can also be used to treat or prevent atherosclerosis, restenosis after posterior balloon or graft angiography, inflammation, stomach and duodenal ulcer, cancer, prostate hypertrophy, erectile dysfunction, hearing loss, cataract, Chronic bronchitis, asthma, Gram-negative septicemia, shock, sickle-shaped red blood cell deficiency, spheroid nephritis, renal colic, glaucoma, treatment and prevention of diabetic complications, vascular or cardiac surgery or organ transplantation Complications, ring _12· This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1303245 A7 B7 V. Description of invention (ΊΟ) Complications, pain, hyperlipidemia of spores treatment and Other diseases known to be associated with endothelin are currently known. The compounds can be administered orally, rectally, parentally, for example, by intravenous, intramuscular, subcutaneous, intrathecal or transdermal administration, or sublingually or as an ophthalmic preparation, or by aerosol administration. Examples of use are capsules, tablets, suspensions or solutions for oral administration, suppositories, injections, eye drops, ointments or aerosols/atomizers. Fortunately, the application is intravenous, intramuscular or oral administration, as well as eye drops. The dosage used will depend on the particular active ingredient type, the age and need of the patient, and the type of application. A dose of 0.1-50 mg/kg body weight per day is generally considered. Formulations containing the compound may contain inert or pharmacologically active agents. For example, tablets or granules gamma contain many binders, fillers, carrier materials or diluents. - The present invention relates to a cerium-ammonium sulfate-sulfide compound of the formula I,

R

ΝΗ R6 /R3

Formula I 12 R2 wherein R1 represents an aryl group; an aryl-low carbon pit group; a heteroaryl group; a heteroaryl group-low carbon environment

_____-13- This paper New Zealand®® Alignment (CNS) Α4 size (21Gχ 297 public) 1303245 A7 B7___ V. Description of invention (11 ) ; cycloalkyl: cycloalkyl-lower alkyl; heterocyclic a heterocyclic group - a lower alkyl group; a lower alkyl group; a hydrogen, or may form a heteroatom or a cyclohexyl ring with R6; R2 represents -013; -(012)11 is not; -(012)111-<:3 (0)(1); a heteroaryl group; R4 represents hydrogen; a trifluoromethyl group; a lower carbon oxime group; a lower carbon pit group-amino group; a lower alkoxy group; a lower alkoxy group-lower alkyl group; Hydroxy-lower alkoxy; lower alkyl-sulfinyl; lower alkylthio; lower alkylthio-lower alkyl; hydroxy-lower alkyl; lower alkyl-oxy -lower alkyl; hydroxy · lower alkyl oxy-lower alkyl; hydroxy-lower alkyl-amino; lower carbon alkyl-amino-lower alkyl; amine; Carboxyalkyl-amine group; and (transcarbo-lower alkyl)-N-(lower alkyl)-amino group; aryl; aryl-amine group; aryl-low carbon pit-amino group ; aryl-thio; aryl-lower alkane -thio; aryloxy; aryl-lower alkyl-oxy; aryl-lower alkyl; aryl-hydrazinyl; heteroaryl 'heteroaryl-oxy; heteroaryl- Lower alkyl-oxy; heteroaryl-amino; heteroaryl-lower alkyl-amino; heteroaryl-thio; heteroaryl-lower alkyl-thio; heteroaryl- Lower alkyl; heteroaryl-sulfinyl; heterocyclic; heterocyclic-lower alkyl-oxy; heterocyclyl-oxy; heterocyclyl-amino; heterocyclyl-low carbon Pityl-amino; heterocyclyl-thio; heterocyclyl-lower alkyl-thio; heterocyclyl-lower alkyl; heterocyclyl-sulfinyl; cycloalkyl; cycloalkyl ·oxyl; cyclo-l-lower alkyl-oxy; cycloalkyl-amino; cycloalkyl-lower alkyl-amino; cycloalkyl-thio; cycloalkyl-lower Alkyl-thio group; cycloalkyl-low carbon, pit group; cycloalkyl-sulfinyl group; R6 represents hydrogen; lower alkyl group; or may form a heterocyclic group together with R1 - or a ring group _^____ -14-___——- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1303245 A7 B7 V. Invention description (12) Ring; X means oxygen: sulfur; -CH2 - Or a bond; Y represents a bond, -0-; -NH-; -NH-S02 - ; -NH-S02 -NH-; 0-CO-; -CO-0- ; -O-CO-NH - ; -NH-CO-O- ^ -NH-CO-NH-: Z represents oxygen or a bond; k represents an integer of 1, 2, 3, 4, 5 or 6; ϋ represents an integer of 2, 3, 4, 5 or 6; m represents an integer of 1, 2, 3, 4 or 5; P represents an integer 〇 (zero), 1, 2 or 3, and Z does not represent oxygen if p represents an integer 〇 (zero);

Ra represents an aryl group; a heteroaryl group; a lower alkyl group; a cycloalkyl group; a hydrogen; and an anthracene independently represents a hydrogen or a lower alkyl group;

Rd represents hydrogen; lower alkyl; aryl; heteroaryl; and optically pure para-isomer, mixture of para-isomers (eg racemate), optically pure diastereomers a mixture of diastereomers, an enantiomeric racemate, a mixture of diastereomeric racemates and a meso form, and a pharmaceutically acceptable salt. In the definition of formula I, unless otherwise stated, the term low carbon means a straight chain and a branched chain group having from one to seven carbon atoms, preferably from 1 to 4 carbon atoms. Examples of lower alkyl and lower alkoxy are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second-butyl, tert-butyl, pentyl Base, hexyl, heptyl, methoxy, ethoxy, propoxy, butoxy, isobutoxy, second-butoxy and tert-butoxy. The lower carbodialkyldioxy group is preferably a methylene-dioxy group and a hypoethyl-dioxy group. The practice of lower alkane fluorenyl __-15- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (13) Examples are acetyl group and propyl sulfhydryl And Ding Yuji. The lower carbene alkenyl group means, for example, a vinylidene group, a propylene group and a butylene group. The lower carbon and lower alkynyl groups are intended to be, for example, B: fefp, propyl, butyl, 2-methyl-propenyl and ethyl, propynyl, butynyl, pentynyl, 2 a group of -methyl-pentynyl. The lower fluorenyloxy group means a propyloxy group, an ethyl hexyloxy group and a propyleneoxy group. The term cycloalkyl means a saturated cyclic hydrocarbon ring having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may be halogenated, Hydroxy-lower alkyl, amine-lower alkyl and lower alkoxy-low carbon pit substituted. The term heterocyclyl means a saturated or unsaturated (but non-aromatic) four, five, six- or seven-membered ring containing one or two nitrogen, oxygen or sulfur atoms which may be the same or different. And the ring may be suitably substituted by a lower alkyl group or a lower alkoxy group, for example, a hexahydropyridyl group, a morpholinyl group, a thiomorpholine group, a hexahydropyridinyl group, a tetrahydropyranyl group, Hydroperyl, 1,4-dioxanthyl, tetrahydropyrrolyl, tetrahydrofuranyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyridyl, tetrahydropyrazolyl and having the above outlined A substituted derivative of such a ring of a substituent. The term heteroaryl means a six-membered aromatic ring containing one to four nitrogen atoms, a benzoquinone fused six-membered aromatic ring containing one to three nitrogen atoms, and a five-membered aromatic ring containing one or one nitrogen or a sulfur atom, a benzoquinone fused five-membered aromatic ring containing one oxygen or one nitrogen or one sulfur atom, a five-membered aromatic ring containing oxygen and nitrogen atoms, and a benzoquinone fused derivative thereof, containing sulfur and a nitrogen atom a five-membered family ring and a benzoquinone fused derivative thereof, a five-membered aromatic ring containing two nitrogen atoms, a benzoquinone fused derivative thereof, a five-membered aromatic ring containing three nitrogen atoms, and a benzoquinone thereof a fused derivative, or a tetrazolyl ring; for example, furyl, pyrenyl, pyrrolyl, pyridyl, pyrimidinyl, fluorenyl, quinolyl, iso-____-16- This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1303245 A7 B7____ V. Description of invention (14) 4 linoleyl, imidazolyl, tri-farming, pyrimidine, thiazolyl, iso-tetrazolyl, argon-based, vomiting Base, isoxazolyl, 5-keto-1,2,4-oxadiazolyl, 5-keto-1,2,4-thiadiazolyl, 5-thioketo-1,2,4 - oxadiazolyl, 2- Keto group·1,2,3,5#^ 二σ坐基' and wherein such a ring may be substituted by the following groups: low carbon pit group, lower alkenyl group, amine group, amine group lower alkyl group, Halogen, mercapto, lower alkoxy, trifluoromethoxy, trifluoromethyl, carboxyl, carboxylammonium, thioanthryl, fluorenyl, lower carbonyl thiol, cyano, a few A base-low carbon pit group, a low carbon pit group-oxy-lower alkyl group or another heteroaryl group or a heterocyclic group-ring. The term aryl means an unsubstituted and mono-, di- or tri-substituted aromatic ring having 6 to 10 carbon atoms, such as a phenyl or indenyl ring, which may be substituted by the following groups: aryl, _ , hydroxy, lower alkyl, lower carbon, lower alkynyl, lower alkoxy, lower alkoxy, lower alkynyl-lower alkyl-oxy, lower carbon, a lower carbitoloxy or lower carbodialkyloxy group having a five- or six-membered ring with a benzene ring, a hydroxy-lower alkyl group, a hydroxy-lower alkenyl group, a hydroxy group lower alkyl group Lower alkynyl, lower alkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-naphthenic Base, heterocyclic group, heteroaryl group. Salts encompassed by the term pharmaceutically acceptable salts can be formed with inorganic or organic acids, such as hydrogen from acids such as hydrochloric acid or hydrobromic acid; sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, and cis-butanedioic acid. , tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like, or if the compound is acidic in nature, is formed with an inorganic base, such as an alkali metal or alkaline earth metal base, such as sodium hydroxide, hydroxide Potassium, calcium hydroxide and the like. The compound of formula I may have one or more asymmetric carbon atoms and can be made into -17- This paper scale is applicable to China National Standard (CNS) Α4 specification (210 X 297 public»)----- 1303245 V. Invention Description (15) Optically pure para-isomers or diastereomers, para-isomers or diastereomers: mixtures of isomers, diastereomeric racemates, diastereoisomers a mixture of racemates, etc., as well as a meso form. The present invention covers all such forms. The mixture can be isolated in a manner known per se, that is, by column chromatography, thin layer chromatography, HPLC or crystallization. Because of the ability of the compounds of formula I and their pharmaceutically acceptable salts to inhibit endothelin binding, they are useful in the treatment of diseases associated with endothelial peptides that increase vascular contraction, agitation or inflammation. Examples of such diseases are hypertension, coronary disease, cardiac insufficiency, renal and cardiac gold deficiency, renal failure, cerebral heliorrhea, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, portal hypertension, and Pulmonary hypertension. It can also be used to treat or prevent atherosclerosis, restenosis after balloon or graft angiography, inflammation, stomach and duodenal ulcer, cancer, prostate hypertrophy, erectile dysfunction, hearing loss, cataract, chronic Tracheitis, asthma, Gram-negative septicemia, shock, sickle cell disease, spheroid nephritis, renal colic, glaucoma, treatment and prevention of diabetic complications, complications after blood vessel or heart surgery or organ transplantation Cyclosporine treatment complications, pain, hyperlipidemia, and other diseases currently known to be associated with endothelin. These compositions may be administered enterally or parentally, for example, as tablets, dragees, gelatin capsules, emulsions, solutions or suspensions, in nasal form, such as in the form of a mouth, or in the form of a suppository. These compounds can also be administered intramuscularly, parenterally or intravenously, e.g., in the form of injectable solutions. These pharmaceutical compositions can contain formulas! Compounds and pharmaceutically acceptable salts thereof 1303245 A7 B7 V. Inventive Note (16), and in combination with inorganic and/or organic excipients commonly used in the pharmaceutical industry, such as lactose, corn or derivatives thereof, talc, stearin Acid or a salt of these substances. As the gelatin capsule, vegetable oils, waxes, fats, liquid or semi-liquid polyols can be used. For the preparation of the solution and syrup, for example, water, polyol, sucrose, glucose can be used. The injectable preparation can be produced, for example, using water, a polyhydric alcohol, an alcohol, glycerin, vegetable oil, lecithin or liposome. Suppositories can be made from natural or hydrogenated oils, waxes, fatty acids (fat), liquid or semi-liquid polyols. The composition may additionally contain a preservative, a stability improving substance, a viscosity improving or regulating substance, a solubility improving substance, a sweetener, a dye, a taste improving compound, a salt for changing the osmotic pressure, a buffer or an antioxidant. The compounds of formula I may also be combined with one or more other therapeutically useful substances, such as or- and /?-blockers, such as testin, phenoxycholamine, amine 8i, and propranolol. ), timolol, methoxybenzol, carteolol and its analogues; vasodilators such as hydrazine, minoxidil, toluene or fluorosis Quinan; calcium-inhibitors, such as diltiazem, nicardipine, nimodipine, isoproterenol or nifedipine; AC £-inhibitors, for example Cilazapril, captopril, enalapril, lisinopril and their analogues; potassium activators such as Pinnacle Pinacidil; angiotensin II receptor antagonists, such as losartan, valsartan, irbesartan, and the like; diuretics, such as dihydrogen, 4 tillage, Thiazolidine, seletonide, butyl phenoxy acid, diuretic amine, metolazone or gas Ketone; anti-sympathetic-19 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 ____B7 V. Description of invention (17) God & medicines such as methyldopa, coronine Qonidine), guanabenz or reserpine, and other therapies used to treat high blood pressure or any heart condition. The dosage can vary over a wide range, but should be adjusted for specific conditions. In general, the daily dose given in an oral form should be between about 3 mg and about 3 g per adult having about 7 kg of body weight, preferably between about 1 mg and about 1 g, especially preferably Between 5 mg and 300 mg. This dose should preferably be administered in a weight of one to three parts per day. In the normal way, children should receive lower doses adjusted for weight and age. A preferred compound is a compound of formula I wherein R3 represents phenyl or a monosubstituted phenyl substituted with a lower alkoxy group (especially a methoxy group), and X represents oxygen' and its optically pure pair Isomers or diastereomers, mixtures of para-isomers or diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and meso forms And a pharmaceutically acceptable salt. A second preferred group of compounds of formula I is a monosubstituted phenyl group wherein R3 represents phenyl or is substituted by lower alkoxy (especially methoxy), X represents oxygen and R2 represents -(CH2)nY-Ra And optically pure collidine or diastereomers, mixtures of palmomers or diastereomers, diastereomeric racemates, diastereomeric Mixtures and meso forms of the rot, as well as pharmaceutically acceptable salts. A third preferred group of compounds of formula I is a monosubstituted phenyl group wherein R3 represents phenyl or is substituted by lower alkoxy (especially methoxy), X represents oxygen and represents -(CH2)2-〇 -Ra (wherein "heteroaryl"), and its optically pure mixture of palmier isomers or diastereomers, palmier isomers or diastereomers ___ ·20- Paper Scale_Central AA Standard (CNS) Α4 Specification (21G X 297 public f) 1303245 A7 B7 V. Description of Invention (18) Mixture of diastereoisomers, diastereomeric racemates And meso forms, as well as pharmaceutically acceptable salts. Another preferred compound is a compound of formula II r1\

乂K NH

Formula II R3

Wherein R1, R2, R3 and R4 are as defined in the above formula I, and optically pure para-isomers or diastereomers, palmier isomers or diastereoisomers of the compounds of formula II Mixtures of compounds, diastereomeric racemates, mixtures of diastereomeric racemates and meso forms, and pharmaceutically acceptable salts. Also preferred is a compound of formula III, 0 R1\ /S, Ν' Η

NH

-21 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm)

A

Formula III 1303245 A7 B7 V. Description of Invention (19) wherein R1, R2 and R4 are as defined above! Definitions, and A represents hydrogen, methyl, ethyl, sulphur, bromine, fluoro, trifluoromethyl or methoxy, and optically pure para-isomers or diastereomers of the hydrazine compound And a mixture of diastereomers or diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and meso forms, and pharmaceutically acceptable salts. Also preferred is a compound of formula IV

Wherein R1, R4 and n are as defined in the above formula I, and A is as defined in the above formula, and R5 represents hydrogen, lower alkyl, aryl, heteroaryl and cyclodecyl, and Optically pure para-isomer or diastereomer of a compound of formula IV, a mixture of para-isomers or diastereomers, diastereomeric racemates, diastereomeric eliminations Mixtures and meso forms of the rot, as well as pharmaceutically acceptable salts. Another group of compounds are compounds of formula V -22- This paper scale applies to Chinese National Standard (CMS) A4 size (210 X 297 mm) 1303245 A7

R

A

O

R5: wherein R is as defined in the above formula 1, A is as defined in the above formula III and R5 represents hydrogen, lower alkyl, aryl, heteroaryl and cycloalkyl, and $v An optically pure pair of palmier isomers or diastereomers, a mixture of palmo- or hetero-isomers, diastereomeric racemates, diastereomeric Mixtures and meso forms of the rot, as well as pharmaceutically acceptable salts. Preferred compounds of the formula V compound are those wherein rS represents a heteroaryl group and its optically pure para-isomer or diastereomer, palmomere or diastereomer. Mixtures, diastereomeric racemates, mixtures of diastereomeric racemates and meso forms, and pharmaceutically acceptable salts. Preferred compounds are: pyridin-2-yl-amine methyl acid 2-[5-(2-methoxy-phenoxy) each (nonylaminosulfonic acid -23- This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1303245 A7 B7 V. Description of invention (21) Amidino)-[2,2*]dipyrimidinyloxy]-ethyl ester; Pyridin-2-yl· Aminomethyl 2-(5-(2-methoxy-phenoxy)-6-(4-methoxy-decylaminosulfonylguanidino)-[2,2']dipyrimidine-4 -yloxy]-ethyl ester·, mercaptoaminosulfonic acid [6·[2-(5-bromo-pyrimidin-2-yloxy)·ethoxy]-5-(2-methoxy -phenoxy)-[2,2']dipyrimidin-4-yl]-decylamine; cyclopropylmethylaminosulfonic acid [6-[2-(5-bromo-pyrimidin-2-yloxy) )-ethoxy]-5-(2·methoxy-phenoxy)-[2,Γ]dipyrimidin-4-yl]-decylamine; furan-2-yl-methylaminosulfonic acid [ 6-[2-(5-Bromopyridin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2*]dipyrimidin-4-yl] - guanamine; cyclopropylamino continued acid [6-[2-(5-, / odoro-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy )-[2,2"|dipyrimidin-4-yl]-decylamine; benzylaminosulfonic acid-[6·[2-(5-bromo-pyrimidin-2-yl) Ethyl)-ethoxy]-5-(2-methoxy-phenoxy)·π-dip-4-yl]-g-amine; mercaptoaminosulfonic acid-[5_(2-gas-5) -methoxy-phenoxy)-6-[2_(5-methylthio-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl]-nonanamine; furan-2-yl -Methylaminosulfonic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(4•gas-winter-precipitate-4·yl]- Amine; cyclopropylmethylamino acid [5-(4-carbo-phenyl)-6-[2-(5-methoxy-u-milyl-2-yloxy)-ethoxy] -a lysyl-4-yl]-S&amine; cyclopropylmethylamino glutamic acid [6-[2-(5. bromo- shout-2-yloxy)-ethoxy]-5 -(4-murine-mugi)-σ-amyl-4-yl]-bristamine; cyclopropylmethylaminosulfonic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)) -ethoxy]-5-p-tolyl-pyrimidin-4-yl]-decylamine; alkylamine-based acid [6-[2-(5-[Moline]-2-yloxy)- Ethoxy]-2·峨 -4--4-yl-24- This paper scale is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1303245 A7 B7 V. Invention description (22) -5-pair Tolyl-pyrimidin-4-yl]-decylamine; benzylamino acid [6-[2-(5-bromo-pyrimidin-2-yloxy)ethoxy]-5-(4-gas -stupid Base)_2-p-precipitate-4-yl-α-density 4-yl]-bristamine; ethylaminosulfonic acid 0 (4-gas-phenyl) each [2-(5-methylthio-pyrimidine) -2-yloxyethoxy]-pyrimidinyl]-decylamine; ethylamino methic acid [5-(4-rh-phenyl)-6-[2-(5-bromo-π-mystosis) -2-yloxy)-ethoxy]-α-amyl-4-yl]-83⁄4 amine; ethylaminotransacid [5-(4-di-phenyl)-6-[2-(5 -Methylthio-σ-dense-2-yloxy)-ethoxy]pyrimidin-4-yl]-decylamine; More preferred compound: Henrylamine-based acid [6-[2-(5 - repeatedly - yttrium 2-yloxy)-ethyloxy]-5-(4-a-phenyl)-3⁄4 ylide-4-yl]• Stuffed fer * fluorenyl sulfonic acid [6- [2-(5-Bromo-pyrimidin-2-yloxy)-ethoxy]-5-(4-bromo-phenyl)- shie-4-yl]--L-amine, 2-pyridylmethyl Aminosulfonic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(4-a-phenyl)-m-butyl-4-yl]-decylamine ; thiophene methylamine traversal [6-[2-(5-溪-σ密密-2-yloxy)yl)-ethylidyl]-5·(4-a-phenyl)-pyrimidine 4-yl]-nonylamine; mercaptoaminosulfonic acid [5-(2-a-5-methoxy-phenoxy)-6-[2-(5-bromo-pyrimidin-2-yloxy) ))-ethoxy]-pyrimidine 4-yl]-guanamine; optimal combination Is: mercaptoaminosulfonic acid [6-0(5-methylthio-pyrimidin-2-yloxy)-ethoxy]-5-(4-bromo-phenyl)---------- Ethylamine-ethylamine; ethylamino glutamic acid [5-(4-carbo-phenyl)-6-[2-(5-> odor-pyran-2-yloxy)-ethoxy-25 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (23) Base]"•Kaolin-4-yl]-Siamine; and its pharmacy Acceptable salt. Another set of preferred compounds is depicted below: -26- This paper scale uses Chinese National Standard (CNS) A4 size (210 X 297 mm) 1303245 A7 B7 V. Description of invention (24)

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7

1303245 A7 B7 V. Description of invention (26)

N:, SN .90 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1303245 A7 B7 V. Description of invention (27

Binding paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Invention description (28)

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7

The compounds of the formula I of the present invention may be simplified and apparent in light of the general series of reactions t outlined below, and sometimes only the portion of the possible methods which result in the synthesis of the compounds of formula I are described. The literature reference series shown in (4) is not at the end of this paragraph. Possible Method A · The desired compound of Formula 1 can be via a compound of Formula 1:

Wherein G1 is a reactive residue, preferably a fluorenyl group, and the other symbols are as defined in the above formula I, and are reacted with a compound of formula 2: R2—〇H, formula 2 or a salt thereof. Wherein the symbols are the same as those defined in the above formula I. Possible method B: The compound of formula I can also be via a compound of formula 3:

1303245 A7 B7 V. Description of invention (3〇) R1

X * N NH Η R4

.R3 Ο Equation 3 (CH2)n

Ck Ή wherein the symbols are the same as those defined in the above formula I, or a salt thereof is reacted with the compound of formula 4: G2 - R5 wherein 4 G2 is a reactive residue, preferably a halogen atom, and R5 is a Same as defined in the above formula iv. Possible method C: The compound of formula I may also be via a compound of formula 5:

Equation 5

-33- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (31) where G3 is a low carbon pit base or a benzene base or a halogen An atom, and the other symbols are the same as those described in the above formula I, or a salt thereof is reacted with a compound of the formula 6: R4·-Η 6 wherein R4 represents: N— 〈〉n— / \ HO / N ...* \ lower alkyl H3C-Ν fsj-, N- '~^^ ~~ cycloalkyl, 〇-, 〇-Ο-N··" ring: t-based \low-carbon aryl aryl ring Hyunji\Low Carbon Tiger Base\HN·... HV ... hV“ /N•... /N ...· Possible methods A to C are also referred to [5] This paper scale applies to China National Standard (CNS) A4 specification (210 X 297) PCT) 1303245

This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1303245 A7 B7 V. Description of invention (33) a) NaOMe, MeOH followed by NH4 Cl; b) K2 C03, acetone, rflx; c) NaOMe, MeOH d) P〇Cl3, N,N-dimethylaniline, 70-130 ° C; e) 8, DMSO ·, f) Na, ethylene glycol; 80-100 ° C; g) ll, THF, NaH, Rt-70 °C. In Scheme 1, the synthetic procedure for the preparation of compounds of formula I is illustrated by the synthetic description of Example 3 and Example 5. Other examples given in this document can be made by the same synthetic route, but by adjusting the substituents and reaction conditions. The literature reference series shown in [] is shown at the end of this paragraph. The hydrazine 2 system is synthesized by standard procedure [1], wherein an appropriate nitrile 1 is reacted with sodium methoxide in methanol, followed by the addition of ammonium hydride. The 2-substituted malonic esters 3 were prepared according to the procedure [2], wherein dimethyl alkoxymalonate (5) was reacted with an appropriate alcohol 4 in acetone, and potassium carbonate was used as a base. Compound 3 was dissolved in methanol, sodium methoxide was added, and stirring was continued for about 30 minutes, followed by the addition of hydrazine derivative 2. Continue to drop for another 8 hours at ambient temperature. After the acidic treatment, it can be from 70 to 90. . Yield 4,6-dihydroxypyrimidine 6 [2]. Converting compound 6 or its tautomeric form to dioxane derivative 7 [3] in the presence of high temperature (60·120 C) and hydrazine, xylene-xylyleneamine, yield 40 to 75 %. Disulfide 7 is reacted with an excess of the appropriate thioguanamine clock salt 8 (prepared as described in Scheme 3) in DMSO at room temperature or 40 to 60 C to give a monogas-caloxide, from The yield of the vinegar is determined to be 70 to 90% after the recrystallization of the ether/ethyl ether or the chromatography of the sulphuric acid with ethyl acetoacetate/heptazone. The pyrimidine derivative 9 is then reacted with ethylene glycol (or another l-ω-diol or monol) in the presence of a base such as potassium butyrate, sodium hydride or sodium at 80-110 ° C. The reaction is carried out for 4 to 16 hours, and the compound 1 is obtained as the first requested compound' yield of 50 to 70. . By using it at room temperature or 50-70 ° C with 2-gas-5. bromopyrimidine (11) (or another suitable pyrimidine or pyridine-36 - this paper size is applicable to the SS standard (CNS) A4 specification. (210X 297 mm) "" ---

Binding

k

1303245 A7 B7 V. INSTRUCTION DESCRIPTION (34) The derivative is reacted in THF/DMF~5/1 to further convert it to compound 12 in a yield of 50-80. . . Figure 2: A graphical representation of the synthesis of examples 47, 48, 50, 51, 53:

___-37- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (35) a) NaOMe, MeOH, rflx; b) Propargyl alcohol, NaH, THF, rflx; c) ethylene glycol, KotBii, 11 (TC: d) NaH, THF followed by 5-bromo-2-pyrimidine, 70 ° C: e) acridine-2-mercapto azide, CDCI3 , 70 ° C, 2 hours, followed by Example 47, 70 X:, 16 hours. Further experimental explanations refer to [1], [2], [3], [5], [6] and [9]. Scheme 3: Preparation of thioguanamine moiety [1〇], [11], [12], [13], [14], [15] and [19], and preparation of substituted pyrimidines [ 16],[17]··

NEt3, DCM

HCI/dioxane

Binding

KOtBu / MeOH NH2

C)

61% Βγ2, H20

POCI3 N, N-dimethylamine Rflx, 6ht 84%

-38- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

A B c D 1303245 VI. Patent Application No. 7 In the figure 4, the symbol indicates the same as defined in the above formula I. [1] W. Gohring, J. Schildknecht, M. Federspiel; Chimia, 1996, 50, 538-543.

[2] W. Neidhart, V. Breu, D. Bur, K. Burri, M. Clozel, G. Hirth, M. Muller, HP Wessel, H. Ramuz; Chimia, 1996, 50, 519-524 and References cited.

[3] W. Neidhart, V. BreuK. Burri, M. Clozel, G. Hirth, U. Klinkhammer, T. Giller, H. Ramuz; Bioorg. Med. Chem. Lett., 1997, 7, 2223-2228. RA Nugent, ST Schlachter, MJ Murphy, GJ Cleek, TJ Poel, DG Whishka, DR Gr aber, Y. Yagi, BJ Keiser, RA Olmsted, LA Kopta, SM Swaney, SMPo ppe, Morris, WG Tarpley, RC Thomas J. Med. Chem" 1998, 41, 3793-3803.

[4] J. March; Advanced Organic Chemistry 4th Edition, 1994, page 499 and references cited therein [5] EP 0 743 307 Al; EP 0 658 548 Bl; EP 0 959 072 A1 (Tanabe Seiyaku [6] EP 0 633 259 Bl; EP 0 526 708 Al; WO 96/19459 (F. Hoffmann-LaRoche) [7] For the synthesis of 5-membered heterocycles, see: Y·Kohara et al; J. Med Chem., 1996, 39, 5228-5235 and references cited therein.

[8] EP 0 882 719 A1 (Yamanouchi Pharmaceuticals) [9] a) R. Graf; Ch^m. Ber., 1959, 92, 509-513. b) G. Weiss, G. Schulze;

Liebigs Ann. Chem., 1969, 729, 40-51. c) J. A. Kloek, K. L. Leschinsky, J. Org. Chem., 1976, 41, 4028-4029. d) R. P. Dickinson, K. N. Dack, C. J.

Long, J. Steele; J. Med. Chem., 1997, 40, 3442-3452. e) E. Cohen, B. Klarberg; J. Am. Chem. Soc, 1962, 84, 1994-2002.

[10] E. Cohen, B. Klarberg; J. Am. Chem. Soc., 1962, 84, 1994. ______ -40- __ This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm)

AB c D 1303245 VI. Application for Patent Model 8 [11] G. Weiss, G. Schulze, Liebigs Ann Chem., 1969, 729, 40· [12] R. Graf, Chem. Ber., 1959, 92, 509.

[13] J. A. Kloek, K. L. Leschinsky, J. Org. Chem” 1976, 41, 4028.

[14] R. E. Olson, T. M. Sielecki et al; J. Med·Chem·, 1999; 42, 1178· [15] R·P·Dickinson, Κ·N. Dack et al; J· Med · Chem·, 1997; 40, 3442.

[16] D. G. Crosby, R. V. Berthold; J. Org. Chem. 5 1960; 25; 1916.

[17] Bayer AG (Maurer, F.; Hammann, I.; Behrenz, W.); US-4, 233, 294 1980.

[18] E. D. Morgan; Tetrahedron, 1967, 23, 1735.

[19] M. J. Tozer, IM Buck et al; Bioorg· Med. Chem. Lett., 1999, 9, 3103. G. Dewynter et al; Tetrahedron, 1993, 49, 65. Examples The following examples are illustrative invention. All temperatures are based on. C indicates. List of abbreviations:

EtOAc ethyl acetate CyHex cyclohexane Hex hexane DMSO dimethyl hydrazine THF tetrahydrofuran MCPBA m-benzoic acid DMF dimethylformamide DCM two gas methane HV high hollow condition rt room temperature tR retention time -41 - 1303245 A7 B7 V. INSTRUCTIONS (39 min DBU DMAP rflx min 1,8-diazabicycloindole [5.4.0] eleven-7-ene (1,5-5) 4-dimethylaminopyridine reflow binding the following compounds It was prepared according to the procedure described above and shown in Figures 1 to 4. All compounds were characterized by lH-NMR (300 MHz) and sometimes by 130 NMR (75 MHz) (Varian Oxford, 300 MHz; chemical shift system) Expressed in ppm relative to the solvent used; multiplicity: s = singlet, d = doublet, t = triplet; m = multiplet), by LC-MS (Waters Micromass; with ESI-probe and joint 2790 HT ZMD-platform; column: 2x30 mm, Gromsil 0DS4, 3 micron, 120A; gradient: 0-100% acetonitrile in water, 6 minutes, containing 0.05 ° / formic acid, flow: 0.45 ml / min ;tR is expressed in minutes), by TLC (TLC-plate from Merck, silicone 60 F2 5 4) and sometimes by melting Identified Reference Example (Synthesis of the precursors): Referential Example 1:

a) Add sodium to a solution of sodium (0.23 g) in methanol (40 ml). % -42 This paper scale applies to China National Standard (CNS) A4 size (210X 297 mm) 1303245 A8 B8 C8 D8

Apply for the patent Fan Guozheng 4-individual bite (_g>. Continue to stir 6 small ^ (5 9 ^ ^ it ϋ ^ 4fa 1L 〇· 接 * I, Tai Li mouth fluorination record * 0 · 9 grams) And continue to stir another 10 small bucket, η 士 \ ”, silly, add ether (120 ml), and after 30 minutes, filter out the precipitate JP as a AG shout wash (2 〇 ml). =. 8 g) stirred suspension in acetone _ ml), followed by heating to 45. Then add dimethyl kelic malonic acid vinegar (6) 2 ml in 20 minutes) in acetone (50 liters) The solution was heated to reflux for 16 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in water and extracted. </ RTI> </ RTI> </ RTI> (the organic layer was dried over sodium sulfate (tetra) and evaporated. The product was crystallized from tri-butyl-methyl-ether to obtain dimethyl-(o-methoxyphenoxy)malonate (86 g). c) sodium methoxide (9·7 g) Add dimethyl(o-methoxyphenoxy)malonate (21.7 g) in methanol (50 ml) over 15 min in a stirred solution of methanol (100 mL) Dissolve Stirring was continued for 3 minutes, followed by the addition of 4·methylmercapto-pyridine hydrochloride (15.0 g) and stirred at room temperature for 2 hrs. The reaction mixture was concentrated in sputum. The solid residue was stirred with ether. The obtained powder was filtered off and dissolved in water (3 mL). Acetic acid was added to pH = 4. The precipitated product was filtered, washed with water and dried at room temperature at 5 ° C. -(o-methoxyphenoxy)-4,6-di-based-2-(4-indolyl)-pyridine (20.1 g) (may also exist as tautomers &gt; (o-A) Oxyphenoxy)-2-(4-pyridyl)-tetrahydropyrimidine-4,6-dione) d) 5-(o-methoxyxyoxy)-4,6-di Several bases-2-(4-0 ratio bite base bite (10g) ____-43- This paper scale applies to the Chinese national standard rate (CNS> Α4 size (210 X 297 mm) 1303245 A7 B7 V. Invention description ( 41), N-diisopropylethylamine (11.2 g), vaporized tetraethylammonium (11 g) and phosphorus pentoxide (13.8 g) dissolved in phosphorus oxide (25 ml) and heated to reflux 3 Hour the mixture in the air, add toluene and steam again The mixture was dissolved in DCM and poured into ice/water. The layers were separated, washed with water, dried over sodium sulfate and evaporated. After recrystallization from acetone, 4,6-di-hexane-5 -(o-methoxyphenoxy)-(2-(44 pyridine)-pyrimidine (6.52 g). e) 4-Iso-propyl-anilinosulfonyl decylamine (642 mg; Reference Example 17) Sodium hydride (250 mg) was added to a solution in DMF (9 mL). The mixture was allowed to warm to 45 ° C for 30 minutes, then 4,6-di-gas-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (1.044 g) was added. The reaction mixture was stirred at room temperature for 60 hours. After acid treatment and chromatography on ruthenium with hexane / EtOAc = 2/5, 4-iso-propyl-anilinosulfonic acid-[6-gas-5-(o-methoxy-phenoxy) can be isolated. 2-(4-pyridyl) pralinyl]-nonylamine (0.42 g). Reference example 2:

a) 4,6-dihydroxy-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine [or its tautomer 5-(o-methoxyphenoxy) )-2-(2-σ-Bite)-Tetrahydro-Sigma-Sensor 4,6-Dione], as described in EP 0 526 708 A1, from 2-methylindenyl-cyclohexane and dimethyl Base-(o-methoxyphenoxy)malonate. b) 4,6-dioxa-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine, such as — -- -- -- -- -------- - __________ ——p—— This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Invention description (42) EP 0 526 708 A1 Revised from 4,6-dihydroxy-5-(o-methoxyxylenyl)-2-(2-pyrimidinyl)-pyrimidine (which may also be in the form of tautomers 5-(o-A) Oxyphenoxyl)-tetrahydro-[alpha]-precipitated 4,6-dione is present). Reference example 3:

a) A solution of dimethyl-(o-methoxyphenoxy)malonate (1 g) in anhydrous methanol (80 mL) was cooled to EtOAc. Sodium methoxide (6.71 g) was added in portions. To the suspension was added acetamidine hydrochloride (2.84 g), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the~~~~~ The solid was filtered, washed with EtOAc (EtOAc)EtOAc The pH was adjusted to 4 by the addition of glacial acetic acid (25 mL). The white precipitate formed was filtered off, washed with water and dried to give 5-(o-methoxyphenoxy)-4,6-di-propyl-2-methyl-snack (5.17 g). (or tautomer) as a white powder. b) a solution of 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-methyl-pyridine (10.9 g) (or tautomer) in POC 13 (150 ml) 5 (TC was stirred for 72 hours. Excess P0C13 was evaporated, toluene was added to co-evaporate a small amount of p〇ci3. Finally, the ice/water mixture was carefully added to the residue, and the pH was adjusted to 8 using a 3N sodium hydroxide solution. The mixture was further diluted with water (300 mL) and EtOAc (EtOAc)EtOAc. The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (43) In DCM, it is filtered through a silicone gasket and dissolved in DCM. The solvent is removed in the air. The residue was formed to supply 4,6·dioxa o-methoxyphenoxy)-2-methyl-sigmine (8.7 g) as a beige powder. Reference example 4:

a) A solution of dimethyl-(o-methoxyphenoxy)malonate (32.75 g) in methanol (250 mL) was cooled to 0. Sodium methoxide (20.0 g) was added portionwise, and the mixture was stirred at room temperature for 6 hours upon completion of the addition. Then, morpholinylguanidine hydrobromide (25.0 g) was added and stirring was continued for 72 hours. The solvent of the beige suspension was evaporated and the residue was washed twice with diethyl ether (150 ml). The residual powder was dissolved in water (200 ml). When the pH was adjusted to 4 with acetic acid (50 ml), a sediment was formed. The precipitate was collected, washed with water and dried under high openness to give 5-(o-methoxyphenoxy)-4,6-di-diyl-2-(N-moffolinyl)-σ A bite (17.01 g) (or tautomer) with a slightly beige powder. b) Carefully add POCI3 (50 mL) to Hunig's base (27.5 mL) at 0 °C. To this mixture was added 5-(o-methoxyphenoxy)-4,6-dimethyl-2-(N-norfos)-pyrimidine (17 g) in portions. The resulting mixture was allowed to fall overnight at i3 °C. Excess reagent was evaporated and traces of POCI3 were removed by co-evaporation with toluene. The black residue is a mixture of DCM (50 ml) and water/ice _____________-4β - ___ κ This paper scale is in Chinese National Standard (CNS) Α4 size (210Χ 297 mm) &quot; ~ - 1303245 A7 ——____B7_______ V. Description of invention (44) (3 liters) processing. After stirring for 15 minutes, the mixture was diluted with water (4 mL) and DCM (400 mL). The organic layer was separated and washed with water (3 Torr). The aqueous layer was extracted with DCM (400 mL). The combined DCM layers were dehydrated with % s 〇 4 and the solvent was removed to a volume of approximately 1 liter. The residual solution was filtered on silica gel (50 g) and dissolved in DCM. The filtrate was evaporated. The resulting residue was suspended in diethyl ether (50 mL). The solid was filtered off and dried to give 4,6-diox·5-(Zheng-methoxyphenoxy)·2-(ν-morpholinyl)-pyrimidine (13.85 g) as a white shame Powder. Reference example 5:

a) Sodium decoxide (12.7 g) was added in portions to dimethyl-(o-methoxyphenoxy)malonate (18·9 g) in methanol (450 ml) at 5 °C. Within the solution. Upon completion of the addition, the mixture was continuously stirred at room temperature for 30 minutes, followed by the addition of formazan hydrochloride (6 g). The mixture was stirred at room temperature for 72 hours. Finally, the solvent was removed under reduced pressure and the residue was suspended in diethyl ether. The solid material was filtered off and dissolved in water (100 mL). The solution was acidified with concentrated hydrochloric acid. A white precipitate formed. The precipitate was collected, washed with water and dried to give 5-(o-methoxyphenoxy)-4,6-dihydroxy^-pyridine (15.1 g) (or tautomer) as a white powder. . b) Add N,N-dimethylaniline to a solution of 5-(o-methoxyphenoxy)-4,6-dihydroxypyridine (7.5 g) in P〇Cl3 (90 liters) (24 ml). Mixture 1 _ -47- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1303245 A7 __ B7 ______ V. Description of invention (45) Heat to 160 ° C and stir for 2.5 hours. Excess POCy was distilled off under reduced pressure. The trace POCI3 system was co-evaporated with toluene. The residual oil was treated with a water·ice mixture. The mixture was acidified with 1N hydrochloric acid and extracted twice with EtOAc. The combined organic layers were washed twice with dilute aqueous hydrochloric acid to dryness and evaporated. The residual solid was washed with methanol and dried. This gave 4,6-di-gas-5-(o-methoxyoxybutoxylate (4.75 g)' as a pale yellow powder. Reference Example 6 ··

a) A solution of sodium methoxide (6.8 g) in methanol (200 mL) was cooled to hydr. (:. Slowly add a solution of 2-(p-tolyl)-malonic acid diethyl ester (1 〇 3 g) in methanol (5 〇 ml). When the mash is added, warm the solution to the chamber. The mixture was warmed and added with <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; The solution was extracted with diethyl ether, and then adjusted to pH 5 with a 10 NaOH solution. The precipitate was formed. The precipitate was collected, washed with cold water and dried at 60 ° C under high hollowing. This gave 4,6·2 Hydroxy-2-(4-pyridyl)&gt;5•(p. _ phenyl)- shouting (8.77 g) (or tautomer), which is an orange crystal. b) at 4,6- Add 2-ethylamine (25 ml) at room temperature in a mixture of -2-(4-7 ratio)-5-(p-carbyl) sebiter (8 g) and POCI3 (100 ml) The mixture was stirred at 60 ° C for 16 hours. Excess p〇cu -:--------- -- 4R -______ was distilled under reduced pressure. This paper was applicable to China National Standard (CNS) A4. Specifications (210 X 297 mm) 1303245 A7 B7 V. Description of invention ( The residue was taken up in water (3 mL). Dehydration drying and evaporation. The resulting residue is suspended in isopropanol. The solid material is collected, washed with isopropanol and diethyl ether and dried to give a 4,6-diox ratio of the base -5-( P-tolyl)_. The precipitate (7.2 g) was a white crystalline powder. Reference example 7:

a) A solution of 2-(p-tolyl)-malonic acid diethyl ester (ΐ4·2 g) in methanol (5 mL) was slowly added to sodium methoxide (9.4 g) at 0 °C. In a solution of methanol (3 mL). Upon completion of the addition, the mixture was allowed to warm and the formazan hydrochloride (5.4 g) was added. The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was purified mjjjjjjj This suspension was stirred for 0.5 hours. The pH was carefully adjusted to 4 using a 10 Torr sodium hydroxide solution at 〇-5 °C. The sediments were collected, washed with cold water, isopropanol and washed at 65 眞 under high open air to give 4,6-dihydroxy-5-(p-methylphenyl)-pyrimidine (11.2 g) (or Tautomer), as a white powder. b) Add hydrazine, hydrazine-xylyleneamine (10 ml) to a mixture of 4,6-diamino-5, (p-tolyl)-pyrimidine (5.1 g) and POCI3 (75 ml) at room temperature Inside. The anti-mad mixture was stirred at 70 ° C for 16 hours. Excess P〇Cl3 was distilled off, and the residual oil was treated with ice: water: and extracted three times with diethyl ether. The combined organic layers were applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 (8) aqueous hydrochloric acid solution, followed by brine washing, dehydration drying with MgS〇4 and evaporation. The residual brown oil was crystallized from isopropanol. Light yellow crystals were collected, washed with cold iso-alcohol and dried under high hollow to supply 4,6-di-gas ice (p-tolypyrimidine (4.1 g). Reference Example 8:

a) Add dimethyl-(2. methoxyphenoxy)malonic acid g (2 Ug) to a solution of sodium (5.17 g) in methanol (2 liters) and make the mixture Stir at room temperature for 30 minutes. To the slurry, cyclopropylguanidine hydrochloride (12 g) was added. The mixture was allowed to stir for 22 hours at a temperature. Finally, remove the solvent in the air. The remaining residue was suspended in diethyl ether (25 mL). The ether was poured off and the residual solid was taken in water (250 mL). Take 25〇/. The aqueous solution of hydrochloric acid is acidified. The resulting precipitate was collected, washed with water and dried at 6 Torr under high open air, and 5-(2-methoxyphenoxy) 4,6-dihydroxy-2-cyclopropyl amide was known. (19·26 g), a typical color powder. LC-MS: tR = 2.74 min [M+l]+= 275.24, [Μ-1 卜 273.29· b) at 5-(2-methoxyphenoxy) 4·6-Dihydroxyindolecyclopropyl-pyrimidine (8 g) In a suspension of P〇Cl3 (87 ml), hydrazine, s-tritylamine (12 ml) was added. The mixture became clear and was shaken for 3 hours at 13 (TC). Excess POCI3 was removed in the air, and the residual micropoq was co-evaporated with toluene. The residual slurry was poured into an ice-water mixture, and the resulting solution was diethyl ether. Extraction three times -----, ^, 50,. This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Invention description (48). The organic layers are combined to 1N hydrochloric acid. The aqueous solution was washed once and washed twice with water, treated with activated charcoal, dehydrated with MgS04 and evaporated. The residue was crystallized from diethyl ether/hexane to give 4,6-di-s--2-cyclopropyl-5-(2) -Methoxyphenoxy)-pyrimidine (6.64 g) was a beige powder. LC-MS: tR = 5.36 min [M+l]+ = 311.19. Reference Example 9: According to Reference Examples 1 to 8 and the literature [2 The procedures described in [3], [5], [6] and [8] were used to prepare the following 4,6-dioxapyrimidine precursors.

_____-51 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) binding

k

1303245 A7 B7 V. Description of invention (49) Reference example 10 ··

Sodium hydride (42 mg) was added to a solution of 4-t-butyl-anilinium sulfonamide (228 mg, mp. Then, 4,6-dioxa-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (305 mg) was added with a Honig base (0.17 ml), and the reaction mixture was 6〇. . Stir for 5 hours. After acid treatment and crystallization, the third butyl-anilinosulfonic acid · [6-gas-5-(o-methoxyphenoxy)-2-(4-pyridyl) winter can be isolated. Pyrimidinyl&gt; decylamine (〇15 g). tR = 5.54 minutes (l〇 ; [m+H]+= 540.44 (ES+); Reference example 11:

The subsequence described in the order of 5-methyl-pyridin-2-aminosulfonate guanamine (252 mg, succinctly) and 4,6-digas-5_ (o-A) Oxyphenoxy)-binding

1303245 A7 B7 V. Description of the invention (5〇) 2-(4-Pyridyl)-pyrimidine (410 mg, see example ld)), which gives 5·methyl·pyridin-2-aminotransacid-[6 - gas-5-(o-methoxyphenoxy). 2-(4-ρ ratio) _4 "milk base" - decylamine (100 mg). tR = 4.02 min (LC); [M +H]+ = 499.33 (ES+); Reference example 12:

According to the procedure described in Reference Example le), pyridinium sulfonate decylamine (6 〇 克 'Reference Example 21) and 4,6-dioxa-5-(o-methoxyphenoxy)- 2-(4•pyridyl P-bite (100 mg, reference example M)) was reacted to give pyridinyl sulfonate (o-methoxyphenoxy)-2-(4-pyridyl) Winter calls pyridine]-guanamine (10 〇 mg). tR = 3.83 minutes (LC); [M-H]+ = 483.33 (ES-); Reference example 13:

_ According to the reference example! The procedure described in e), the ethylaminosuccinylamine (40 &quot; Reference Example 22) and 4,6-di-5-(o-methoxyphenoxy)-2-(4) ^Bite

A4 size (210 X 297 mm) 1303245 A7 B7 V. Description of the invention (51 base) - pyrimidine (100 gram, reference example ld)) reaction, and get pyridine 2 - amino sulfonic acid - [6-gas Winter (o-methoxyphenoxy...pyridyl) pralidyryl]-nonylamine (7 mg). tR=4.40 minutes (LC); (10) Qi Bu hunnation sand);

Reference Example 14: In a solution of 4,6-dichloro-5-p-tolyl-pyridinium (Reference Example 7) (2 g) dissolved in dms (35 ml), di-isopropyl group was added. _Ethyl-amine (1 46 ml), followed by potassium 4-methyl-anilinium sulfonate (2·78 g) [produced from the product described in Reference Example 19 and the third in methanol Potassium butyrate, followed by evaporation of the solvent]. The mixture was stirred at room temperature for 48 hours, then poured into water (5 liters), diethyl ether (250 liters) was added and the solution was stirred for 3 hrs. The layers were separated and the aqueous layer was acidified with EtOAc (EtOAc) It took 丨 hours. The precipitated product was filtered off, washed with water and diethyl ether and dried to give &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&& 2 grams). tR=5.00 minutes (LC); [M+H]+= 389,11 (ES+); Reference example 15:

This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm)

AB c D 1303245 VI. Scope of application 2 in a solution of 4,6-diox-5-(4-a-phenyl)-pyrimidine (Reference Example 9) (2.59 g) dissolved in DMSO (14 ml) Di-isopropyl-ethyl-amine (1.8 ml) was added followed by potassium decylamine sulfonate (2.25 g) [made from the product described in Reference Example 22 and the third in methanol - Potassium butyrate, followed by evaporation of the solvent]. The mixture was stirred at room temperature for 24 hours then poured over water (300 mL). The liquid layer was separated, and the aqueous layer was acidified with solid citric acid (pH == 3) and cooled to 0 ° C for one hour. The precipitated product is filtered off, washed with water and recrystallized from methanol to give benzylaminosulfonylfes-[6-gas-5-(p-gas-woody)-4-0-dense base]S stupid Amine (1.8 g). tR=4.94 minutes (LC) ; [M+H]+= 410.90 (ES+); __-55- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (53) Reference Example 16: According to the procedure for synthesizing Reference Example 15, the following compounds were prepared.

LC-MS: tR: 4.84; [M+H]+: 414.77

N XI LC-MS: tR: 4.66; (M+H)+: 400.88

LC-MS: tR: 4.76; [M-Hf: 351.03 V

NH

N, CI LC-MS: tR: 5.10; [M+Hf: 403.05 0,

U H

N

N, CI (Xs

v N , NH

N XI

LC-MS: tR: 4.84; [M+Hf: 466.11° X° N^NHH LC-MS: tR: 4.65; [M+H]+: 375.05

N

N,, CI v° (Xv LC-MS: tR: 4.45; [M+H]+: 453.03

N XI LC-MS: tR: 5.06; [M+H]+: 486.01 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1303245 A7 B7

This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1303245 A7

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

Binding

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1303245 A7 B7

This paper scale applies to the Chinese National Standard &lt;CNS) A4 Specification (210 x 297 mm) Binding

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1303245 A7 B7

This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1303245 A7 B7

1303245 A7 B7 V. INSTRUCTIONS (59) REFERENCE EXAMPLE 16 (continued) Δ °^°

Br LC-MS: tR: 4.41; [M+Hf: 392.95 LC-MS: tR: 4.61; [M+H]+: 360,99

Synthesis of amide sulfonamide: Aminesulfonyl group (NH2-S〇2-Cl) was prepared according to the procedures shown in [11] and [12]. Reference Example 17: 4-iso-propylaniline (25.6 ml) was added via a funnel at 0 ° C over a solution of the aminesulfonyl group in benzene (0.09 mol in 70 ml). The suspension was diluted with benzene (80 mL) and stirred for 20 min. Add NaOHaq (36 ml-62- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1303245 A7 B7 V. Invention description (6〇) ' 5N) 'And make this suspension fully vibrating Do it. Add £tQAC (500 mL) and add concentrated hydrochloric acid under ice cooling until pH = 6. The water was separated and evaporated to Et. The brown residue was shaken twice in a pit, followed by a sodium hydroxide/glutle solution (5N). The mixture was extracted three times with ugly. The aqueous layer was cooled to 〇 ° c and the pH was adjusted to 2 by the addition of concentrated hydrochloric acid. The product was precipitated and filtered off and washed with cold water. After drying at high open air, winter isopropyl-phenyl-aminosulfonate (3.47 g) was obtained. Reference example 18:

According to the procedure described in Reference Example 17, 't-butyl phenyl-amino decanoate was prepared. Reference example 19:

According to the procedure described in Referential Example 17, methyl phenyl-aminosulfonate decylamine was produced. Reference example 20:

This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (61) in 2-amino-5-methylpyramidine (3.24 g) in THF (30 love Sodium hydride (1.2 g; 60% dispersion in mineral oil) was added to the solution in liter. The mixture was allowed to warm to 45 ° C for 30 minutes. After cooling to 10 ° C, a solution of the aminesulfonyl group in diethyl ether (0.0445 mol in 62.5 ml) was added over 30 minutes, followed by stirring at room temperature for 30 minutes and evaporation of solvent. A sodium hydroxide solution (5 N, 15 mL) was added to this residue. The mixture was extracted several times with toluene. The aqueous layer was cooled to 0 ° C and the pH was adjusted to 7 by the addition of concentrated hydrochloric acid. The product was crystallized and filtered to give 5-methyl-p-pyridin-2-amino decanoate (5 g). Reference example 21:

Pyridyl-2-aminosulfonate amide was prepared according to the procedure described in Reference Example 20. Further cycloalkyl-, aryl- or heteroaryl-amino sulfonate decylamine (as shown in the formula of Figure 1) can be used according to the procedure described in the Reference Examples (for cycloalkyl and aryl derivatives) Or made according to the procedure described in Reference Example 21 (for heteroaryl derivatives) or according to the procedure described in Reference Example 22 (for cycloalkyl derivatives). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (62 Figure 1:

Η αΌι父 N NH2 Η Cl

Η Λ \/0 9 νη2 α ΓΎ a/ V3 Ο ^N^N/S^NH2 Η 2 Η γ Ν ΝΗ 2 Η Λ /- , κ νη2 αχ

V. Ν ΝΗ〇Η 2 Reference Example 22: [19] ΐΓ, ΝΗ2 ΧΑΛ Η Η 1, ΝΗ2 U Η 芊 thioguanamine a) Dissolve the gas-sulfonyl isocyanate (14.14 g) in DCM (50 ml), And cooled to 0 °C. A solution of the third-butanol (9.6 ml) in DCM (50 mL) was added over 30 min. Continue to stir for another 30 minutes at room temperature. b) The solution prepared as described in a) was then added to a solution of decylamine (10.7 g) and triethylamine (15.32 ml) in DCM (200 mL). Stirring was continued for 10 hours at room temperature. Concentrate the mixture in the air, dissolve the paper size to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

A BCD 1303245 6. Apply in a franchise (500 ml) and wash with water (2 x 40 ml) and brine (30 ml), dry with magnesium sulfate and concentrate again in the air. The crude material was crystallized from EtOAc (EtOAc) elute ZP1 was dissolved in dioxane (20 ml), and 120 ml of a 4 M HCl solution of dioxane was added over 1 hour at room temperature. Stirring was continued for 8 hours, then the solvent was completely evaporated and dried on HV to give decyl sulphonamide (9.47 g). Further -HN-CH2-aryl/-HN-CH2-heteroaryl/-HN-CH2-alkyl/-HN-CH]-cyclopropyl/-HN-CH2-heterocyclyl and other amine transacids The amine (as shown in the formula of Figure 2) can be made according to the procedure described in Reference Example 22. __-66- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1303245 A7 B7 V. Invention description (64) Figure 2

Och3

j, nh2, N

Eight v°(PY^n/S\NH2H

, N, NH2 H V^Nh °x° M NH2

°x° N ^NH2 °W°

°X° , N \NH2 H °X° 1 , nh2

, N, NH2 H

P, V

N, NH2 H CTnhO^x °V^° , N , NH2

H °V^°

,nh2 Ψ ^nh2

, N, NH2 H 〇n °x° NJ NH〇

V° , N〆 \NH2 H v°

, NH 2 67 This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1303245 A7 B7 V. Description of invention (65) Example 1:

Add sodium hydride (100 mg, 60% dispersion in mineral oil) to a mixture of methanol (1 mL) and THF (2 mL), followed by 4-iso-propyl-anilinosulfonic acid-[6 -Gas-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-decylamine (100 mg, reference example le)). DMF (0.5 mL) was added and the reaction mixture was heated to 8 ° C for 2 hrs. The agent was evaporated, and water (14 ml) and 10% citric acid solution were added until pH 値 was 3. The precipitate was filtered off and washed with water to give 4-iso-propyl-anilinosulfonic acid-[6-methoxy-5-(o-methoxyphenylyl)-2-(4-7 ratio Bite base - σ-dense-4-yl]-nonylamine (1 〇〇 mg). tR= 5·08 minutes (LC) ; [Μ+ΗΓ= 522.45 (ES+). Example 2 ·· Binding

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• 68 · This paper size applies to the Chinese National Standard (CNS) Α4 size (210 X 297 mm) 1303245 A7 B7 5. Inventive Note (66) In a mixture of propanol (1 ml) and THF (2 ml), Add sodium hydride (1 〇〇 mg '60 〇 in the mineral oil / dispersion), followed by 4-iso-propyl-anilino acid-[6-gas-5-(o-methoxybenzene) Oxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amine (100 mg, reference example le)). DMF (0.5 mL) was added, and the reaction mixture was heated to 8 (TC over 20 s. solvent evaporated, water (14 mL) and 10% citric acid solution until pH 3 was 3. The precipitate was filtered off and The water-washed strips were purified by chromatography on EtOAc/Hex = 3:2 to give 4-iso-propyl-benzene sulfonic acid-[6-allyloxy-5-(o-methoxy). Phenoxy)-2-(4-pyridyl)-mercapto-4-yl]-nonylamine (1 mg). tR== 5 36 minutes (LC) ; [M+H疒=548 46 (ES+). Example 3:

Sodium hydride (17 mg, 60% dispersion in mineral oil) was added to ethylene glycol (1.2 mL) followed by dimethoxyethane (5 mL). Continue to stir for 30 minutes, then add 4-iso-propyl-anilinosulfonic acid-[6·Ga-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine ice-based ]-guanamine (45 mg, reference example ie)) and the reaction mixture was heated to 80 ° C for 48 hours. Evaporate the solvent, add L _; _- 69 · This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1303245 A7 B7 V. Description of invention (67) Add water (10 ml) and 1 〇 °. The citric acid solution was until pH 3 3 and then extracted with EtOAc. The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on EtOAc to yield 4-iso-propyl-anilinesulfonic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy). -2-(4-Pyridyl)-pyrimidin-4-yl]-nonylamine (38 mg). tR=4.56 minutes (LC); [Μ+Η]+= 552·36 (ES+). Example 4:

N NH

Γ NH

N〆 〇

4-iso-propyl-anilinosulfonic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine- 4-Methyl]-guanamine (60 mg, Example 3) was dissolved in THF (8 mL) and sodium hydride (14 mg, 60% dispersion in mineral oil) was added and stirring was continued for 10 min. 2-Ga-pyridine (22 mg) was added, and the mixture was heated to 60 ° C for 90 minutes. DMF (0.5 mL) was added and the solution was stirred at room temperature for 48 hr. The solvent was evaporated, and water (12 ml) and hydrazine citric acid solution was added until pH 値 was 3. The precipitate was filtered off and washed with water and purified by recrystallization from diethyl ether to give 4-iso-propyl-anilinesulfonic acid-[6-[2-(pyrimidin-2-yloxy)-ethoxy] ·5·(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidinyl]-醯_____ -70 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297) PCT 1303245 A7 B7 V. INSTRUCTIONS (68) Amine (50 mg). tR = 4.80 minutes (LC); [Μ+ΗΓ= 630.91 (ES+)· Example 5:

Oxy)-2-(4-pyridinyl)-pyrimidin-4-yl]-guanamine (60 mg, Example 3) was dissolved in THF (8 mL). Sodium hydride (14 mg, 60% in mineral oil) was added and stirring was continued for 10 minutes. 5·Bromo-2-a-pyrimidine (37 mg) was added, and the mixture was heated to 60 ° C for 120 minutes. DMF (0.5 mL) was added and the solution was stirred at room temperature for 48 hr. Evaporate the solvent, add water (12 mL) and 10 °. The citric acid solution was until pH 値 was 3. The precipitate was filtered off and washed with water and purified by chromatography eluting with EtOAc/Hex = 1:1 to give 4-iso-propyl-anilinesulfonic acid-[6-[2-(5-bromo-pyrimidine) -2-yloxy)-ethoxy]-5-(o-methoxy-phenoxy)-2-(4-p ratio octyl)-callin-4-yl]-Siamine (55.4 Mg). tR= 5.30 minutes (LC) ; [M+Hr=710.35(ES+). ___- 71 . This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (69 ) Example 6:

4-iso-propyl-anilinosulfonic acid-[6-(2-hydroxy-ethoxy)-5,(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine The hydrazide (50 g, Example 3) was dissolved in THF (8 mL). • Add sodium hydride (12 mg, 6% dispersion in mineral oil) and continue to stir for 10 minutes. 5-Trifluoromethyl helium gas pyridine (28 mg) was added and the mixture was heated to 60 C over 180 minutes. The solvent was evaporated, water (12 mL) and 10 were added. . The citric acid solution was until pH 値 was 3. The precipitate was filtered off, washed with water and purified by diethyl ether to give 4-iso-propyl-anilinosulfonic acid-[6-[2-(5-trifluoromethyl-r-pyridine-2) -yloxy)-ethoxy]-5-(o-methoxy-phenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-decylamine (41 mg). tR= 5.81 minutes (LC) ; [M+H]+ = 697.17 (ES+)· __:···72 - This paper size applies to Chinese National Standard (CNS) Α4 size (210 x 297 mm) 1303245 A7 B7 Five , invention description (7 〇 example 7 · ·

b)

c)

a) 4,6-dioxa-5-(o-methoxyphenoxy&gt;2_(4-pyridyl&gt;pyrimidine (29 g, reference example Id)) was suspended in dioxane (3) 〇ml) and introduce ammonia (gaseous) until the solution is saturated. Stir for 7 days while repeating the reaction mixture with ammonia (gaseous) every 16 to 20 hours. Evaporate the solvent, add water to the residue and filter out Precipitate. After drying at HV/50 ° C, 4-amino-m--5-(o-methoxyphenoxy)-2-(4-p-pyridyl)-pyrimidine (2.7 g) was obtained. b) Dissolve 'amino-6-gas-5-(o-methoxyphenoxy)_2-(4^pyridyl)-pyrimidine (1 mg) in THF (5 ml) with DCM (5 ml). DBU (46 mg) and DMAP (37 mg) were added followed by ethyl-amine sulfonate (from ethylamine hydrochloride and sulphur). The mixture was stirred at room temperature for 12 hours. Evaporation solvent The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 _____B7 V. Invention description (71). Add water with 10°. Bar-like red; trough solution, followed by extraction with £t〇Ac and DCM. The combined organic layers were dried over sodium sulfate and evaporated. After purifying the residue on silica gel with EtOAc / methanol / ammonia == 4 : 1 : 〇.5, ethylaminosulfonic acid-[6- gas (o-methoxy-phenoxypyridyl) was obtained. - °Bite-4-yl]-nonylamine (10 g). tR=4.31 min (LC); [Μ+Η]+== 436.14 (ES+)· c) Ethylaminosulfonic acid-[Heart-5-(o-methoxy-phenoxy)-2- (4-Pyridyl)-pyrimidin-4-yl]-nonylamine (14 mg) was suspended in methanol (1 mL), followed by the addition of potassium tri-butylate (8.5 g) in methanol (1 mL) Solution in ). The mixture was heated to 85 ° C for 18 hours. Evaporate the solvent and add water to 1 Torr. /. Citric acid solution. The precipitate was filtered off and washed with water. After HV drying, an ethylamine-based [6-methoxy*yl&quot;-(o-methoxy-winteroxy)-2-(4-p-bito-methylidene-4-yl group is obtained. ]-guanamine (10 mg). tR = 4.25 min (LC); [Μ+Η]+= 432.32 (ES+). Example 8:

Sodium hydride (1 mg, 60% dispersion in mineral oil) was dissolved in methanol (1.2 mL). 5-Methyl-2-pyridylaminosulfonic acid-[6-gas-5-(o-methoxy-phenoxy)-2-(4-0 ratio) ice was added. Dense base]-bristamine (9) gram 'Reference example 11), this paper scale (4) SS home 搮 (CNS) A4 specification _ x 1303245 A7 B7 V, invention description (72) DMF (0.5 ml) and THF ( 1 ml), and the solution was stirred at 80 ° C for 30 hours. The solvent was evaporated, the residue was washed with hexane (3x) A 1 Torr citric acid solution was added and the precipitate was filtered off and washed with water. After drying under HV, 5-methylpyridin-2-aminosulfonic acid-[6-methoxy-5-(o-methoxy-phenoxy(4-pyridyl)-4-pyrimidine is obtained. Base l-decylamine (37 mg). tR = 3.73 min (LC); [M+H]+ =495.38 (ES+), Example 9 ··

Making p a phospho-2-amine-acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-0-pyrimidinyl)-4-pyrimidinyl]-decylamine ( 15 mg, Reference Example 12) was suspended in THF (1 mL) and DMF (0.2 mL). The mixture was stirred at 80 ° C for 90 hours, then the solvent was evaporated. A hydrazine % citric acid solution was added to the residue. The precipitate was filtered off and washed with water. After drying under HV, pyridyl-2-aminosulfonic acid-[6-methoxy-5-(o-methoxyphenoxy)-2-(4-p-pyridyl M-pyrimidinyl]-decylamine is obtained. (7 mg). tR = 3.55 minutes (LC); [MH]+ = 479.41 (ES-). _ - __ -7 gas a paper scale for Chinese National Standard (CNS) A4 size (210X 297 mm) 1303245 A7 B7 V. Description of invention (73) Example 10 ··

OH Sodium hydride (28 mg, 60 〇 / 〇 dispersion in mineral oil) was dissolved in ethylene glycol (1.2 mL) and 1,2-dimethoxyethane (1 mL). Add 4-tert-butyl-anilinosulfonic acid-[6-Gapent-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-decylamine ( 75 mg, refer to Example 10), and stirring was continued at 80 ° C for 90 hours. The mixture was evaporated and added to 10 °. Citric acid solution. The precipitate was filtered off and washed with water. After purification by EtOAc on silica gel, 4-tris-butyl-anilinosulfonic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxy-phenoxy) can be isolated. )-2-(4-Pyridinyl)-4-pyrimidinyl]-decylamine (40 mg). tR = 4.81 minutes (LC); [M+H]+= 566.35 (ES_). Example 11: Binding

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This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (74) in 1,2-methoxyethane (15 ml) and ethylene glycol (40) Sodium (298 mg) was added in small portions in a mixture of ML). The mixture was stirred until the sodium was completely dissolved. Then DMF (15 ml) was added followed by 4-methyl-anilinosulfonic acid-[6-gas-5-(p-tolyl)-4-pyrimidinyl]-decylamine (1·〇克, reference example 14). Stirring was continued for 4 days at 100 °C. The mixture was evaporated, and water (150 mL) was evaporated. The precipitate was filtered off, washed with water and dried. The crude material was purified by chromatography on EtOAc / EtOAc / EtOAc / EtOAc (25%) -5-(p-tolyl) pralinyl]-decylamine (500 mg). tR = 4.38 (LC) ; [M+H]+ = 415.19 (ES+). Example 12:

Dissolved in 4-methyl-anilinosulfonic acid-[6-(2-hydroxy-ethoxy)-5.(p-tolyl)-4-pyrimidinyl]-decylamine (47 mg, Example 11) Sodium hydride (14.6 mg, 60% dispersion in mineral oil) was added to a solution of THF (8 mL) and stirring was continued for 15 minutes, followed by the addition of 5-bromo-methanol-methane (39 mg). Stirring was continued for 2 hours at 5 °C and 80 hours at room temperature. The mixture was evaporated and 10 was added. . Citric acid __ -77 -______ This paper scale applies to China National Standard (CNS) A4 specification &lt;210 X 297 public interest) 1303245 A7 B7 V. Invention description (75 solution. Remove sediment, wash with water) Purification by chromatography on EtOAc/Hex = 1/1 to give 4-methyl-anilinosulfonic acid-[6-[2-(5-bromo-pyrimidin-2-yloxy)-B Oxy]-5-(p-tolyl) pralinyl]-nonylamine (34 mg). tR = 5.34 (LC); [M+H]+= 573.02 (ES+)· Example 13:

0Η Dissolve the third potassium butoxide (3.5 gram) in ethylene glycol (35 ml) and add the succinic acid-[6-gas-5-(4-gas-phenyl)-4 - Shouting base] - Stuffed limbs (1.8 g, see Example 15) and heating the mixture to 102 ° C for 11 hours. The mixture was poured into ice/water and acidified to pH = 4 with solid citric acid, and the precipitated product was decanted, washed with water and dried under HV to give a succinyl group. 5-(4-Gas-phenyl)-4. Dense base]-bristamine (1.77 g). tR = 4.36 (LC); [M+H]+= 435.09 (ES+). 78- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (76 examples) 14 :

The mercaptoamino sulfonic acid was dissolved in THF (30 ml) via benzyl-ethoxy)-5-(4- gas-phenyl M-cyanyl)- guanamine (375 mg, Example 13). Add sodium chloride (60 ° / dispersion in mineral oil) (140 mg). Stir the mixture for 3 minutes, then add 5-bromo-2-a-cyclohexane (320 mg) at 60 ° C. Stirring was continued for 8 hours. The reaction mixture was poured into ice/water and acidified with solid citric acid. The precipitate was filtered and purified on silica gel eluting with hexane / EtOAc = 2/1. Acid 4642-(5-amplung-2-yloxy)-ethoxy]-5-(4-carb-phenyl)-crylidyl]-decylamine (198 mg). tR = 5.32 ( LC); [M+H]+= 592.68 (ES+). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1303245 A7 B7 V. Description of invention (77) Table 3: R1-N^NH |^VCI, person r2 Example number R1 R2 LC- MS 15 σ ,丫o(ch2)2 H3CCT^^N tR = 5.00 [M+Hf: 543.18 16 σ·' h3c^ 丫o(ch 2) 2 tR = 4.95 [M+Hf: 527.28 17 cr = 3.28 [M+H]+: 435.65 18 cr ,丫o(ch2)2 Br^ tR = 4.46 [M+H]+: 594.25 19 σ' /丫o(ch2)2 tR = 4.03 [M+H]+: 544.10 20 cr ,丫〇(ch2)2 tR = 5.21 [M+H]+: 599.20 21 cr h3c〇〆,丫o(ch2)2 V /N = 4.84 [M+H]+: 546.97 -80- This paper size applies to the Chinese National Standard &lt;CNS) A4 Specification (210 X 297 mm) 1303245 A7 B7 V. Invention Description (78) Table 4 ·· v ° Cl Example number R1 R2 LC-MS 22 cr ^Nv.O(CH2)2 tR = 5.67 [M+H]+: 585.75 23 cr ,丫〇(ch2)2 h3co^^n tR = 4.67 [M+ H]+: 532.77 24 CT. / 丫o(ch2)2 Br^&quot;N tR = 5.07 [M+Hf: 582.71 -81 -

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This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Invention description (79) Table 5: R1—N'b, NH rv1 person r2 Example number R1 R2 LC-MS 25 a&quot;- tR = 4.07 [M+Hf: 479.11 26 σ'... ,丫o(ch2)2 tR = 4.88 [M+H]+: 637.54 27 σ' ,丫〇(ch2)2 h3co^n tR = 4.51 [MH]+: 584.93 -82- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)

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1303245 A7 B7 V. INSTRUCTIONS (8Q) TABLE 6:

-83- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Invention description (81) Table 7: v〇fPY^N^O^2 / Example number R1 R2 LC -MS 33 σ'... ,丫〇(ch2)2 tR = 5.00 [M+Hf: 616.18 34 σ'... H 丫0(CH2)2 tR = 4,47 [M+H]+: 612.41 °v° R1—j^b, NH /w·' eight, tR = 4.27 35 &lt;〇Aj HO^&quot; [M+H]+: 459.15

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-84 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (82) Table 8: rA> 〇H- \=Ν Ν again (4) 2 Example number R1 R2 LC-MS 36 α Ησ^^' tR = 4.13 (M+H)+: 525.17 37 σ /v〇(ch2)2 ΒΓΧΧ tR = 4.87 [M+H]+: 682.50 38 σ ,丫o(ch2)2 H3co^^n tR = 4.55 [M+Hf: 631.05 39 〇r, ,丫〇(ch2)2 tR = 4.38 [M+H]+: 603.45 40 σ' /v〇(ch2)2 ,οΧΧ tR = 5.31 [M+Hf: 670.27 41 Η 丫 丫 0 (ch2) 2 tR = 4.36 [M+Hf: 645.11 42 σ'. Η ^NJ/Ny〇(CH2)2 tR = 4.29 {M+Hf: 646.12 -85 This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1303245 A7 B7 V. Invention description (83) Table 9: R1--n^s-Nh Λ \=N N-^〇-r2 Example No. R1 R2 LC-MS 43 (X·,·· H 丫0(CH2)2 tR = 4.89 [M+H]+; 644.24 44 σ' ............... / = 4.60 [M+Hf: 519.18 45 σ'··· ”...·· tR = 4.74 [M+Hf: 521.21 46 〇r,', Cr,,, tR = 4.71 [M+H]+: 565.66 47 H3co^^ tR = 4.10 [M+Hf: 555.59 48 ΧΎ'&quot; H3CO into ^ ^Y〇mi)2 tR = 4.8 2 [M+Hf: 713.18 49 h3co^^ , 丫〇(CH2)2 h3co人^^ tp = 4.52 [Μ+ΗΓ: 663.54 -86- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 Binding)

1303245 A7 B7 V. INSTRUCTIONS (84) TABLE 10: R^N^S-NH / \ \=NN 〇-R2 Example number. R1 R2 LC-MS 50 H 丫广丫0(Ch2)2 tR = 4.32 {M+H]+: 675.34 51 H3C〇/ σ' Η3σ' tR = 4.51 [M+H]+: 524.91 52 (Υ' tR = 4.67 [M+Hf: 595.20 53 丨· / tp = 4.65 (M +Hf: 549.33 54 cK c tR = 4.35 [M+H]+: 559.30 55 cK 〇,丫o(ch2)2 h3co^^h tR = 4.79 {M+H】+: 667.34 56 0 ,丫o(ch2 ) 2 tR = 5.11 [M+Hf: 717.09 -87- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (85) Table 11: r, n / -NH n-^0~r2 Example number R1 R2 LC-MS 57 Meaning... H ^yNY〇(CH2)2 tR =4.71 [MH]' 678.68 58 cr ho^^·〆tR = 3.93 (M+Hf : 515.38 59 &lt;Τ&quot;·' ,丫o(ch2)2 tR = 4.46 [Μ+ΗΓ: 623.48 60 cr ,丫o(ch2)2 tR = 4.75 [M+H]+: 673.39 61 cr H ^j -nY〇(ch2)2 tR = 4.15 [M+H]+: 636.34 183 tR = 3.72 [M+H]+: 462.98 184 ,丫〇(CH2)2 tR = 4.54 [M+H].: 619.06 - 88- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. INSTRUCTIONS (86) TABLE 12: R1--N^S-NH ί~\ Ν—C〇-R2 Example No. R1 R2 LC-MS 62 0 Production,, = 3.38 [M+H]+ : 526.04 63 〇r' ”...·· tR = 4.29 [M+Hf: 521.79 64 〇r,· tR = 4.10 [M+Hf: 520.10 65 (T,· H3c&quot;... = 3.87 [M+H]+: 496.09 66 0 ,丫〇(ch2)2 tR = 4.40 [M+Hf: 683.15 67 σ'.. tp - 4.30 {Μ+ΗΓ: 525.25 68 or. H3C·...· tR = 4.84 [MH]+: 493.13 - 89- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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k 1303245 A7 B7 V. INSTRUCTIONS (87) TABLE 13: R1--N^5-NH /-Λ 〇Λν^Η— Ν=/ Ν—^〇—r2 Example No. R1 R2 LC-MS 69 σ' I丨...· / tR = 4.95 [M-Hf: 517.58 70 σ' ”...·· tR = 5.13 [M+H]+: 521.30 71 (Τ' / 丫o(ch2)2 tR = 5.22 [M+H] +: 683.42 __-90- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding

1303245 A7 B7 V. INSTRUCTIONS (88) Table 14 Example number R1 R2 LC-MS 72 (Τ' tR = 3.79 [M+H]+: 524.28 73 σ' , 丫o(ch2)2 tR = 4.76 [M +Hf: 681.59 74 σ' , 丫〇(ch2)2 h3cs^^&quot;n tR = 4.70 [M+H]+: 648·25 75 (Τ' H ^^Νγ〇(〇Η2)2 tp = 4.30 [Μ+ΗΓ: 645.65 76 cr HO'^〆= 3.73 tM+Hf: 530.25 77 &lt;Τ&quot;&quot;' ,=::;„;;__________/ tR = 4.38 [M+H]+: 524.23 78 cr tR = 4.59 ΙΜ+ΗΓ: 526.10 -91 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1303245 A7 B7 V. Invention description (89) Table 15: r1^n^^nh n〇 Hn^〇H- W 乂〇-R2 Example number R1 R2 LC-MS 79 CT h3c,' tf^= 4.36 [M+Hf: 500.14 80 cr- , 丫〇(ch2)2 tR = 4.82 [M+Hf :688.54 81 Ο&quot;...' Η 丫 丫 0 (Ch2) 2 tR = 4.25 [M+H]+: 650.09 82 οσ' ==_/ tR = 4.43 [M+Hf: 562.16 -92- This paper The scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1303245 A7 B7 V. Description of invention (90) Table 16: R1—M^S-NH hn4 Η 〇- Ν_^0 - R2 Example number R1 R2 LC -MS 83 〇r... tp = 3.38 [M+H]+: 488.30 84 〇r ,丫〇(ch2)2 Br^ = 4.46 [M+H]+: 646.17 85 σ'. ,丫o(ch2)2 H3co^^n tR = 4.15 [M+H]+: 596.31 86 σ,.' H 丫广丫0(Ch2)2 tR = 3.96 [M+H]+: 608.69 87 c H(T^' tR = 4.77 [M+Hf: 488.18 88 c Br^ , 丫0(ch2)2 tp = 5.89 {M+H]+: 644.83 89 0 h3co〆,丫〇(ch2)2 tR = 5.56 [Μ+ΗΓ: 595.20 -93 -

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Line paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Invention description (91) Table 17: R^N^^NH /~\ H NJ W C&gt;~( / -° °— n-^o-r2 Example No. R1 R2 LC-MS 90 (Τ' , 丫o(ch2)2 h3csx^^n tR = 5.82 [M+Hf:611.19 91 σ' H 丫广丫0 (Ch2)2 tR = 5.31 [M+Hf: 607.32 -94- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (92) Table 18: R1— .n^sCnh N-^0-R2 Example Number R1 R2 LC-MS 92 X tR = 2.54 [M+H]+: 448.08 93 CT 乂丫d(ch2)2 tR = 4.20 [M+H]+: 605.54 94 CT h3co〆,丫〇(ch2)2 tp = 3.82 [M+H]+: 556.15 95 〇r.,' tR = 4.14 [M+H]+: 447.26 96 σ, ' ^Nv/0(CH2 ) 2 jt tR = 5.10 [M+H]+: 604.67 97 ιΓ^Υ&quot;,, h3cs^, 丫〇(ch2)2 tR = 5.01 [M+H]+: 571.18 98 〇r... H丫〇(CH2)2 tR = 4.53 {M+H]+: 567.23 ___-95- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1303245 A7 B7 V. Invention description (93) 19 : R1-N^NH ί^γΒΓ hnVU example R1 R2 LC-MS 99 (T. tR = 4.46 [M+Hf: 481.20 100 〇r·, ,丫o(ch2)2 B人^ tp = 5.55 [M+H]+: 637.07 101 a&quot;- ,丫o(ch2)2 H3CO person tR = 5.14 [M+Hf: 589.15 102 (X,,, ,丫o(ch2)2 h3cs^^n tR = 5.55 [M+Hf: 603.27 103 = 3.88 [M+Hf: 419.01 104 ,Y〇(ch2)2 Br^ tR = 4.93 [M+H]+: 575.13 105 / 丫〇(ch2)2 h3cs^^n tR = 4.84 [M+H]+: 543.20 ___-96- Ben Paper scale applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1303245 A7 B7 V. Invention description (94) Table 20: Example number R1 R2 LC-MS 106 &lt;, ',, HO^^〆tR = 4.12 [M+Hf: 445.11 107 V , 丫o(ch2)2 Br^/N tR = 5.03 [M+H]+: 601.28 108 \T' , 丫〇(ch2)2 h3cs/^^n tR = 4.98 [M+H]+: 568.44 r1-N^NH Vr2 109 (X. ,丫〇&lt;ch2)2 tR = 4.92 [M+H]+: 670.30 110 σ..' , 丫o(ch2)2 H3cs^n tR = 5.07 IM+H]+: 636.34 111 ,丫o(ch2)2 h3co^^n tR = 4.76 [M+H]+: 620.07 -97- This paper size applies to Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) 1303245 A7 B7

1303245 A7 B7 V. INSTRUCTIONS (96) TABLE 22: V. ^vcr Instance number R1 R2 LC-MS 119, 丫〇(ch2)2 B person I tp = 5.20 [M+H]+: 537.14 120 &lt;, ',, ,丫〇(ch2)2 l^CO^ ^N tR = 4,77 [M+H]'· 487.25 121 ,丫o(ch2)2 S^N tp = 4.56 [M+Hf: 456.89 144 C σ' tR = 4.27 [M+Hf: 459.15 145 0 (Τ ,丫o(ch2)2 Br^^N tR = 5.77 [M+H]+: 616.66 146 〈:] 0 h3c〇” ,丫o(ch2)2 VN tR = 6.01 [M+Hf: 567.36 147 C 0 h3cs^ , 丫o(ch2)2 k/N tR = 5.22 [M+Hf: 582.88 -99 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1303245 A7 B7 V. Invention Description (97) Table 23: Example No. R1 R2 LC-MS 122 tp = 3.63 [M+H]+: 488.49 123 , 丫o(ch2)2 tR = 4.66 [M+Hf: 646.30 124 〇*·- ,丫〇(ch2)2 h2cg^^h tR = 4.29 [M+H]+: 596.44 125 0; tR = 3.96 [M+H]+: 489.56 126 σ ,丫o(ch2)2 Br^^N tR = 4.79 [M+H]+: 645.07 127 Cr ,丫〇(ch2)2 h3co^^/N tR = 4.47 [M+H]+: 597.31 128 /N, / α =—, tR = 4.47 [M+H 】+: 483.34 -100- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1303245 A7 B7 , invention description (98) Table 24: /V*^nA, nh 〇〆 Example number R1 R2 LC-MS 129 tR = 4.29 [M+H]+: 530.49 130 〇.·.· / 丫o(ch2) 2 tR = 5.35 [M+H]+: 688.27 131 ,丫o(ch2)2 tR = 4.93 [M+Hf: 638.64 132 0; tR = 4.70 [M+H]+: 531.54 133 〇·- , 丫0 (ch2)2 tR = 5.39 [M+Hf: 689.26 134 〇··· , 丫o(ch2)2 h3co^^n tR = 5.06 [M+Hf: 639.36 135 α /v〇(ch2)2 ,〇XJ tR = 5.83 [M+H]+: 676.34 -101 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (99) Table 25: Example number R1 R2 LC-MS 136 σ hct^〆' tR = 4.11 [M+Hf: 491.29 137 〇··*&quot; /v〇(ch2)2 BrXX tR = 4.88 [M+Hf: 649.18 138 σ·. ,丫o (ch2)2 tR = 4.82 [M+Hf: 615.67 102- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (100) Table 26: ^〇〆 Example No. R1 R2 LC-MS 139 α. tR = 4.27 [M+H]+: 543.37 140 0; H3C·...· tR = 4.55 [M+Hf: 513.31 141 0; cr, tR = 4.70 [M+H ]+: 583 .52 142 α. ,丫o(ch2)2 tR = 4.92 [M+Hf: 701.37 143 σ ,丫o(ch2)2 h3co^^n tR = 4:60 [M+Hf :651.40 -103- This paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (101) Table 27: cr^ Example number R1 R2 LC-MS 148 〇*·' I-丨/ tR = 4.43 [M+Hf: 562.16 149 〇〆H3C·...· tR = 4.27 [M+Hf: 538.18 upper 2 〇, 150 Η〆 HO&quot;^〆. tR = 4.37 [MH]+: 522.83 151 Η·〆,丫o(ch2)2 tR = 5.21 [M+H]+: 682.98 152 Η·' , 丫o(ch2)2 h3co^n tR = 4.86 [MH]+: 631.19 -104- This paper scale applies to Chinese national standards (CNS) A4 size (210 X 297 mm) 1303245 A7 B7 V. Description of invention (102) Table 28: / y--hrs, NH 匕Η Ν^γ°-R1 Ν人0, Cr^ ό R2 Example No. R1 R2 LC-MS 153 0 HO^^' tR = 3.15 [M-Hf: 523.09 154 rNr ho^^'· tR = 3.20 [M+H]+: 526.44 155 fV ,丫o(ch2)2 h3cs ^n tR = 3.96 [M+H]+: 650.39 156 rV ^N^O(CH2)2 BrXX tp = 4.00 {M+H】V684.29 157 〇·- ^^xO(CH2)2 tp = 3.86 [ M+Hf: 609.32 158 C h3cs^ 一丫o(ch2) 2 tR = 4.14 [M+H]+: 649.30 -105 - This paper scale applies to Chinese national standards (CNS> A4 specification (210X 297 mm) 1303245 A7 B7 V. Invention description (103) Table 29: Λ Or R1 person N person 0, ^ J Example number R1 R2 LC-MS 160 ry.· ------------------ / tR = 4.58 [M+H]+: 548.41 161 〇· * H3C·...· tR = 4.32 [M+H]+: 524.19 /0_〇-^〇a R Everyone 〇Y 162 H·〆tR =4.41 [M+Hf: 511.11 163 H〆· ,丫0( Ch2)2 Br^N tR = 5.26 [M+H]+: 668.91 164 H·' , 丫o(ch2)2 η3οο^%^ν tR = 4.98 [M+Hf: 619.17 -106 - This paper size applies to China National Standard &lt;CNS) A4 Specification (210 X 297 mm) 1303245 A7 B7 V. Description of Invention (104) Table 30: v --N-^^NH or&quot; T \ R1 Ν人0,^^ Instance No. R1 R2 LC-MS 165 σ tR = 3.90 585.52 166 ^^〇(CH2)2 tR = 4.69 [M+Hf: 743.19 167 σ ,丫o(ch2)2 k/N tR = 4.24 [M+H]+ : 663.47 168 σ H 0(CH2)2 U Ϊ tR = 4.78 [M+Hf: 704.54 -107- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (105) Table 3 1 : R1 and Ν person 0, ^^ Example number R1 R2 LC-MS 169 0; HO production, ' tR = 4.16 [M+H]+: 555.69 170 0; / 丫o(ch2)2 tR = 4.76 [ M+Hf: 713.26 171 α / 丫o(ch2)2 k/N tR = 4.45 [M+H]+: 633.64 172 σ H /0(CH2)2 CTX tR = 4.98 [M+H]+: 674.55 - 108 - The paper size applies to the Chinese National Standard &lt;CNS) A4 Specification (210X 297 mm) 1303245 A7 B7 V. Invention Description (106) Table 32: H nV°yS, long time p Example number R1 R2 LC-MS 173 0; HO^^' tR = 4.20 [M+Hf: 555.37 174 〇- , 丫o(ch2)2 Βγ^&quot;Ν tR = 4.99 [M+H]+: 713.35 175 0; ,丫〇(ch2 ) 2 tR = 4.45 [M+H]+: 633.70 176 σ Η U ϊ tR = 4.99 [M+H]+: 674.95 -109 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. INSTRUCTIONS (107) TABLE 33: ΗΝνΛ R1 Ν人0,^&quot;^ Instance No. R1 R2 LC-MS 177 〇Ν-^1 η3ο .... tR = 4.54 [M+H] +: 508.22 178 η 丨 丨 __ / tR = 4.62 [Μ+ΗΓ: 532.23 179 tR = 3.90 [M+H]+: 538.33 180 ο..·.. \〇~ tR = 4.46 [M+Hf: 552 .27 181 ο ·〆· Η 丫0(CH2)2 tR = 4.78 [M+Hf: 657.46 182 r ,丫o(ch2)2 tR = 4.91 [M+H广:696.51 -110- This paper size applies to China National Standard (CNS) A4 Specification (210 X 297 mm) 1303245 A7 B7 V. Description of Invention (1(38) Table 34: ^ N-^O -R2 Example Number R1 R2 LC-MS 185 〇rr h3c·... · tR = 4.84 507.15 186 Η〇^^'· tR = 4.51 [M+H]+: 539.47 187 „(ch2)2 tR = 5.18 [M-Hf: 695.09 188 〇rr ,丫〇(ch2)2 h3co^ ^n tp = 4.86 [M+H]+: 647.43 189 〇〇- = 3.56 [M+Hf: 505.35 190 , 丫0(ch2)2 Βγ^Ν = 4.38 [M+H]+: 663.05 191 Ύ ,丫〇(ch2)2 h3cs^^n tR = 4.77 [M+H]+: 615.32 -111 - Gutter This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Invention Description (1Q9 Table 35: R1 Two S, NH Example Number R1 R2 LC-MS 192 〇rr tR = 4.84 [MH]+: 447.17 193 〇Ύ. , 丫o(ch2)2 tR = 5.66 [M+H]+ : 607.22 194 〇rr ,丫o(ch2)2 H3CCT^^N tR = 5.31 [M+H]+: 557.42 V rU, NH V] ^Br , 〇-R2 195 HO~, tR = 3.92 [M+H ]+: 431 .09 196 ,丫0(ch2)2 Br^^N tR = 4.99 [M+Hf: 587.13 197 ,丫o(ch2)2 h3cs^^n tR = 4.90 [M+H]+: 555.18 -112- Binding This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (110) Table 36: or&quot; H NVrS R1 Everyone Example Number R1 R2 LC-MS 198 , 丫o (ch2)2 k/N tR = 4.11 [M+H]+: 551.34 199 α. ,丫o(ch2)2 tR = 4.61 [M+Hf: 633.37 200 0: ,丫o(ch2)2 tR = 4.35 [M+H]+: 583.40 201 0; ^N^O(CH2)2 tR = 5.05 (M+H)+: 617.98 202 〇··- , 丫o(ch2)2 Br^^N tR = 4.51 [ M+H】+: 632.16 -113- This paper scale applies to Chinese national standard &lt;CNS) A4 specification (210 X 297 mm) 1303245 A7 B7

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm).

Line 1303245 A7 . ______ B7 V. INSTRUCTIONS (m) a) 4,6-di-gas-5-(2-methoxy-phenoxy)-2-methyllitholine according to the procedure described in [5] · The preparation of shouting is achieved by condensing thiourea (6.4 g) with dimethyl 2-(2-methoxy-phenoxy)-malonate (2 〇 32 g), followed by 2 巯 巯The reaction was carried out with ruthenium (2 methoxy-p-oxy)-pyrimidine-4,6-diol oxime iodide (5.9 ml), and then gasified with oxygenated phosphorus/rhodium, hydrazine-dimethylaniline. Yield: ι8·6 g; LC-MS: tR=5.73; [M+H]+= 318.2. b) 4,6-di-5-(2-methoxy-phenoxy)-2 Methylthiopyridine (1.5 g) was dissolved in DMSO (30 ml), and potassium decylamine sulfonate (212 g, Reference Example 22) was added. Stirring was continued for 18 hours. The reaction mixture was poured into water and acidified by solid citric acid (1.9 g). (:, the precipitate was filtered off and purified on a celite gel using hexane / EtOAc = 2/1 column chromatography to give the mercaptoamines as acid [6-gas-5-(2·methoxy) Benzyl-phenoxy)-2-methylsulfanyl-pyroline 4.-decylamine (1·75 g)' is a white powder. LC-MS: tR=5.27; [Μ+Η]+ = 467· 04· c) Add fluorenylaminosulfonic acid [6-Gapent-5-(2-methoxy-phenoxy)_2-methylthio-cyano-4-yl]-decylamine (1.75 g) To a solution of potassium tert-butyrate (187 g) in ethylene glycol (3 ml) was stirred for 40 hours at 10 °C. The reaction mixture was poured into water (120 mL), evaporated and evaporated. The precipitate was filtered off, washed with water and dried over HV to give [2-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2- Methylthio-pyrimidinyl]-SI amine (Example 203). LC-MS ·· tR= 4.70 ; [M+H]+ = 493.09· d) [6-(2-hydroxy-ethoxy)phosphonium 2-methoxy-phenoxy)-2 -Methylthio:pyrimidin-4-yl]-nonylamine (1.49 g) was dissolved in DCM (50 mL) and cooled to 0 C. 700 〇) A solution in DCM (15 ml). Stirring at 〇 °C for 30 minutes and 1.5 ft at room temperature _- -115, _ This paper size is applicable to Ningguo National Standard (CNS) A4 size (210 x 297 mm) 1303245 A7 B7 V. Invention description (old ) Time. The mixture was concentrated in the sputum until the product began to precipitate. The product was filtered off and purified by chromatography eluting with EtOAc / hexane = 2:1 to give decylaminosulfonic acid [6-(2-hydroxy-ethoxy)-2-methanesulfonyl-5- (2-Methoxy-phenoxy)-pyrimidin-4-yl]-nonylamine (Example 204) (1.4 g) as a white powder. LC-MS : tR=4.12; [M+H], 525.09. e) succinylamino acid [6-(2-carbo-ethoxy)-2-methane s-yl-5- -Methoxy-phenoxy)-pyrimidin-4-yl]-decylamine (85 mg) was dissolved in THF (2 mL). The reaction mixture was stirred at EtOAc (EtOAc) (EtOAc) The combined EtOAc layer was 1 Torr. The citric acid solution and brine were washed, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on toluene / Et.sub.sup.sup.1/l/l to give the mercaptoamines acid [6-(2-carbo-ethoxy)-5-(2-methoxy Benzyloxy)-2-morpholine-4-yl-pyrimidine]-decylamine (Example 205) (60 mg). LC-MS : tR = 4·69; [M+H]+= 532.15. decylaminosulfonic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy] -5-(2-methoxy-phenoxy)-2-moffin-4-yl-pyrimidin-4-yl]-decylamine (Example 206) (40 mg). [LC-MS: tR = 5.63 ; [M+H]+= 690.50} according to the procedure described in Examples 5, 12 and 14 from [6-(2-hydroxy-ethoxy)-5-(2-methyl) Oxy-phenoxy)-2-morpholine 4-yl-pyrimidin-4-yl]-decylamine (Example 205) (50 g). According to the procedure used to prepare Examples 203-206, the following compounds were prepared: -116- 1303245

This paper scale applies to the Chinese National Standard &lt;CNS) A4 Specification (210 X 297 mm) 1303245 A7 B7 V. Invention Description (115) The same way. Example 207:

Dress

Line a) 4-[4,6-dioxa-5-(2-methoxy-phenoxy)-α-melan-2-yl]-p-precipitate-2-carbonitrile can be used according to WO 96/19459 Made as described in WO 00/42035. b) 4-[4,6-Dioxa-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carbonitrile (3.2 g) dissolved in DMSO (20 mL) Among them, N-ethyldiisopropylamine (1.7 ml) and potassium decylamine sulfonate (3.52 g) were added. The mixture was stirred at room temperature for 18 hours, poured into ice/water, acidified with solid citric acid, and the precipitate was taken and recrystallized from EtOAc to give decylamine sulfonic acid. Cyano-pyridylsyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-decylamine (4.17 g) °LC- This paper scale is suitable for a standard (CNS) A4 specification (21G X 297 public 1303245 A7 B7 V. Description of invention (116 ) MS: tR=5.55 ; [Μ+Η]+= 523.29. c) Hydrazinyl sulfonic acid [6-gas-2-(2) -Cyanopyridin-4-ylmethoxy-phenoxy)-pyrimidin-4-yl]-nonylamine (4.17 g) was dissolved in DMF (55 mL). Sodium azide (5.2 g) and ammonium sulfide (4.28 g) were added, and the mixture was stirred at 8 ° C for 20 hours. The mixture was then poured into water and extracted with Et.Ac. The layers were separated, the aqueous layer was acidified to pH~5, and extracted with EtOAc. The combined organic layers from the second extraction were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude material was purified by chromatography on EtOAc / MeOH / EtOAc / EtOAc / EtOAc EtOAc EtOAc -[2-(ΙΗ-四吐-5-yl)-卩 症-4-yl]-p-dimethyl-4-yl]-guanamine (1.67 g). LC-MS: tR = 5.02; [ Μ + ΗΓ = 566.36. d) decylaminosulfonic acid [6-Ga-5-(2-methoxy) according to the procedures described in Examples 1, 8 and 9. -Phenoxy)-2-[2-(1Η-tetrazol-5-yl)-pyridin-4-yl]-pyrimidinyl-yl-nonylamine (150 mg) was converted to benzylaminosulfonic acid [6 -Methoxy-5-(2-methoxy-phenoxy)yl]-2-[2-(1Η-tetras--5-yl)-12-precipitate **4-yl]-biti-4- Base]-bristamine (50 mg) (Example 207). LC-MS: tR=4.84; [Μ+Η]+=562·29. Example 208:

-119- The paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1303245 A7 B7 V. Description of invention (117) Sulfhydryl sulfonic acid [6-(2-hydroxy-ethoxy) -5-(2-methoxy-phenoxy (1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl]-decylamine (1.5 g) was according to Example 207d Prepared by the procedure described. LC-MS ·· tR = 4·28; [M+H]+= 592.63. Example 209:

Nonylaminosulfonic acid [6-allyloxy-5-(2-methoxy-phenoxy)-2-[2-(1Η·tetrakis-5-yl)-pyridin-4-yl] - Pyrimidinyl yl)-decylamine (94 mg) was prepared according to the procedure described in Example 207d. LC-MS: tR = 4.96; [M+H]+= 588.70. Example 210:

N^NH N octagonal Ν=Ν 'Ν=Ν Example 210 decylaminosulfonic acid [5-(2-methoxy-phenoxy)-6-prop-2-ynyloxy-120- Paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 public) 1303245 A7 B7 V. Description of invention (118) Tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl]-醯The amine (100 mg) was made according to the procedure described in Example 207d. LC-MS: tR = 4·77; [Μ+ΗΓ = 486.51. Example 211-212: CI ΗΟ

a)

0 CI b) N〆 OH Cl

N, OH

Example 212 〇丫乂

Br 2-gas-5-methoxy-phenol was prepared according to the procedure described in the literature [M. Julia, J. de Rosnay; Chimie Therapeutique, 1969, 4, P334-343.]. ______ A 121 paper size for the National Standard (CNS) A4 specification &lt;210X297 mm) 1303245 A7 ______ B7 1-5, invention description () a) According to the procedure described in Reference Example lb, make 2-gas-5- The methoxy-phenol is reacted with dimethyl malonate and potassium carbonate in acetone to obtain 2-(2-a-5-methoxyphenoxy)-malonic acid dimethyl vinegar. b) 5-(2-Ga-5-methoxy-phenoxy)-pyrimidine-4,6-diol from 2-(2-Ga-5-A) according to the procedure described in Reference Example lc Dimethyl oxy-phenoxy)-malonate and formamidine hydrochloride. c) 4,6-di-gas-5-(2-a-5-methoxy-phenoxy)-pyrimidine system was prepared from 5-(2-gas-5-A according to the procedure described in Reference Example 3b Oxy-phenoxy)-pyrimidine-4,6-diol. LC-MS: tR=5.18; [M+H]+= 306.40; 1 H-NMR (CDC13): 8.7 ppm (s, 1H); 7.4 ppm (d,lH); 6.6 ppm (d,lH); 6.02 Ppm(s,lH); 3.86 ppm(s,3H)· d) Benzylaminosulfonic acid [6-Ga-5-(2-a-5-methoxy), according to the procedure described in Reference Example 15. Phenoxy)-pyrimidine 4-yl]-nonylamine (0.7 g) is prepared from 4,6-dioxa-5-(2-a-5-methoxy-phenoxy)-pyrimidine (1 g) Potassium amide with mercaptoamine sulfonate (1.21 g). LC-MS: tR = 5.13; [M+H]+ = 456.91. e) according to the procedure described in Example 3, 10 or 13; arylaminosulfonic acid [5-(2-a-5-methoxy) -Phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-nonylamine (0.6 g) (Example 211) was prepared from mercaptoamine sulfonic acid [6·gas- 5-(2-Ga-5-methoxy-phenoxy)-pyrimidin-4-yl]-decylamine (0.697 g). LC-MS: tR = 4.50; [ Μ + ΗΓ = 481·12· f) decylaminosulfonic acid [6-indole (5-bromo-pyrimidin-2-yloxy) according to the procedure described in Example 14. )-ethoxy]-5-(2-a-5-methoxy-phenoxy)-pyrimidin-4-yl]-decylamine (77 mg) (Example 212) was prepared from mercaptoamine sulfonate Acid [5-(2-Ga-5-methoxy-phenoxy)-6-(2-#i-ethoxy)-pyrimidin-4-yl]-decylamine (120 mg) (Example 211 ) with 5-bromo-2-pyrimidine (100 mg). LC-MS : tR= 5·29 ; [Μ+Η]+= 639.04. Example 213 : -122- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1303245 A7 B7 V. Description of invention (120)

According to the procedure described in Example 14, mercaptoaminosulfonic acid [6-0(5-methylsulfanyl-indole-2-yloxy)-ethoxy]-5-(2-gas- 5-Methoxy-phenoxy)-p-melt-4-yl]-nonylamine (138 mg) (Example 213) was prepared from benzylaminosulfonate (2-a-5-methoxy) -phenoxy)-6-(2-carbamic-ethoxylatin-4-yl]-guanamine (240 mg) (Example 211) and 5-methylthio-2-pyrimidine (180 mg) LC-MS : tR= 5.22 ; [M+H]+= 606.75·

Example 214:

According to the general procedure described in the literature, benzylaminosulfonic acid [5-(2-a-5-methyl-hydroxy-phenoxy)-6-[2-(5-Pitonic Brewing Precipitate - 2-Alkyloxy)-ethoxy]-σ密___-123- This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1303245 A7 B7

1303245 A7 B7 V. INSTRUCTIONS (122) Compounds prepared by the above procedures are not limited to the molecules depicted in the drawings. In addition, the side bonds of the thiol amine moiety of the molecule and the 6th position of the core pyrimidine ring can be achieved via the same route. Example 215 · The compounds disclosed in Table a) can be prepared using the methods described in the Examples above and Figures 1 to 4 and the cited references:

+ indicates the connection of a substituent to a core unit of a core unit — ' —........ 1 1 — _ I幺. One

This paper scale applies to China National Standard (CNS) A4 specification 297 public) 1303245 A7 B7

Claims (1)

A8 B8 13 03 2 Pan &amp; 0130769 Application Chinese Patent Application Replacement (December 96) 哉 Patent Application Fan Park Announcement 1. A compound of the general formula I, modified replacement 冢 year f arch / 曰 XN And NH.R3 X is a formula I wherein R1 represents a phenyl group which is optionally substituted with a alkyl group having 1 to 4 carbon atoms; a phenylalkyl group, wherein the phenyl group is optionally selected from the group consisting of _ and a single or secondary substitution of a substituent consisting of a group of alkoxy groups of 4 carbon atoms, wherein the alkyl group is an alkyl group having 1 to 4 carbon atoms; optionally 1 to 4 a pyridyl group substituted with an alkyl group of a carbon atom; a pyrenyl group, a thiol group, a butyl group, a P group, a P group, a benzyl group, or a benzodioxol group, wherein the The alkyl group of a thienyl-alkyl group, a furyl-alkyl group, a pyridyl-alkyl group and a benzodioxolanyl-alkyl group is a group having 1 to 4 carbon atoms, and has 3 to 7 a cycloalkyl group of a carbon atom, wherein the cycloalkyl group has a cycloalkyl group having 3 to 7 carbon atoms, and wherein the alkyl group is an alkyl group having 1 to 4 carbon atoms;丨 to 7 a carbon atom-based group; or may form a sulfonyl group with R6 and a nitrogen atom carrying the same, R2 represents ·&lt;:Η3,·-(CH2)nY-Ra; -CH2-C^CH·. This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) ' ----___ 1303245 A8 B8 C8 -------- -D8 VI. Patent application scope (iDk-CWXRld; or CH2-tetrachloromethane · 2_ group; R represents a phenyl group, which is optionally composed of an alkoxy group selected from the group consisting of halogen, having 1 to 4 carbon atoms &lt; alkyl group and having 丨 to 4 carbon atoms a single or secondary substitution of a substituent of the group; R represents a hydrogenthio group having 1 to 4 carbon atoms; a phenyl group; a pyridine ring, a pyrimidine ring or a pyrazole ring optionally substituted with a tetrazolyl group a morpholinyl group; or a cycloalkyl group having 3 to 7 carbon atoms; R represents hydrogen, an alkyl group having 1 to 4 carbon atoms; or may form a morpholinyl group together with Ri and a nitrogen atom carrying the same; X represents oxygen or a bond; Y represents a bond; or _0-C0-NH_; Z represents a bond; k represents an integer of 1, 2, 3, 4, 5 or 6; η represents 2, 3, 4, 5 Or an integer of 6; R&quot; represents phenyl; pyr a ring, a pyrimidine ring or a pyrazole ring, which is optionally substituted with a diterpene monofluoromethyl group, a burnt group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms; a thiazolyl group; An alkyl group having 1 to 4 carbon atoms; or hydrogen; Rb and hydrogen; Rd represents hydrazine; or a pharmaceutically acceptable salt thereof. 2. A compound of formula I according to claim 1 wherein X represents oxygen And R3 represents a phenyl group or a monosubstituted phenyl group substituted by halogen, an alkyl group having 4 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, · -2- Home Standard (CNS) A4 Specification (210 X 297 mm) '&quot;&quot; ----- 1303245 A8 B8 C8 D8 VI. Scope of application or pharmaceutically acceptable salt of this compound. 3) A compound of the formula I according to the scope of claim 1, wherein X represents oxygen, R3 represents a phenyl group or a monosubstituted phenyl group substituted by an alkoxy group having 1 to 4 carbon atoms, and R2 represents _(CH2 n_Y_Ra; or a pharmaceutically acceptable salt of the compound. 4. A compound of formula I according to claim 1 wherein χ represents oxygen, R3 represents phenyl or a monosubstituted phenyl substituted by an alkoxy group having from i to 4 carbon atoms, and R2 represents _(CH2 2-〇-Ra; or a pharmaceutically acceptable salt of the compound. 5. According to the compound of formula I in the scope of patent application, the formula is a type of workman Wherein R1, R2, R3 and R4 are as defined in claim i, or a pharmaceutically acceptable salt of a compound of formula II. 6. According to the compound of formula I in the scope of patent application, the formula is the formula j π -3- The paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) A8 B8 C8 D8 1303245 VI. Patent application Fan Yuan Wherein R1, R2 and R4 are as defined in claim 1 of the patent application, and A is 7 hydroxy, methyl, ethyl, gaseous, bromo, fluoro or methoxy, or a pharmaceutically acceptable compound of formula III salt. 7. According to the formula j formula i, the formula j compound, the formula is the formula ιν Wherein R1, R4 and η are as defined in the formula j of claim 1; the lanthanide is as defined in the formula 111 of claim 6; and R5 represents hydrogen, having 1 to 4 carbon atoms. An alkyl 'phenyl group, or a fluorenyl group, a pyrimidinyl group or a pyrazolyl group, optionally having an alkyl group of 1 to 4 carbon atoms or having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms. The oxy group is taken -4- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x 297 mm) A8 B8 C8 VI. Scope of Application for Patent — ~--- 1303245 Generation; or a pharmaceutically acceptable salt of a compound of formula IV. 8. According to the formula J of the patent application Fan Park, the formula is V R1\ where R1 is as defined in Formula I of claim 1 and A is as defined in the formula π I of claim 6 and R5 represents hydrogen, an alkane having 1 to 4 carbon atoms A phenyl group, or a pyridyl group, a pyrimidinyl group or a pyridyl group, which is optionally subjected to a halogen, a trifluoromethyl group, a alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms. Substituted; or a pharmaceutically acceptable salt of a compound of formula V. 9. A compound of formula I according to item 0.001 of the claim, wherein R5 in formula v according to claim 8 represents pyridyl, pyrimidinyl or pyrazolyl, which is optionally subjected to a Or a trifluoromethyl group, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, or a pharmaceutically acceptable salt thereof. 10. The compound according to any one of the claims 1 to 9 is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm). A8 B8 C8 D8 1303245 6. Patent application scope pyridine-2 - Amino-amino acid 2-[5-(2-methoxy-phenoxy&gt;6-(decylaminosulfonylguanidino)-[2,2']dipyrimidin-4yl Oxy]-ethyl ester; pyridin-2-yl-amine carbamic acid 2-[5·(2-methoxy-phenoxy)_6_(4-methoxy-benzylamino decanoate Base)-[2,2'] two shouting ''oxyl'-ethyl styrene; arylamino sulfonic acid [6-[2-(5-bromo-pyridin-2-yloxy)&gt;Ethoxy^(2-methoxy-phenoxy)-[2,2']dipyrimidin-4-yl]-decylamine; cyclopropylmethylamino acid [6-[2-(5) -Bromo-p-densyloxy)-ethoxy]-5-(2-methoxyphenoxy)-[2,2,]dipyrimidinyl]-decylamine; furan-2-yl- Methylaminosulfonic acid [6-[2-(5-bromo-cyclohexane-2-yloxyethoxy)-5-(2-methoxy-phenoxy H2,2,] dimer嗓 ]]· decylamine; cyclopropylaminosulfonic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]_5_(2-methoxy-phenoxy)- [2,2']dipyrimidin-4-yl]- Benzylamine; benzylaminosulfonic acid-[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methyloxy-phenoxy)-pyrimidine- 4_yl]-nonylamine; furan-2-yl-methylaminosulfonic acid [6-[2_(5-bromo-m-butyl-2-n-oxy)-ethoxy]-5-(4- Chloro-phenyl)-pyrimidin-4-yl]-decylamine; cyclopropyldecylaminosulfonic acid [5-(4-chloro-phenyl)-642-(5-methoxy- 唆-2 -yloxy)-ethoxy]-naphthyl-4-yl]-decylamine; cyclopropylmethylaminosulfonic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)) -ethoxy]-5-(4-chlorophenyl)-pyrimidin-4-yl]-decylamine; cyclopropyl sylamino sulfonic acid [6-[2-(5-bromo-pyrimidine-2) -yloxy)-ethoxy]_5_p-tolyl^mididineyl]-decylamine; mercaptoaminosulfonic acid [6·[2-(5-bromo"metidin-2-yloxy) Base)_Ethoxy]Teng-6 - This paper scale applies to Chinese National Standard (CNS) Α4 Specification (210 X 297 mm) 1303245 A8 B8 C8 D8 VI. Application for Patent Fan Yuan-4-yl-5-pair -Tphenyl-cyano-4-yl]-nonylamine; mercaptoaminosulfonic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]_5_('chlorine _ phenyl)-2-p-precipitate-4-yl-p-precipitate 4-yl]-bristamine; ethyl [5-(4-Bromo-phenyl)-6-[2-(5-bromo-methane-2-yloxy)-ethoxy]-melan-4-yl]-guanamine; [6-[2-(5. bromo-pyrimidin-2-yloxy)-ethoxy]-5-(4-chloro-phenyl)------ 4-yl]-bristamine , arylamino glutamic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5_(4_溪_phenyl)-p-melt-4-yl] -Acrylic amine, pyridin-2-yl-methylaminosulfonic acid [6-[2-(5-bromo-furanyl-2-yloxy)-ethoxy]-5-(4-chloro-benzene Thiophen-2-yl-methylaminosulfonic acid [6-[2-(5-bromo-rhodium 1-yloxy)-ethoxy]-5 -(4-chloro-phenyl)-molecule_4_yl]-bristamine; mercaptoaminosulfonic acid [5-(2-chloro-5-decyloxy-phenoxy)&gt;6_[2_( 5-bromo-pyrimidine-2-yloxy)-ethoxy]-pyrimidine 4-yl]-decylamine; ethylaminosulfonic acid [5-(4-chlorophenyl) each [2_(5 _ _ _ 啶 j 基 基 ) ) ) ) ) 。 。 。 ; ; ; ; ; ; ; ; 。 。 。 。 。 。 。 。 11. The compound according to any one of claims 1 to 9 which is selected from the group consisting of /, outer biting -2 -yl-methylaminosulfonic acid [5-(4-chloro-phenyl) winter [2_(5-bromo-pyridin-2-yloxy)·ethoxy]-m-mentyl-4-yl]-nonylamine; oxime-2-yl-methylaminosulfonic acid [5_( 4-chloro-phenyl)_6-[2-(5-methoxy-pyrazin-2-yloxy)-ethoxy]-τι-dense winter base> decylamine; this paper scale applies to China Standard (CNS) A4 specification (210X297 public) 1303245 as B8 C8 D8 VI. Patent application range Cyclopropylamine bromate-phenyl)-6-[2-(5-bromo-predomide-2-yloxy) ))-ethoxy] lyl-4-yl]-slip amine; ethylaminosulfonic acid 1&gt;(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidine-2- (yloxy)-ethoxy]-chary-4-yl]-total amine; ethylaminosulfonic acid [5-(4-chloro-phenyl)-6-[2-(5-methoxy) -pyrimidine-2-yloxy)-ethoxy]-pyrimidin-4-yl]-decylamine; butylamino-based acid [5-(4-lacyl-phenyl)-6-[2-(5 -bromo-m-butyl-2-yloxy)-ethoxy]pyrimidin-4-yl]-decylamine; N-mercaptomethylaminosulfonic acid [5-(4-chloro-phenyl)- 6-[2-(5-bromo-precipitate-2-yloxy)-ethoxy ]-pyrimidin-4-yl]-decylamine; N-benzylmethylaminosulfonic acid [5-(4-chloro-phenyl)-6-[2-(5-methoxy-pyrimidine-2- Methoxy)-ethoxy]-pyrimidin-4-yl]-guanamine; or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical composition for the treatment of a condition associated with the role of the endothelin, which comprises a compound according to any one of claims IX to 9 and a common carrier substance and an adjuvant. 13. The pharmaceutical composition according to claim 12, wherein the condition is a circulatory condition or a proliferative condition. 14. The pharmaceutical composition according to claim 3, wherein the circulatory condition is blood pressure, blood stasis, vasospasm or palpitations, and the proliferative disorder is cancer. 15. The pharmaceutical composition according to claim 12, wherein the condition is migraine, asthma, hyperlipidemia or an inflammatory condition. 16. A compound according to any one of claims i to 9 of the patent application, which is -8 1303245 , k is used to (7) treat drugs that are associated with the role of the endothelin. 17. 2 A compound according to claim 16 wherein the condition is a % conditional proliferative condition, migraine or inflammatory condition. Mouth, the compound of claim 17, wherein the circulatory condition returns blood pressure, blood stasis, vasospasm, palpitations or blood fat and the proliferative disorder is cancer. 19. A compound according to any one of the items (1) of the scope of the patent application, for use in the treatment of a condition associated with the role of the endothelin and which requires both blocking and sputum receptors. A compound according to any one of the claims of the present application, "for the treatment of a disease associated with the role of the endothelin, i-sex eta-receptor blockade. A compound according to any one of the claims (1), wherein the agent is used for the treatment of a condition associated with the role of the endothelin and for the treatment of sexual ETB-receptor blockade.