TWI298323B - Arylalkane-sulfonamides for treating disorders associated with a role of endothelin and pharmaceutical compositions comprising the same - Google Patents

Description

1298323 A7 B7 V. INSTRUCTION DESCRIPTION (1) The present invention relates to a novel arylalkane-sulfonamide of the formula I, and the use thereof as an active ingredient in the preparation of a pharmaceutical composition. The invention is also related to methods of making a compound, a pharmaceutical composition comprising one or more compounds of formula I, especially for use as an endothelin receptor antagonist. Endothelin (ET-1, ET-2 and ET-3) are peptides of 21 amino acids that are active in almost all tissues (Yanagisawa M et al.: Nature (1988), 332: 411). Endothelin is a potent angiotensin and is an important mediator of heart, kidney, endocrine and immune functions (McMillen MA et al.: J Am Coll Surg (1995) 180:621). It is involved in bronchoconstriction and the regulation of the release of neurotransmitters, activation of luminescent cells, fibrogenesis, cell proliferation and cell differentiation (Rubanyi GM et al.: Pharmacol Rev (1994) 46: 328). Two endothelin receptors have been selected and identified 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 and ET-2 than for ET-3. It is mainly in vascular smooth muscle cells and can regulate vasoconstriction and proliferative responses (Ohlstein EH et al.: Drug Dev Res (1993) 29·108). In contrast, the ETB receptor has considerable affinity for the three endothelin isopeptides and binds to the linear form of endothelin, 肆-ala-endothelin, and sarafotoxin S6C (Ogawa Y et al:: BBRC (1991) 178 :248). This receptor is located in the vascular endothelium and smooth muscle and is particularly rich in the lungs and brain. The etb receptor from endothelial I cells can mediate transient vasodilatation responses to ET-1 and ET-3 via the release of nitric oxide and/or prostacyclin, while ETB receptors from smooth muscle cells exhibit Vasoconstriction (Sumner MJ et al.: -4- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1298323 A7 _B7____ V. Inventive Note (3), including 25 mM MnCl2, 1 mM EDTA and 0.5% (w/v) BSA in a polypropylene microtiter plate. The membrane containing 0.5 μg of protein was incubated at 20 °C for 2 hours with 8 pM [125I]ET-1 (4000 cpm) And the concentration of unlabeled antagonists. The maximum and minimum binding systems were estimated in samples with no 1 〇〇 nM ET-1. After 2 hours, the membrane was on the filter disk (containing GF/C filter paper, Unifilterplates). Filtration from Canberra Packard S. A. Ziirich, Switzerland. Add 50 μl of liquid scintillation counting admixture (MicroScint 20, Canberra Packard SA Ziirich, Switzerland) in each well > Counting on the disc counter (TopCount, Canberra Packard SA Zfirich, Switz Erland) All test compounds were soluble, diluted in and added to DMSO. The assay was performed in 2.5% DMSO and was found to not significantly interfere with binding. IC5G was estimated to inhibit ET-1 specificity. Binding to 50% antagonist concentration. For reference compounds, the following IC5G値 can be seen: ETA cells: 0.075 nM (n=8) at ET-1 and 118 nM (n=8) at ET-3; ETB cells: 0.067 nM ( η = 8) ΕΊΜ and 0.092 nM (η = 3) in ΕΤ-3. The IC5 所得 obtained by the compound of the formula I is shown in Table 1. -6 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1298323 A7 B7 V. INSTRUCTIONS (4) Table 1: Example compounds IC5〇ETA[nM] IC50 ETB[nM] Example 1 27 6650 Example 2 20 899 Example 5 3 323 Example 7 4 3310 Example 1 0 9 2410 Example 1 3 4 3680 Example 1 4 6 2230 Example 1 9 3 1930 Example 2 9 10 406 Example 3 9 3 261 Example 4 6 7 2360 Example 4 7 24 2720 Example 49 4 2490 Example 5 2 5 1770 Example 6 1 10 1140 Example 7 1 115 > 10000 Example 8 1 24 824 2 ) In the isolated rat aorta ring (ETA receptor) and rat tracheal ring (Ε Inhibition of Endothelin-Axonal Contraction by Τβ Receptor) Assessing the Inhibitory Intensity of Endothelin Antagonists, Assessing the Inhibition of Endothelin-1 Hypertrophy on Rat Aortic Rings (ETA Receptors), and Evaluating The paper size of the rat tracheal ring (ETB receptor) induced by sarafotoxin S6c is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1298323 A7 ~--- B7 _-__ V. Description of the invention (5) Inhibition. Adult rats were anesthetized and bled. The large thoracic artery or trachea was cut out, dissected and cut into 3 _ 5 mm rings. Slowly rub the inner surface to remove the endothelium/epithelial. Each loop was suspended in 1 〇 ml of the separated organ bath filled with Krebs-Henseleit solution (in mM; NaCl 115, KC1 4·7 'MgS04 1.2 'KH2P〇4 1.5, NaHC03 25, CaCl2 2.5, glucose 10) Maintain at 37 ° C and fill with 95% 〇 2 and 5% CO 2 gas. The loop is connected to the force transducer and the power tension is recorded (EMKA Technologies SA, -Pans, France). The ring is stretched to a rest of 3 grams (aorta) or 2 grams (trache). The cumulative dose of sputum (aorta) or sarafotoxin S6c (trache) was added after incubation with the test compound or its vehicle for 1 minute. The functional inhibitory strength of the test compound is evaluated by estimating the concentration ratio of the concentration of the test compound, i.e., the shift of ECw to the right. ECw is the endothelin concentration required to achieve maximum contraction ' ' 'pA〗 is the negative logarithm of the antagonist concentration that can double the displacement in EC" 値. Obtained by the compound of formula I!) 八値 is shown in the table 2. Table 2: Example compound pA2 (aortic ring) PA2 (trache) Example 5 8.38 7.02 Example 7 8.83 7.07 Example 8 7.43 Example 3 4 · 7.67 Example 6 1 7.83 7.07 Example 7 5 7.76 • -8 - This paper scale applies Chinese National Standard (CNS) A4 Specification (210X297 mm) 1298323 A7 _____B7 .___ V. INSTRUCTIONS (6) Because of its ability to inhibit endothelin binding, the compounds can be used to treat endothelin and vasoconstriction, proliferation or Inflammation increases the disease associated with this disease. Examples of this disease are hypertension, coronary disease, cardiac dysfunction, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage 'Renault' syndrome, portal vein Hypertension and pulmonary hypertension. It can also be used for atherosclerosis to prevent restenosis after balloon or stent vascular stenosis, inflammation, 'stomach and duodenal ulcers, cancer, prostatic hypertrophy Erectile dysfunction, dysfunction, hearing loss, cataract, chronic bronchitis, asthma, Gram-negative bacteremia, stroke, sickle-type anemia, glomerulonephritis, renal large intestine, glaucoma, treatment of diabetic complications And prevention, complications of vascular or cardiac surgery, or complications after organ transplantation, complications of cyclocycline treatment, pain, and other diseases currently known to be associated with endothelin. Compounds can be administered orally, transanal, parenteral, For example, intravenous, intramuscular, subcutaneous, intrathecal or transdermal administration or sublingual administration, or ophthalmic preparation or in aerosol form. Examples of application include capsules, lozenges, oral suspensions or solutions. Agent, suppository, injection, eye drop, ointment or aerosol/nasal spray. Preferred application is intravenous, intramuscular, or oral and eye drops. The dosage used depends on the specific active ingredient type. The age and condition of the patient, and the type of application. Generally, a dose of _1_5〇mg per kilogram of body weight per day may be considered. The compound preparation may contain an inert or pharmacologically active form. For example, lozenges or granules may contain a plurality of binders, filling excipients, carrier materials or diluents. The present invention relates to aryl acetamidines of formula I, -9-benz The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1298323 A7

V. Description of invention (7)

N^V"X, R3 丫

Wherein R1 and R2 represent an aryl group; a heteroaryl group; R3 represents a phenyl group; a mono-, di- or tri-substituted phenyl group is substituted by the following: a lower alkyl group, a lower sulfhydryl group, a lower alkyne group Base, phenyl, lower alkoxy, amine, lower alkylamino, amino-lower alkyl, trifluoromethyl, trifluoromethoxy, hydrazine, low carbon thiol, transbasic, Alkyl-low carbon alkyl 'cyano' carboxyl group, lower alkyl alkano group, formyl group; benzofuranyl group; aryl group; heteroaryl group; R4 represents hydrogen; halogen; trifluoromethyl group; lower alkyl group ; lower alkyl-amino; lower alkoxy; lower alkyl-fluorenyl; 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-neck; lower alkyl-amino - lower alkyl; amine; di-lower alkyl-amino; [Ν-(trans-carbocarbo)-oxime-(lower alkyl)]amine; aryl; aryl- Amine; aryl-lower alkyl-amino; aryl-thio; aryl-10- This paper scale is suitable for a standard ((10)) Α 4 specification (21G X 297 公公) 1298323 A7 _____B7 V. Description of Invention (9) A "" The oxy group has a straight and branched chain of 1 to 7 carbon atoms, preferably 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, n-butyl lactyl 'isobutyl lactyl' di-butoxy and tert-butoxy. The lower alkyl alkanedioxy group is preferably a methylenedioxy group, an ethylenedioxy group, a propylenedioxy group and a butylenedioxy group. Examples of the lower alkane group are an ethyl group, a propyl group and a butyl group. The low carbon thiol group is represented by, for example, a vinyl group, a propylene group and a butenyl group. Lower fluorenyl and lower alkynyl are represented by an extended ethyl group, a propyl group, a butyl group, a 2-methyl-propenyl group, an exoacetylene group, a propargyl group, a propynyl group, a pentynylene group. , 2-methyl-exetylene group and the like. The lower methoxy group represents 晞 propyloxy, ethoxylated, propyloxy and others. And cycloalkyl represents a cyclic hydrocarbon having 3 to 7 carbon atoms saturated, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may be lower alkyl, hydroxy-low Carboalkyl, amino-lower alkyl, lower alkoxy-lower alkyl and low carbon exocyclic. Heterocyclyl means a saturated or partially unsaturated four, five, six or seven membered ring containing one or two nitrogen, oxygen or sulfur atoms which may be the same or different and which may be suitably substituted as follows: low Carboalkyl, amine, nitro, alkoxy, lower alkoxy, such as piperidinyl, flupronyl, thiomorpholine, piperidinyl, tetrahydropyranyl, dihydropyran Base, 1,4-dioxanyl, pyrrole aryl, tetrahydroanthranyl 'dihydrop-bihaki, dihydromyristyl, dihydro ρ thiol, pyrazole bond, 5-keto -1,2,4-oxadiazolyl, 5-keto-1,2,4.thiadiazolyl, 5-thioketo-1,2,4-oxadiazolyl, 2-keto- 1,2,3,5-indole-oxadiazolyl (such as [7]) and derivatives on the ring substituted by the above substituents - This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210X297 mm) 1298323 A7

Things. Heteroaryl denotes a six-membered aromatic ring containing one to four nitrogen atoms, a pyrene ring, and a benzene-fused benzene of the three nitrogen atoms, containing one: one having a nitrogen or a sulfur atom A member of the aromatic ring, containing - oxygen or a bismuth atom fused to the five-membered aromatic ring, 虱子 π## A mouth with milk and nitrogen source 炙 five shells 袄 , ,, and it is thick and thick a derivative containing a five-membered aromatic ring of sulfur and a benzo-fused derivative thereof, and a five-membered aromatic ring of a nitrogen atom of π 3 and a benzo-fused derivative thereof, a five-membered aromatic ring of a nitrogen atom and a benzo-fused derivative thereof, or a tetra-n-based ring such as a sulfhydryl group, a thienyl group, a pyrrolyl group, a pyridyl group, a pyrimidinyl group, a fluorenyl group, or a porphyrin group. 'Isoquinolinyl, imidazolyl, tri-negative, thioglycolyl, thiazolyl, iso-farolyl, tarotyl, oxazolyl, isoxazolyl, etc., which is substituted by the following: Lower alkyl, lower sulfhydryl, amine, amine _ lower alkyl, iS, hydroxy, lower alkoxy, trifluoromethoxy, trifluoromethyl, thiol ' Base, low carbon pitoxy-cyano group, a few groups - a lower alkyl group, a lower alkoxy group - a lower alkyl group or another heteroaryl group (preferably a tetradecyl group) or a heterocyclic group - ring (preferably 5-keto-1,2,4-succinyl, 5-keto-1,2,4-trisyl, 5-keto-1,2,4-decane dioxime Base, 5·thioketo-1,2,4-oxadiazolyl or 2-keto-1,2,3,5-oxadiazolyl (eg [7])). The aryl group represents an unsubstituted and mono-, di- or tri-substituted aromatic ring having 6 to 10 carbon atoms such as a phenyl or an indenyl ring which may be substituted with an aryl group, a tooth, a hydroxyl group. , lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower methoxy,? a carbynyl-lower alkyl-oxy group, a low-carbon thiol group, a low-carbon decyloxy group, a low-carbon decyloxy group or a low-carbo-oxydioxy group, forming a five- or six-membered ring with a benzene ring Ring, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy- -13- This paper scale is suitable for the standard of the product (S10) A4 specification (21QX297 public mold _ order

t 1298323 A7 B7 V. INSTRUCTIONS (") Lower alkyl-lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy, trifluoromethyl, three Fluoromethoxy, cycloalkyl, hydroxy-cycloalkyl, heterocyclic, heteroaryl. It is understood that the substituents related to the above cycloalkyl, heterocyclic, heteroaryl and aryl are clear For the sake of the definitions of the formulae (I) to (V) of the first to the first paragraphs of the patent application, the definitions of the formulae (I) to (V) of the first to the first paragraphs of the patent application are defined. It is to be construed as being included herein. A preferred compound is a compound of formula I wherein R3 represents a phenyl group or a monosubstituted phenyl group which may be substituted with a lower alkoxy group, especially a methoxy group, and X represents oxygen. A second preferred group of compounds of formula I wherein R3 represents a phenyl group or a monosubstituted phenyl group, is substituted by a lower alkoxy group, especially a methoxy group, and wherein X, γ and Ζ represent oxygen A third preferred group of compounds of formula I is those wherein R 3 represents a phenyl group or a monosubstituted phenyl group, which is substituted by a lower alkoxy group, especially a methoxy group, and wherein χ, γ and Ζ represent oxygen and Q generation -(CH2)k-, k = 2 or 3. A fourth preferred group of compounds of formula I wherein R2 represents a heteroaryl group, R3 represents a phenyl group or a mono-substituted phenyl group, substituted by a lower alkoxy group, In particular, methoxy, X, Y and Z represent oxygen, and Q represents _(cH2)k-, k = 2 or 3. The fifth group of compounds of formula I are those wherein R2 represents a heteroaryl group and R3 represents a benzene group. A phenyl or a monosubstituted phenyl' is substituted by the following: hydrazine, lower alkyl, lower fluorenyl, methoxy, fluorenyl, lower alkyl-amino, lower alkyl-thio, hydroxy, hydroxy Methyl and low carbon decyl; X, γ and z represent oxygen, and Q represents -(ch2)2·. Another preferred compound is compound-14 of formula 11-

1298323 A7 B7 V. Description of invention (12)

Formula II and wherein R, R2, R3, R4, Y, Q, Z and η are as defined above for Formula I, are pharmaceutically acceptable salts of Formula II. Also preferred is a compound of formula III

-15- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X 297 mm) 1298323 A7 B7 V. Description of invention (13) where R1, R2, R4, Y, Q, Z and η are as in Formula I above Definitions, and pharmaceutically acceptable salts of the formula III. Also preferred is a compound of formula IV

I

Wherein R1, R2, R4, Q and η are as defined above in formula I, and a pharmaceutically acceptable salt of formula IV. Another preferred compound is a compound of formula V.

Ν 0 Formula ν -16- 〇\ R2 This paper size is applicable to China National Standard (CNS) Α4 specification (210X 297 mm) 1298323

Treatment and prevention of symptoms, complications after vascular or cardiac surgery or organ transplantation, complications of yttrium treatment, pain, and other diseases currently known to be associated with endothelin. These compositions may be administered in the form of enteral or oral form, such as lozenges, pills, gelatin capsules, emulsions, solutions or suspensions, in nasal form such as sprays or via the anal suppository form. These compounds can also be administered intramuscularly, parenterally or intravenously, such as in the form of injectable solutions. These pharmaceutical compositions may contain a compound of formula I, as well as a pharmaceutically acceptable salt thereof, in combination with an inorganic and/or organic excipient which is generally used in the pharmaceutical industry, such as lactose, corn. Starch or its derivatives, talc, stearic acid or salts of these substances. As the gelatin capsule, vegetable oil, wax, lipid, liquid or semi-liquid polyol can be used. For the preparation of solutions and syrups, such as water, polyols, sugars, glucose, etc. can be used. The preparation of the injection uses, for example, water, a polyol, an alcohol, glycerin, a vegetable oil, a lecithin, a liposome or the like. The suppository can be prepared by using natural or hydrogenated oils, waxes, fatty acids (lipids), liquid or semi-liquid polyols, and the like. The composition may additionally contain a preservative, a substance for improving stability, a substance for improving or regulating viscosity, a solubility improving substance, a sweetener, a dye, a taste improving substance, a salt for changing isotonic pressure, a buffer substance, an anti-oxidant, etc. . The compounds of formula I may be combined with one or more other therapeutically useful substances such as [alpha]-[beta]-blockers such as phentolamine, phenoxybenzylamine, amoxicillin: (atenolol) 'Principal (pr〇pran) 〇i〇i) ' timolol, methoxyphene, (metoprolol), carteolol, etc.; vasodilators, such as phthalocyanine -18- 1298323 A7 B7 V, invention description (16) (hydralazine), long pressure ( Minoxidil), diazoxide, flosequinan, etc.; #5 - antagonists such as diltiazem, nicardipine, verapamil, nifedipine, etc; ACE-inhibitors such as cilazapril, captopril, enalapril'lisinopril, etc.; Agents such as pinacidil; vasopressin 11 antagonist; diuretics such as dihydrochloride p-plug well, chloride edge v well, acetolamide, tympanic acid, diuretic amine, metolazone, chlortalidone, etc.; sympathetic block Such as methyldopa, can be Ning, guanabenz, equal to blood; and other therapeutic agents used to treat high blood pressure or any heart disorder. The dosage can vary widely, but should be adapted to a specific condition. In general, the oral dosage form shown should be between 3 mg and about 3 g, preferably between about 10 mg and about 1 g, especially between about 5 mg and 300 mg, for each adult. 70 kg weight scale. The dose should be administered in an amount of 1 to 3 doses per day, which is equivalent. As for normal children, lower doses should be accepted depending on body weight and age. The compounds of the formula I according to the invention can be prepared in the following reaction sequence. For the sake of simplification and clarification, sometimes the synthetic possibility part only describes the part of the compound of formula I. The literature references shown in box ([]) are listed at the end of this paragraph. Possibility A: A compound of the formula I, which can be prepared by formulating a compound of the formula:

-19- This paper wave scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1298323 A7 B7 V. Description of invention (17 where G1 is a reactive residue, preferably a chlorine atom, and another symbol Reaction with a compound of formula 2 as defined in formula I: Η Z—Q—Υ 2 wherein the symbols are the same as defined in the above formula I, or a salt thereof. Possibility B: The compound of formula I may also be Formula 3 compound··

Loading

R4 person ν'

Ύ I zΗ order

Wherein the symbol is the same as defined in the above formula I, or a salt thereof, and reacted with the compound of the formula 4 to prepare G2-R2 Formula 4-20- The paper size is applicable to the Chinese National Standard (CNS) Α4 specification (210 X 297 public) PCT) 1298323 A7 B7 V. Inventive Note (18) wherein G2 is a reactive residue such as a halogen atom, and R2 is as defined in Formula I. Possibility C: The compound of formula I can be a compound of formula 5:

Type 5

Wherein G 3 is a lower alkylsulfonyl or phenylsulfonyl or a halogen atom, and the other symbols are the same as those described in the general formula I, or a salt thereof, which is prepared by reacting with a compound of the formula 6: H—R 4 Formula 6 Wherein R4 is as defined above in formula I, or a salt thereof. See also [5] for possibilities A to C. -21 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1298323 A7 B7 V. Invention description (19) Process 1: Preparation of precursors 1 and 3, X, Y and Z represent oxygen :

Analog of Formula 1 L Analog of Formula 3 a) NaOMe, MeOH followed by NH4C1 or LiN(Si(CH3)3)2, followed by HCl/i-PrOH; b) K2C03, acetone; c) NaOMe, MeOH; d) POCl3; e) NH3/THF followed by KOtBu, MeOH; f) DMSO; g) NaH, THF, DMF; oxime 8 synthesis using standard method [1], suitable nitrile 7 and The sodium is reacted in methanol, followed by the addition of ammonium sulfate, or with hexamethyldioxane, followed by the addition of hydrochloric acid to isopropanol. 2 -Substituted malonate 1 0, -22- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1298323

λ* (Step [2] Preparation' is to react dimethylchloromalonate (7) with palatable, drunk 1 1 in acetone' and use potassium carbonate as a base. Compound 1 is dissolved in methanol' plus methyl Na, and (d) about 3G minutes, plus human cockroach derivative 8 / continue to stir at ambient temperature for another 8 hours. After acid treatment, μ · 焱 密 4 4 can be 70-90% [2] yield Separation. Compound 12 or its mutual isomeric form is converted to a gas derivative i 3, using a scale gas in the presence of n, n-dimethylaniline at elevated temperature (6 (M2 (rc), yield is 4〇_75% [3]. In some cases, a better yield can be obtained by adding pci5 or benzyl-triethylammonium gas. One vapor 13 and an excess of suitable sulfonamide potassium salt 丨5 Reaction (prepared from sulfogas 14 by standard methods) (see [9], [1〇] for preparation of 14), pyrimidine 16 can be produced at DMS and rt, yield 70-90%, from EA/ After recrystallization in diethyl ether or chromatography on EA/heptane by gelatin, pyrimidine derivative 16 is a key intermediate 'which can be converted to the desired end product of formula I, or the step shown in possibility A, or Convertible derivative 18, with formula 1 7 The bis-hydroxyl compound represented by the reaction, in the presence of a base (such as sodium hydride) and a solvent (THF), at rt to 9 (TC, and can be converted to the formula I according to the procedure listed in the possibility b The final product. For further experimental explanation, see [1], [2], [3], [6]. Compounds in which X ' Y or Z are non-oxygen, can be synthesized in a similar manner. -23- This paper scale applies China National Standard (CNS) A4 Specification (210X 297 mm) 1298323 A7 B7 V. Description of Invention (21)

Process 2: Preparation of the precursor 5, X, Y and Z represent oxygen:

a) I) thiourea, NaOMe, MeOH, rt; ii) CH3I, DMSO, rt; iii) POCl3, dimethylaniline, 100-120 〇C; b) ΚΛ((:Η2)η-802-ΝΗΚ, DMSO, rt; c) R2-0-Q-0H, NaH, THF/DMF, rt or 60-80 °C or HO-Q-OH, NaH, THF/DMF, rt4 60-80 °C, HG2- R2, NaH, THF, 60-80 〇C; d) MCPBA, DCM, rt. For further experimental explanation, see [1], [2], [3], [5], [6]. The substitution of sulfonyl groups and bases is especially visible [5]. ' -24- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1298323 A7 B7 V. Description of invention (22) Compound, X, Y or Z non-oxygen synthesis, can be similar steps get on. Scheme 3: Preparation of a precursor to synthesize a compound of formula I wherein X represents a bond [5]:

As described in Scheme 1; to the final product of Formula I -25 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298323 A7 B7 V. Description of invention (23) In Processes 1 to 3 The symbols are the same as defined in the above formula I. [1] W. Giihring, J. Schildknecht, M. Federspiel; Chimia, 50 (1996), 538-543. [2] W. Neidhart, V. Breu, D. Bur, K. Burri, M. Clozel, G Hirth, M. Miiller, Η. P. Wessel, H. Ramuz; Chimia, 50 (1996), 519-524 and references cited there. $« [3] W. Neidhart, V. Breu, K. Burri, M Clozel, G. Hirth, U. Klinkhammer, T. Giller, H. Ramuz; Bioorg. Med. Chem. Lett., 7 (1997), 2223-2228. RA Nugent, ST Schlachter, MJ Murphy, GJ Cleek, TJ Poel, DG Whishka, DR Graber, Y. Yagi, BJ Keiser, RA Olmsted, LA Kopta, SM Swaney, SM Poppe, J. Morris, WG Tarpley, RC Thomas; J. Med. Chem., 41 (1998), 3793 -3803. Order

[4] J. March; Advanced Organic Chemistry, 4th Ed., 1994, p. 499 and references cited there.

[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] Synthesis of 5-membered heterocyclic ring: Y. Kohara et al; J. Med. Chem., 39 (1996), 5228-5235 and references therein [8] EP 0 882 719 A1 (Yamanouchi Pharmaceutical) Co·,Ltd) [9] Z. Zhong, JA Bibbs, W. Yuan, C.-H. Wong, J. Am. Chem..

Soc. 113, (1991), 2259-2263 ~ [10] DJ Kempf, L. Codavoci, XC Wang, WE Kohlbrenner, -26- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1298323 A7 B7 V. INSTRUCTIONS (24) NE Wideburg, A. Saldivar, S. Vasavanonda, KC Marsh, P. Bryant, HL Sham, BE Green, DA Betebenner, J. Erikson, DW Norbeck, J. Med. Chem. 36 (1993), 320-330 Reference example (synthesis of precursors): abbreviations list; CyHex cyclohexane DCM di-methane methane DME 1,2-dimethoxyethane DMF dimethylformamide DMSO飒EA ethyl acetate Hex hexane ΗV high open condition MCPBA meta-chloroperbenzoic acid min min rt room temperature THF tetrahydrofuran sat. Saturated tR residence time The invention is illustrated by the following examples without limiting its scope. The following compounds were prepared as described above and shown in Schemes 1 through 3. All compounds were identified by 1H-NMR (300 MHz) and often using 13C-NMR (75 MHz) (Varian Oxford, 300 MHz; chemical shifts in ppm relative to the solvent used; multiplicity: s = single peak, d = doublet, t = wife peak, m = multimodal, coupling constant J by Η z), LC-MS (Waters -27- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1298323 A7 B7 V. Description of invention (25 ) ' -*—

Micromass; ZMD_ flat type, with ESI_probe, Auiance 279〇ht; column; 2X30 mm, GromsilODS4, 3 μm, l2〇A; gradient 〇 · 100% acetonitrile in water, 6 minutes, 0.05% formic acid, Flow rate · 〇 45 ml / min; 4 in minutes), TLC (TLC_ plate, from Merck, silicone 60 F254) and often utilized melting point. All temperatures are in order. C shows. Reference example 1

a) Sodium methylate (17 g) was dissolved in methanol in 〇eC (600 mL). 2. Para-tolyl-diethyl malonate (24.5 ml, available from Aldrich) was dissolved in 150 ml of methanol and added over 30 minutes. Stirring was continued for 1 hour while slowly warming the mixture to rt. Formazan hydrochloride (9.9 g, commercially available from Fluka) was added and stirring was continued for 16 hours. The solvent was evaporated, and 2 Torr of hydrogen acid (200 mL) was added to the residue, and then 1 〇 sodium hydroxide was slowly added to adjust the pH to 5. The precipitated product was filtered off and washed sequentially with water and diethyl ether. After drying, 5-----tolyl-pyrimidine _4,6-diol (17.7 g) was obtained. ^-NMR (300 MHz, d6-DMSO): 8·0 (s, 1H); 7·4 (d, 2H); 7·1 (d, 2H); 2.25 (s, 3H). b) 5-P-tolyl-pyrimidine-4,6-diol (17.2 g) was dissolved in phosphorus helium (250 ml), followed by n,N-dimethylaniline (25 ml). The mixture was stirred at 7 ° C for 16 hours and concentrated under a vacuum. The residue was poured into ice water and extracted with diethyl ether (3x). The mixed organic extracts were prepared on a 1N hydrochloric acid.28-paper scale using Chinese National Standard (CNS) A4 size (210 X 297 mm). 1298323 A7 B7 5. Inventive Note (26 Wash with saturated sodium chloride solution, Dry over magnesium sulfate, filter and evaporate the filtrate. The crude brown material was recrystallized from isopropyl alcohol to give 4,6-diox-5-para-tolyl-pyrimidine (13.5 g). iH-NMR (CDC13 ): 8,78 (s,1H),7.35 (d,2H); 7.20 (d,2H); 2.41 (s,3H). c) 2 - Preparation of the winter base In the step shown, phenylethyl mercaptan is oxidized with N-gas amber quinone. Moldy d) 2 -Phenylethanesulfonate (40.94 g) in THF (250 mL) was cooled to -20 ° C and treated with saturated aqueous ammonia. The brown suspension was stirred at rt for 16 hours. The mixture was neutralized with an aqueous solution of HCl and the organic solvent was evaporated. The remaining suspension was diluted with water and extracted four times with EA. The organic layer was combined and evaporated to give the bis-phenyl-ethanesulfonic acid decylamine (33.06 g) as an orange solid. 1H-NMR (300 MHz, CDC13): 3.15-3.21 (m, 2H), 3·38-3·45 (m, 2H), 4.59 (s br, 2H), 7·21-7·37 (m, 5H). Order

e) To a solution of 2-phenyl-ethanesulfonate decylamine (33.06 g) in methanol (300 ml), EtOAc (20.03 g). The resulting solution was stirred for 15 minutes and then evaporated. The residue was washed with diethyl ether (4 liters) and dried under high venting to give 2- phenyl-ethanesulfonic acid decylamine potassium salt (37.93 g) as an orange powder. f) 2-Phenyl-ethanesulfonate decylamine potassium salt (3.0 g), 4,6-digas-5-p-tolyl-pyrimidine (2.15 g) and Hunig's test (1.57 ml) in DMSO The solution (50 ml) was stirred at rt for 20 hours, then diluted with water (500 mL) and extracted with EtOAc (250 mL). The aqueous phase is acidified with acetic acid. The resulting suspension was cooled to 5 ° C and filtered. The solid substance is washed with water and diethyl ether and dried at 4 ° C and high open air to produce 2-phenyl-ethanesulfonic acid (6 - gas-5 -para- -29- China National Standard (CNS) A4 Specification (210X297 mm) 1298323 A7 B7 V. Description of Invention (27) Tolyl-pyrimidine·4-yl)-guanamine (2.08 g) is a gray powder. LC-MS: tR = 5.23 min, [Μ+1]+=388·18, [Μ-1Γ=386·14. t· g) 2-phenyl-ethanesulfonic acid (6-gas-5-p-tolyl-pyrimidin-4yl)-decylamine (850 mg) was added to the third potassium butyrate (1.1 g) ) in a solution of ethylene glycol (15 ml). The mixture was stirred at 120 ° C for 27 hours, then diluted with water (100 mL) and acidified with 10% aqueous citric acid (13 mL). The resulting precipitate is collected, washed with water and diethyl ether, and dried to give [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidine-4 as 2-phenyl-ethanesulfonic acid. -Based on - decylamine (716 mg) was a succulent powder. LC-MS : tR=4.44 min, [Μ+1]+=414·18,[Μ-1Γ=412·13 0 Reference example 2

Order

a) To a solution of sodium (0.23 g) in methanol (40 ml), 4-cyanopyridine (10.62 g) was added at room temperature. Stirring was continued for 6 hours, then ammonium chloride (5.9 g) was added and stirring was continued for another 1 hour. Diethyl ether (120 ml) was then added and the precipitate was filtered after 30 min and washed with diethyl ether (20 mL). The product was dried under high venting to give 4-ytyl-pyridine hydrochloride (14.95 g) as a white powder. b) A solution of sodium methyl (6.8 g) in methanol (200 mL) was cooled to 0 °C. Then slowly add 2-(p-tolyl)-diethyl malonate (10.3 g) to methanol-30- This paper scale applies Chinese National Standard (CNS) A4 size (210 X 297 mm) 1298323 A7 B7 V. Solution to the invention (28) (50 ml). Once completely added, the solution was returned to room temperature and 4 -mercapto-p ratio hydrochloride (7.57 g) was added. The mixture was stirred at room temperature for 16 hours. Finally, the solvent was removed under reduced pressure and the residue left was dissolved in 2 EtOAc. The solution was extracted with diethyl ether and adjusted to ρ with 1 〇 NaOH. A precipitate can be formed. The sediments were collected, washed with cold water, and dried at 6 ° C and high open air. 4,6-Di-mercapto-2-(4-pyridyl)-5-(p-tolyl)-pyrimidine (8.77 g) (or tautomer) can be formed as an orange crystal. c) To a mixture of 5 _(p-tolyl)-4,6-dihydroxy-pyrimidine (8.0 g) and p.sub.3Cl.sub.3 (100 mL). The mixture was stirred at 60 ° C for 16 hours. Excess P0C13 was removed by distillation under reduced pressure. The remaining oil was dissolved in DCM (300 mL) and treated with water (3 mL). The aqueous layer was separated and extracted three times with D C Μ. The combined organic layers were washed with water and brine. Dry on MgS04 and evaporate. The remaining residue is suspended in isopropanol. The solid matter was collected, washed with isopropanol and diethyl ether, and dried to give 4,6-<-gas ratio to decyl)-5-(p-tolyl)-salt (7.2 g) as white crystal Powder. LC-MS: tR = 5.49 min, [M+l] + = 315.89. d) 4,6-dioxa-2·(4-pyridyl)-5-(p-tolyl)-pyrimidine (1.5 g), 2-phenyl-ethanesulfonate decylamine potassium salt (ι· 44 g, Reference Example 1 e) and a solution of Hunig's base (1 ml) in DMSO (20 ml), stirred at rt for 24 hours, then diluted with water (150 mL) and twice with diethyl ether. The aqueous layer is acidified with acetic acid. The precipitate was collected and further purified by silica gel column chromatography, and dissolved in hexane:EA 1 :1 to give 2-phenyl-ethanesulfonic acid (6-gas-2-p ratio -4-yl-) 5-p-Tolyl-Methyl-4-yl)-bristamine (480 mg) was obtained as a foam. LC-MS : tR=5.08 min, [Μ+1]+=465·13, -31 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

1298323 A7 B7 V. INSTRUCTIONS (29 ) [Μ-1]-=462·96 0 e) 2 - Winter base-Ethyl tiger acid (6-gas-2-p ratio -4- base-5-pair Toluene-tolyl-pyrimidin-4-yl)-guanamine (480 mg) was added to a solution of a third potassium butyrate (580 mg) in ethylene glycol (5 mL). The mixture was stirred at ll ° C for 72 hours, then diluted with water (100 mL) and acidified with 10% citric acid (3 mL). The resulting precipitate is collected, washed with water and diethyl ether, and dried to give 2-phenyl-ethylhexanoic acid [6-(2-alkyl-ethoxy)-2-pyridin-4-yl-5-pair Bit-tolyl-pyrimidin-4-yl]-decylamine is a gray-brown powder. LC-MS: tR = 4.17 min, [Μ+1]+=491.24, [Μ-1]·=489·08. Reference example 3

2-N-based-ethylidene acid [6-(2-3⁄4-yl-ethoxy)_5·para-tolyl·[2,2']bispyrimidinyl-4-yl]-decylamine The procedure shown in Example 2 was prepared starting from 2-mercapto-pyrimidine hydrochloride (e.g., 〇 〇 526 708 Α 1). LC-MS: tR = 4.42 min, [Μ+1]+=492·30, [Μ·1]·Μ9〇 27. Reference example 4

This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1298323

2-Phenyl-ethanesulfonic acid [5·(4·Bromo-phenyl)·6_(2·hydroxy-ethoxypyrimidin-4-yl]-guanamine prepared in a manner similar to that of Reference 5 Substituting methyl 4-bromophenylacetate for methyl 4-bromophenylacetate in the step &), and replacing 2-thiophenyl-2-yl-B with 2-phenylene-ethyl citrate potassium citrate Alkyl sulfonate amide # salt, in step d). LC-MS : tR=4.60 min, [M+1]+=48〇 〇7, [Μ-1]-=475.76 ο Reference Example 5

Ti % line mad) (similar to J. Am. Chem. Soc. 122 (2000), steps 1360-1370). In Pd(OAc) 2 (455 mg), 2-(di-tert-butyl-phosphino)-biphenyl (1.21 g) and Κ3Ρ04 (39.6 g) in THF (200 mL) To the suspension of the ester (12.85 g), 1-bromo-3,4-dimethyl-benzene (15.0 g) was added under argon. The mixture was refluxed for 16 hours, cooled to rt then diluted with EtOAc (EtOAc) and filtered. The mash liquid is evaporated, and the resulting color oil is purified on the crushed rubber to form 2-(3,4-dimethyl-phenyl)-malonic acid by heptane: EA 4 : 1 to 1: 1 Methyl ester (16.2 g) is a colorless oil that slowly crystallizes. 1H-NMR (300 MHz, CDC13): 2.25 (s, 3H), 2.26 (s, 3H), 3·75 (s, 6H), 4.59 (s, 1H), 7·10-7·20 (m, 3H). b) 2-Phenyl-ethanesulfonic acid [5-(3,4-dimethyl-phenyl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-decylamine, Similar to Reference Example 1, the preparation was carried out using dimethyl 2-(3,4-dimethyl-phenyl)-malonate. LC-MS: tR = 4.61 min, [Μ+1]+=428·19, [Μ-1]·=426·07. -33- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1298323 A7 B7 V. Description of invention (

Reference Example 6 a) (Similar to Step 1 of J. Am. Chem. Soc. 122 (2000), 1360-1370). In a suspension of Pd(OAc) 2 (758 mg), 2-(di-t-butylphosphino)biphenyl (2.02 g) ruthenium 3Ρ04 (65.95 g) in THF (350 mL) Dimethyl ketone (21.42 g) and 1-bromo-2,4-dimethyl-benzene (25 g) under argon. The mixture was refluxed for 96 hours, cooled to rt then diluted with EtOAc (300 mL) and filtered. The filtrate is evaporated, and the brown oil is purified on silica gel. It is separated by heptane: EA 4 : 1 to 1: 1 and distilled (bp 95-100 ° C, 0.064 mbar) to form 2-(2,4- Dimethyl dimethyl-phenyl)-malonate (5·66 g) was obtained as a colorless oil. 1H-NMR (300 MHz, CDC13): 2·30 (s, 6Η), 3·75 (s, 6Η), 4·87 (s, 1Η), 6·98·7·05 (m, 2Η), 7·25-7·28 (m,1H) 〇b) 2-Phenyl-ethanesulfonic acid [5-(2,4-dimethyl-phenyl)-6-(2-hydroxy-ethoxyl )--------------------------------------------------------------- LC-MS: tR=4.54 min, [Μ+1]+=428.23, [Μ-1]·=426·07. Reference example 7

This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 1298323 A7 ____B7 V. Description of invention (32) a) 2-methoxy-phenol (guaiacol) (48 ml) It was added to a stirred suspension of potassium carbonate (70.8 g) in acetone (480 ml) and heated to 45 °C. Further, dimethyl chloromalonate (63 2 ml) was added to acetone (50 ml) over 20 minutes, and the reaction mixture was heated to reflux for 16 hours. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted with EtOAc. The mixed organic layer was dried on sulfuric acid steel and evaporated. The oily product crystallized from methyl-tert-butyl ether to give dimethyl(2-methoxyphenoxy)malonate (86 g). b) Add dimethyl-(2-methoxyphenoxy)malonate (21.7 g) to a stirred solution of methyl sodium (9.7 g) in methanol (1 mL) over 15 min. Methanol (50 mL) was added and stirring was continued for 3 hrs, and then phosphinyl-pyridine hydrochloride (15 g, Ref. 2) was then stirred at room temperature for 2 hrs. The reaction mixture was concentrated under a hollow. The solid residue was stirred with diethyl ether. The filter is filtered out at the end, and the valley is in the water (3 〇 q loves to rise). Add acetic acid to p Η = 4. The precipitated product was filtered off, washed with water and dried (5 ° C and dried) to give white powder ' 5-(ortho-methoxyphenoxy)_4,6-dihydroxy-2-(4- Pyridyl)-methane (20·1 g, possibly also tautomeric 5-(2-methoxyphenoxy)-2-(4-pyridyl)-tetrapyrimidine-4,6-di ketone). c> 5-(2-Methoxyphenoxy)-4,6-dihydroxy-2-(4-pyridyl)-pyrimidine (10 g), N-ethyldiisopropylamine (11.2 g), four Ethyl ammonium chloride (11 g) and five gasified phosphorus (13.8 g) were dissolved in phosphorus brewing gas (25 ml) and heated to reflux for 3 hours. The mixture was evaporated to dryness, toluene was added and the mixture evaporated again. The residue is absorbed by D C ’ and poured into ice/water. The layers were separated and the organic layer was washed with water and dried over sodium sulfate. Recrystallization from acetone, can be obtained pure _ -35 - This paper scale is applicable to China National Standard (CNS) Α4 specification (210X 297 mm) 1298323 A7 _B7____ V. Invention description (33) 4,6-two gas- 5-(2-Methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (6.52 g) ° d) 4,6-di-gas-5-(2-methyllacylphenoxy)- 2-(4-峨 基 基 ( (2 g) and 2-phenyl-ethanesulfonate decylamine potassium salt (2.82 g, refer to Example 1 e) in DMF (50 liters) solution at rt Stir for 16 hours. The large volume of the solvent was evaporated first and then diluted with diethyl ether (50 ml). The mixture was acidified with 10% citric acid. The formed precipitate was collected, washed with diethyl ether (1 mL) and dried. 2-Phenyl-ethanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-decylamine (2.23 g) ) grayish brown powder. LC-MS: tR = 4.93 min, [Μ+1]+=497·22, [Μ-1]-=494·96. e) For NaH (644 mg, 60% in mineral oil) In a suspension of DME (15 ml), ethylene glycol (15 ml) was added. Once the gas overflow has ceased, 2-phenyl-ethanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl] is added. - decylamine (800 mg), and the resulting solution was stirred at 90 ° C for 16 hours. A portion of NaH (322 mg) was added and stirring was continued for 4 days at 90 X:. The mixture was diluted with E A (200 mL) and washed once with 1% citric acid in water and three times with water. The organic phase was evaporated and the residue was suspended in diethyl ether. The solid matter is collected, washed with diacetic acid, and dried to give [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-2-phenyl-ethanesulfonate. Pyridin-4-yl-pyrimidin-4-yl]-decylamine (513 mg) as a brown solid. LC-MS: tR = 4.05 min, [ Μ +1] + = 523·10, [Μ-1]-=521·24. Reference example 8

This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X 297 mm) 1298323 A7 ___ B7 V. Description of invention (34) a) 2-Phenylethanesulfonic acid [6-chloro-5-(2-A Oxy-phenoxy)-2-(2-pyrimidinyl)-4-nutrientyl]-bristamine, prepared in analogy to Reference Example 7, prepared from 4,6-dithia-(2-methoxybenzene Oxy)-2-(2-pyrimidinyl)-pyrimidine (prepared as disclosed in [6]) and 2-phenylethanesulfonamide potassium salt (Reference Example 1). LC-MS: tR = 4.85 min, [Μ+1]+= 498·38, [Μ-1]-=496·19. b) For NaH (803 mg, 60% dispersion in mineral oil) in DMF (15 mL), carefully add ethylene glycol (15 mL). After the H2-gas overflow is stopped, 2-phenylethanesulfonic acid [6-gas-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] is added] - guanamine (1 g). The resulting solution was heated to 9 ° C and stirred for 16 hours. The pale yellow solution was re-cooled to rt, diluted with EtOAc (1 mL) and then extracted three times with EA (50 mL). The combined organic layers were washed more than once with 10% aqueous citric acid solution, washed with brine (50 mL) and evaporated. The remaining residue was suspended in water (15 ml). The solid was filtered off, washed with methanol (50 ml) and diethyl ether (50 ml) and then dried to give 2-phenylethanesulfonic acid [6-(2-hydroxy-ethoxy)-5- (2) -Methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-decylamine (766 mg) as a white solid. LC-MS: tR = 4.32 min, [Μ+1]+=524.47, [Μ-1]-=522·29. Reference example 9

[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyrylene-2-yl-pyrimidin-4-yl 2-phenyl-ethanesulfonic acid ]-Acetamine according to the example shown in Example 7 -37- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1298323 A7 B7

V. Description of invention (35) ^=4.37 minutes,

Prepared from 2-mercapto-pyrazine hydrochloride. LC_MS

[Μ+1]+=524·18,[Μ-1]·=522·44 〇 Reference example 1Ο

2-Phenyl-ethyl benzoic acid [6-(2-monoethylethoxy)-2·Noffolin I-based]-bristamine, according to the reference example;淋-4-carboxy 眯 gas desertification hms: *, eight clocks, [Μ Γ Γ = 531 · 25, [Μ-1] · = 529 5 〇. R ·:> Knife Reference Example 11

2-Phenylethyl succinic acid [6_(2-carbo-ethoxy)-5-(2-methoxy-benzoinyl)-(tetra)·4·yl]•enamines according to Reference Example 7 The steps are shown to be prepared, starting with a vein hydrochloride. LC-MS: tR = 4.35 min, [MW. , [μ_ι:

Binding

=444.11 0 Reference example 12

1298323 A7 B7 V. INSTRUCTIONS (36) a) To a solution of 3-methoxyphenol (115 g) in acetone (1000 ml) was added K2C03 (115 g). The suspension was stirred at 4 (TC) for 15 minutes. A solution of dimethylchloromalonate (133 ml) in acetone was added over 45 minutes. The resulting brown suspension was stirred overnight at 70 ° C. Finally, solvent The residue was taken up in water (1 mL) and EtOAc (EtOAc)EtOAc. Base-(3-methoxyphenoxy)malonate (230 g) in orange oil. The product was no longer purified. b) p-Dimethyl-(3-methoxyphenoxy)-propane A solution of the diester (11·19 g) in methanol (100 mL) was added methyl sodium (6.48 g). The yellow solution was stirred at rt for 6 hours. Further, morpholine-4-carboxyindole hydrobromide (8.40 g) was added, and the mixture was stirred at rt for 16 hours. The solvent was removed in vacuo and the residue dissolved in water (150 ml) The aqueous phase was acidified with a 10% aqueous solution of citric acid. The separated solid was collected, washed with water, and evaporated twice in EA, and dried under high hollow to give 5-(3-methoxy-phenyllactyl)-2-moff-4-yl-σ- Precipitate-4,6-diol (9.66 g) was a brown powder. LC-MS: tR=2.88 min, [Μ+1]+=320·19, [Μ-1]· =318.02. Ο 5-(3-Methoxy-phenoxy)-2-iflufen-4-yl-salient-4,6-diol (9.66 g) was added to P0C13 (1 mL) and Hunig's In a mixture of bases (5 liters). The black suspension was heated to 110 ° C and stirred for 16 hours. The mixture was cooled, N,N-dimethylaniline was added and heating was continued for another 24 hours. The large solvent evaporates and the remaining oil is poured into the water. The dark solution was treated with charcoal and extracted once with E A (3 〇 mL). The organic phase is washed with brine and water at -39- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1298323 A7 ______B7_ V. Invention description (37) ^ —

Dry on MgS〇4 and evaporate. The remaining oil was chromatographed on silica gel and dissolved in heptane: E A . The product is recrystallized from 2-propanol, and the pale yellow crystals are washed with diethyl ether to give 4-(4,6-di--5-(3-methoxyphenoxy)-pyrimidinyl]-? Porphyrin (7.48 g) 〇LC-MS: tR=5.56 min, [Μ+1]+=355·99. d) 4-[4,6-dichloro-5-(3-methoxy-phenoxy) a solution of pyrimidine·2·kibofoline (1.0 g) and 2-phenyl-ethanesulfonate guanamine potassium salt (1·57 g, refer to Example 1 e) in DMSO (15 ml) Stir under 6 24 for 24 hours. The solution was diluted with water (75 mL) and then extracted twice with diacetic acid (75 mL) and then acidified with 10% aqueous citric acid. The mixture was extracted twice with E a (丨 5 mL). The organic phase was washed with water (50 mL). The product can be sanitized by evaporation of the solvent. The solid was collected, washed with diethyl ether and dried to give 2-phenyl-ethane-cross-acid [6- s--5-(3-methoxy-phenoxy)- 2- phenofyl-4-yl-pyrimidine 4-yl; the amine (1.28 g) is white powder. LC-MS: tR = 5.34 min, [Μ+1]+=505·12, [Μ·1]·=502·97. e) 2 -Phenyl-ethanesulfonic acid [6-Gapent-5-(3-methoxyphenoxy)-2-ifluent-4-yl-pyrimidin-4-yl]-nonylamine (ΐ·27 A suspension of ethylene glycol (12 mL) was treated with potassium tri-butyrate (2.82 g). The resulting solution was stirred at i〇〇eC for 12 days. The solution was cooled to rt, diluted with 10% aqueous EtOAc (150 mL) and EtOAc (EtOAc) The organic phase was washed with water (50 mL) and evaporated. The crude product is purified by gelatin chromatography and eluted with heptane: EA (1:1 to 1:2) to form [6-(2-hydroxy-ethoxy)·5· (3 -Methyl-mercapto-oxatol)-2 -Walfolin-4-yl-m-butyl-4-yl]-S-transamine (1.1 g) as a white solid. LC-MS: tR = 4.66 min, [Μ+1]+= 531.20, [M-1]· = 529.14. -40- This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1298323 A7 B7 V. Invention description (38)

Reference Example 1 3 2-Phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxymethoxy-phenoxy)-pyrimidin-4-yl]-chatoline, as shown in Reference Example 12 The procedure was prepared starting from formazan hydrochloride. ^-NMR (300 MHz, CDC13): 3.14-3.21 (m, 2H), 3.70-3.74 (m, 2H), 3·79 (s, 3H), 3.94-4.01 (m, 2H), 4.4〇-4 · 46 (m, 2H), 6.41 (dd, J = 2.4, 8.4, 1H), 6.47 (t, J = 2.4, ih), 6.66 (dd, J = 1.8, 8.4, 1H), 7.16-7.32 (m,6H),8·37 (s,1H); LC-MS: tR=4.33 min, [M+l]+=446.27,[Ml]-=444.05. Reference example 14

a) The 2-thiophenyl-2-ylethanesulfonyl group gas was obtained according to the procedure shown in the literature (J. Am. Chem. Soc. 103 (1981), 1525-1533) from the product 2-(2). - 7 odor-ethyl) phenanthrene. b) A solution of the crude 2 -thioxan-2-yl-ethyl hydride (5 5 g) in THF (400 mL). The mixture was stirred at rt for 16 hours and then neutralized with a 25% aqueous HCl solution (60 liters). Large group T H F evaporates. The aqueous solution was extracted twice with E A . Organic phase washed with water -41 ·

^状跳财H S 家料_) A4_21QX 297 public $ 1298323 A7 B7 V, invention description (39) re-evaporation. The oil remaining is purified by silica gel chromatography and can be dissolved in heptane: EA (1:1). The product was recrystallized from diethyl ether / pentane to give further purified product to give the title compound (yield: 8.46 g) of 2-thiophenyl-2-yl-ethanesulfonate as white crystals. .NMR (300 MHz, CDC13): 3.36-3.50 (m, 4H), 4.54 (s br, 2H), 6.89-6.92 (m, ih), 6.95 (dd, J = 3.5, 5.1, 1H), 7· 20 (dd, J=ll, 5.0,1H) 〇c) 2-Choxa-2-yl-ethanesulfonate decylamine (3.77 g) in methanol (200 mL) (2·21 g), stirred at rt for 15 minutes, evaporated, and dried under venting to give 2-bromobenzene-2-yl-ethanesulfonic acid decylamine potassium salt (4.5 g) as a yellow powder. d) 2-Chlorophenyl-2-yl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-decylamine, using the above 2 -Thionyl-2-yl-ethanesulfonate decylamine potassium salt, prepared according to the procedure shown in Reference Example 1. Ifj-NMR (300 MHz, CDC13): 2·42 (s, 3H), 3.33-3.41 (m, 2H), 3.81-3.86 (m, 2H), 3.99-4.07 (m, 2H), 4.46-4.51 ( m,2H),6.82-6.86 (m,1H), 6.92 (dd,J=3.5,5.1,1H),7.13-7.18 (m,3H),7.28-7.32 (m, 2H),8.51 (s,1H) LC-MS : tR=4.18 min, [M+l]+=420.24, [Μ-1]·=418.20 〇

Reference example 15

a) 35 °C in 4-phenylphenylacetate (52 g) in THF (170 ml). This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1298323 A7 — _ B7 Inventive Note (4〇) In a solution, it was carefully added to a suspension of NaH (15.6 g) in anhydrous THF (5503⁄4 L) over 70 min. Stirring was continued for 4 minutes without heating and the temperature dropped to 29 C. At this point, the escape of the gas ceremony was stopped before the dropwise addition of dimethyl carbonate (94.8 liters) while the temperature of the mixture was maintained at 25-28 °C. Once the gas evolution ceased, the mixture was diluted with THF (200 mL) and stirring was continued at rt for 72 hours. The mixture was carefully acidified with aqueous HCI and then a large portion of THF was removed from vacuo. The residue was dissolved in diethyl ether (1200 mL), washed with EtOAc EtOAc EtOAc. After the residue was formed, it was collected, washed with diethyl ether and dried to give diethyl 2-(4-chloro-phenyl)-malonate (42 g) as white crystals. b) A solution of 2-(4-phenylphenyl)-malonic acid dimethyl ester (18.90 g) in methanol (200 ml) was added dropwise at 0 ° C to methyl sodium (14.60 g) in methanol ( 150 ml) in solution. The mixture was stirred at 0 ° C for 1 hour, and then formazanic acid (7.66 g) was added. The suspension was stirred at rt for 20 hours. The solvent was removed and the residue was suspended in 2N aqueous HCI (200 mL). The pH of the suspension was adjusted to 4-5 by adding 10 Μ NaOH (20 ml) and stirring was continued for 30 minutes. The white precipitate was collected, washed with water and diethyl ether and dried to give 5-(4- phenylphenyl)-pyrimidine-4,6-diol (16.44 g) as a white powder. 1^-]^13:, = 2.75 minutes, [Μ+1]+=222·96, [Μ-1]-=220·92.

c) For the suspension of 5-(4-phenylphenyl)-pyrimidine-4,6-diol (16.44 g) in P0C13 (165 ml), carefully add N,N-dimethylaniline (16.5 ml) . The mixture was refluxed for 1.5 hours. The dark green solution evaporated and the residue was poured into ice/water. The suspension was diluted with 2 N HCl (200 ml), and water (800 ml) was added and 2 ° C -43-. The paper scale was applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1298323 A7 B7 V. Invention Stir under the instruction (41) for 1 hour. The precipitate was collected, washed with water, and dried to give 4,6-di-methane- 5-(4-phenylphenyl)-methane (18.66 g). d) 4,6-dioxa-5-(4-phenylphenyl)-pyrimidine (848 mg), 2-thiophenyl-2-yl-ethanesulfonate decylamine potassium salt (1.5 g, reference example 1 4 And a solution of Hunig, base (1 liter) in DMSO (20 mL), stirred at rt for 24 h then diluted with water (200 mL) and twice with diethyl ether. The aqueous layer is acidified with acetic acid. The precipitate is collected, washed with water and diethyl ether, and dried to form 2-thiobenzene-2-yl-ethyl group [6-gas-5-(4-air-benzidine-4-yl)- Amine (93 g) is a gray-brown powder. LC-MS ·· tR=5.01 min, [Μ+1]+=413·49, [Μ-1]-=411·93 〇e ) 2 -Sulfur -2-yl-ethyl-anti-continuation &ι[6-milk-5-(4-carbo-phenyl)-mlyl-4-yl]-guanamine (930 mg) was added to the third potassium butyrate (l·16 g) in a solution of ethylene glycol (lo ml). The mixture was stirred at 110 ° C for 12 hours and then diluted with water (150 mL). The resulting precipitate is collected, washed with water and diethyl ether, and dried to give (820 mg) of 2-thiophenyl-2-yl-ethyl succinic acid [5-(4- gas-phenyl)-6-(2 -Phenyl-ethoxy)-pyrimidin-4-yl]-decylamine, a grayish brown powder. lc-MS: tR = 4.43 minutes, [Μ+1]+=440·01, [Μ-1]·=437·99. Reference example 1ό

2-thiophenyl-2-yl'ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-.44- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298323 A7 B7

Phenoxy)-2-pyridin-4-ylpyrimidin-4-yl]-guanamine, prepared according to the procedure shown in Referential Example 7, and desalting salt with 2-thiophenyl-2-yl-ethanesulfonate amide (Reference Example 14); LC-MS: tR=4.00 min, [μ+1]+=529·29, [μ 1]. =526.97 〇Reference example 1 7

2-Chlorophenyl-2-yl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5(2-methoxy-phenoxy)-2-histan-4-yl- Pyrimidine-4-carbetamine, prepared according to the procedure shown in Reference Example 10, using potassium salt of 2-thiophenyl-2-yl-ethanesulfonic acid (Reference Example 14); LC-MS: tR = 4.62 Minutes, [Μ+1]+=537.21, [M-1]- =534.96. Reference example 1 8

a) 2 - Pyridin-2-yl·ethanesulfonate Hydrochloric acid according to the procedure of j. Med chem 36 (1993), 320-330, prepared from commercial 2-pyridine-2·ethane can acid. b) 2-pyridine-2-yl-yl-ethyl ruthenium sulphate, prepared according to the procedures of Reference Examples 丨*b and 14c, prepared from the above 2·pyridin-2-yl-ethanesulfonate gas hydrochloride . c) 4,6--disorder - 5·(2-methyllactyloxy)-2-(4-p-pyrylmidine (I.75) This paper scale applies to China National Standard (CNS) Α4 specification ( 210 X 297 mm) 1298323 A7 _B7 Five Inventions (43) """" grams, reference example 7) and 2-pyridin-2-yl-ethanesulfonate decylamine potassium salt (1.13 g) A solution of DMSO (30 mL) was stirred at rt for 24 hours. Triethylamine (6 5 7 gram) was added and continued for another s s s s s s s s s s s s s The aqueous solution is washed with water and the aqueous phase is extracted with EA twice. The organic phase is dried on Mg S04 and evaporated. The crude product is purified by silica gel column chromatography using EA with 〇_1〇% methanol. 2-峨峨-2-yl-ethyl benzoate [6-chloro-5-(2-methoxy-phenoxy)-2-ylidene-4-pyrimidin-4-yl]-guanamine (950 mg) in brown powder. LC-MS: tR = 3.63 min, [Μ+1]+=498·31, [Μ_1]·=496·10 〇d) for NaH (701 mg, 60% in mineral oil) In a suspension of DMF (15 liters), ethylene glycol (15 ml) was added. Once the evolution of the gas has ceased, 2·pyridine·2-yl·ethanesulfonic acid [6-Gapent-5-(2-methoxy-phenoxy)_2-pyridin-4-yl----- 4-Base]-g of the amine (800 mg), the resulting solution was stirred at 9 ° C for 40 hours. The solution was neutralized with 2 N aqueous HCl (7 mL) and evaporated. The brown residue was purified by preparative tic-plate chromatography eluting with e A: methanol: saturated aqueous ammonia (10 ······1). The product is further purified by recrystallization from methanol: diethyl ether: pentane to give 2-pyridin-2-yl-ethanesulfonic acid [6-gas (2-hydroxy-ethoxy)-5-(2-methoxy) -Phenoxy)_2-pyridyl-4-yl-pyrimidin-4-yl]-decylamine (280 mg) as a tan-brown crystal dH_NMR (300 MHz, CDC13): 3.36-3.43 (m, 2H)V 3.86- 3.90 (m, 2H), 3.94 (s, 3H), 4.23-4.30 (m, 2H), 4.56-4.62 (m, 2H), 6.91 (dt, Jd=1.5,

Jt=7.7, 1H, 7.00 (dd, J=1.7, 8.2, 1H, 7.08-7.20 (m, 4H), 7.57 (dt, Jd=1.8, Jt=7.9, 1H), 8.15 (dd, J=1.7, 4.6, 2H), 8.43 (d3 J=4.4,1H), 8.72 (dd, J=1.7, 4.6, 2H); LC-MS: tR=3.23 minutes, -46- This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1298323 A7 B7 V. Description of invention ([Μ+1]+=524·48, [Μ-1Γ=522·25. Reference example 19

a) Phenyl-methanesulfonamide potassium salt was prepared in a similar manner to the procedures shown in Reference Examples 1 d and 1 e, using commercially available phenylmethanesulfonium chloride. W-NMR (300 MHz DSMO): 3.73 (s, 2H), 7.13-7.30 (m, 5H) 〇b) N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy -Phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]phenyl-methanesulfonamide, prepared in a similar manner to Reference Example 7, using the above phenyl-methanesulfonamide potassium salt. LC-MS : tR=3.99 minutes, [Μ+1]+=509·32,[Μ-1]·=507·31 〇 Reference example 2 0

N_[6-(2-#k-ethoxy)-5-(2-methoxy-phenoxy)-[2 2,] bis-p-butyl-4-yl]-C-phenyl - A marrying amine was prepared in a manner similar to the reference example, using a phenyl-methanesulfonamide potassium salt (Reference Example i 9). LC-MS: tR = 4.15 min, [Μ+1]+=510·34, [Μ-1]-=5〇8·54. This paper scale is applicable to China National Standard (CNS) Α4 specification (210X 297 mm) 1298323 A7 B7 V. Description of invention (45 Reference example 2 1

N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-histan-4-yl-pyrimidin-4-yl]-C-phenyl- Methanesulfonamide was prepared according to Reference Example 1 using phenyl-methanesulfonamide potassium salt (Reference Example 19). LC-MS: tR = 4.54 min, [Μ+1]+=517·32, [Μ-1]-=515·07. Reference example 22

a) The preparation of p-tolyl-methanesulfonyl chloride is the p-tolyl-methanethiol commercialized with ruthenium-aluminum amber quinone imine, similar to the procedure shown in [9]. b) The preparation of the p-tolyl-methanesulfonamide potassium salt is similar to the steps of Reference Examples 1 d and 1 e. 1H-NMR (300 MHz, CDC13) (sulfonamide): 2 36 (s, 3H), 4·27 (s, 2H), 4.63 (s br, 2H), 7.20 (d, J = 7.9, 2H) 7.30 (d, J=8.1, 2H). ' c) Ν-[6·(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2·pyridin-4·yl-pyrimidin-4-yl]-C- The p-tolyl-methanesulfonamide was prepared using the para-tolyl-methanesulfonamide potassium salt, similar to the procedure shown in Reference Example 7. -48- This paper size is applicable to China National Standard (CNS) Α4 specification (210X 297 public 1298323 A7 B7 5. Invention description (46 ) LC-MS : tR=4.18 minutes ' [Μ+1]+=523·22,[ Μ-1]-=521·19 0 Reference example 2 3

Ν-[6-(2-Phenyl-ethoxy)-5-(2-methoxy-phenoxy)-2-ρ ratio ρ Well-2-yl-pyrimidin-4-yl]-C - p-tolyl-methanesulfonamide was prepared using the upper para-tolyl-methylpyramine potassium salt, similar to the procedure shown in Reference Example 9. LC-MS : tR = 4.46 min, [Μ+1]+=524·20, [Μ-1]·=521·93. Reference example 24

% line · a) 3-Phenyl-propyl tiger-1. The preparation of the base gas is based on the Ν-gas number, although the aniline is oxidized and commercialized by 3-phenyl-propanone-1-thiol, similar [ The steps disclosed in 9]. b) 3-Phenyl-propanone-1 - hexanoic acid potassium salt, prepared in a similar manner to the procedures shown in Reference Examples 1 d and 1 e. 1H-NMR (300 MHz, CDC13) (sulfonamide): 2.11-2.23 (m, 2H), 2·76 (t, J = 7.5, 2H), 3.05-3.13 (m, 2H), 4.85 (s br , 2H), 7.14-7.40 (m, 5H) oc) 3-phenyl-propane-1 -sulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolylpyrimidin-4-yl Potassium amine was prepared in a similar manner to that of Reference Example 1, using the above 3-phenyl-propane-1-sulfonic acid decylamine potassium salt. LC-MS : tR=4.66 This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1298323 A7 B7 V. Invention description (minutes, [Μ+1]+=428·24,[Μ- 1].=426·21. Reference example 25

3_Phenyl-propan pit-1·sulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2·pyridine-4-ylpyrimidine_ 4 - Gipperide, prepared in a similar manner to that shown in Reference Example 7, using 3-potassium propane-1-sulfonic acid guanamine potassium salt, with reference to Example 24. LC-MS: tR=4.14 min, [Μ+1]+=537.45, [Μ-1Γ =535.41 〇 Reference example 2 6

3_Phenyl-propane-1-sulfonic acid [6-(2-hydroxy-ethoxy)·5_(2·methoxy-phenoxy)-[2,2']bipyrimidine_4·yl] - decylamine, prepared in a similar manner to the procedure of Reference Example 8, using the potassium salt of 3-phenyl-propane-l-sulfonic acid decylamine, with reference to Example 24. LC-MS : tR=4.37 min, [Μ+1], 538·38, [Μ-1]·=536 27 〇 Reference example 27 "

This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1298323 A7 B7 V. Description of invention (48)

3-Phenyl-propane-1-cross-acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-iorfolin-4-yl-dense 4 _ yl]-amine, prepared in a similar manner to that shown in Reference Example 1 ,, using 3-phenyl-propanone-1-supply acid guanamine potassium salt, with reference to Example 24. LC-MS: tR=4.80 min, [M+l]+=545.40, [Μ-1]-= 543.52 0 Reference Example 2 8 Ν-[6-(3·hydroxy-propoxy)-5-(2 -Methoxy-phenoxy)-[2,2,]bipyrimidinyl-4-yl]-C-phenyl-methyl-carboxamine, prepared in a similar manner to the procedure shown in Reference Example 2, using propane- 1,3_diol replaces ethylene glycol. LC-MS: tR=4.13 min, [Μ+1]+=524·34, [Μ-1]-=522·19. Reference example 2 9

3-Phenyl-propan-1-dylic acid [6-(3-Acidyl-propoxy)·5_p-tolyl_. The chitosan-4-ylamine was prepared in a similar manner to the procedure of Reference Example 24, using a propane-1,3-diol instead of ethylene glycol. LC-MS: tR=4 72 min, [Μ+1]+=442·28, [Μ-1]-=440·22. This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210X 297 mm) 1298323 A7 _ B7_;___ V. INSTRUCTION DESCRIPTION (49) EXAMPLE The following examples illustrate the invention without limiting the scope of the invention. The following reagents have been synthesized to prepare the following examples, based on or similar literature steps: 5-bromo-2-a-pyrimidine (Aust J. Chem. 17 (1964), 794-802; 丄Org. Chem. 25 (1960) ), 1916-1919); 2,5-diox-pyrimidine (similar to 5-bromo-2-hydro-pyrimidine, replacing bromine with chlorine); 2-nitro-5-methyl-pyrimidine (M. Med. Chem. 6 (1963), 697-701; Aust. J. Chem. 30 (1977), 2515-2525); 2 - methanesulfonyl-5-methoxy-pyrimidine (J. Chem. Soc. Perkin Trans. 1 , 1999, 3265-3268; J. Org. Chem. 27 (1962), 3614-3617); 2-chloro-5-methylthioalkyl-peri-dense (II Farmaco 43 (1988), 277-292; Freeh Patent 1 549 494 (1968)); 2. Methanesulfonyl-5-trifluoromethyl-peri-dense (Tetrahedron Lett. 37 (1996), 182 9_1832); 2 - methanesulfonyl-4, 6-Dimethoxy-pyrimidine, prepared by standard methods, starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine. All other reagent components are commercially available components. Example 1

Add sodium hydride (50 mg, 60% in mineral oil) to THF (25 mL) followed by [6-(2-hydroxy-ethoxy)-5-para-toluene 2-phenyl-ethanesulfonic acid Base-pyrimidin-4-yl]-guanamine (15 mg, see Example 1). Mixing mixture at rt __-52- This paper size is applicable to China National Standard (CNS) A4 specification (21〇x 297 mm) 1298323 A7 B7 V. Invention description (5〇) 1 hour 'plus 2 - gas - Pyrimidine (8 6 mg). Stirring was continued for another 7 hours at 80 °c. The solvent was evaporated and diethyl ether (2 mL) was added to the residue. The precipitate was filtered, washed with diethyl ether, dissolved in water (2 liters) and then acidified with citric acid and twice with EA (50 ml). The organic phase was washed with water, dried over NaJO4 and evaporated. The residue was suspended in 2 -propanol (15 mL) and stirred at 70 C for 1 hr and cooled to hydr., then the solid material was collected and washed with 2-propanol (2 mL) Drying, can obtain 2 • phenyl-ethene sulfonic acid {6-[2-(pyrimidin-2-yloxy)-ethoxy]·5-p-tolyl-yin _4_jib Amine (133 mg) in white powder. : tR = 4.97 minutes, [Μ+1]+=492·34, [Μ-1]·=490·28. Example 2

Add sodium hydride (27 mg, 60% in mineral oil) to THF (15 ml), then add 2-phenyl-ethyltransacid [6-(2-carbo-ethoxy)-5-pair Position-tolyl-pyridin-4-yl]-guanamine (80 mg, see Example 1). The mixture was stirred at rt for 1 hour and then 2-chloro-5-trifluoromethyl-pyrimidine (86 mg). Stirring was continued for 1 hour at 80 °C. The solvent was evaporated and the residue was dissolved in water (2 mL) and acidified. The suspension was treated with hexane (15 liters). The solid material was collected, washed with hexane: EA (1:1, 20 ml), and dried to give 2-carbyl-ethyl-succinic acid {5-para-tolyl-6-[2-(5- Three chaotic methyl-deuterium-dioxide-2. This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1298323 A7 B7 V. Description of invention (51) oxy)-ethoxy]-pyrimidine- 4-Gipoxime (96 mg) was a taupe powder. LC-MS ·· tR=5.86 min, [M+1]+=559.20, [Μ-1]-=557·37. Example 3

For the suspension of NaH (17 mg, 60% in mineral oil) in DME (5 mL), 2-(4-bromo-phenoxy)ethanol (111 mg). The mixture was stirred at 5 ° C for 1 hour and then added with 2-phenyl-ethene acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-guanamine (100 mg, reference) Example 1 f) and third · potassium butyrate (25 mg). The mixture was stirred at 7 (TC) for 16 hours. Further further potassium-butyric acid (50 mg) was added and stirring was continued at 70 ° C for 12 hours and at rt for 72 hours. Treated with water (40 ml), acidified with 10% aqueous citric acid, and extracted with EA (50 ml). The organic phase was washed with water and evaporated. The crude product was crystallized from 2-propanol 2-phenyl-ethanesulfonic acid {6-[2-(4-bromo-phenoxy)-ethoxy]-5-p-tolyl-pyrimidin-4-ylbuminamide (127 mg) LC-MS: tR=6.14 min, [Μ+1], 568·38, [Μ-1].=570·15. Example 4

This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X 297 mm) 1298323 A7 B7 V. Description of invention (52) For NaH (29 mg, 60% dispersion phase of mineral oil) in DMF and THF (each 2.5 Suspension of the mixture, adding 2 phenyl ethanesulfonic acid [6_(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl) )-4-pyrimidinyl]-nonylamine (150 mg). Once the gas evolution ceased, 2 · chloropyrimidine (8 2 mg) was added to form a light yellow suspension and stirred at 7 ° C for 4 hours. It was again cooled to rt, diluted with EA (75 mL) and washed with 10% aqueous citric acid (5 mL) and water (50 mL). The organic layer was evaporated, and the residue was poured onto a preparative tic plate (silicone, 〇·5 mm thick plate) of ea:methanol:saturated aqueous ammonia (8:2:1). This completes 2-phenylethanesulfonic acid {5 gas 2-methoxy-phenoxy)_6-[2-(pyrimidin-2-yloxy)-ethoxy]-2-(2-pyrimidine) Base)-4-pyrimidinylpurine, in the form of a pale yellow powder. LC-MS: tR=4.60 min, [M+l]+= 602.69, [Μ-1]·=600·43 实例 Example 5

2.5 ml) suspension of the mixture, adding 2-phenylethyl benzoate [6-(2-carbyl-ethoxy)-5-(2-methoxy-phenoxy)-2-(2- Pyrimidinyl-4-pyrimidinyl]-decylamine (150 mg). Once the gas overflow has ceased, 2-air-5-bromo is added. Precipitate (138 mg). The resulting orange suspension was stirred at 70 ° C for 4 hours. An additional portion of NaH (29 mg, 60% in the dispersed phase of the mineral oil) followed by 2-gas-5-bromo-55- 1298323 A7 B7 5. Inventive Note (53) Pyrimidine (13 8 ml). The performance is heated and stirred for 25 hours. Finally, the reaction mixture was cooled to rt, then diluted with EtOAc (EtOAc) (EtOAc). The organic layer was evaporated, and the residue left was purified on a preparative tic plate (tank, 0.5 mm thick) with E A ··Methanol: a saturated aqueous ammonia solution (8:2:1). This produces 2-phenylethanesulfonic acid {5-(2-methoxy-phenoxy)-6-[2-(5-bromopyrimidin-2-yloxy)-ethoxy]·2 -(2-pyrimidinyl)-4-pyrimidinyl}-decylamine as a pale yellow powder. LC-MS: tR=5.11 min, [Μ+1]+= 680·23, [Μ-1Γ=678·36. Example

% Add 2-phenylethanesulfonic acid [6-(2-hydroxy-B) to a suspension of NaH (29 g, 60% in dispersed phase of mineral oil) in a mixture of DMF and THF (2.5 ml each) Oxy)-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-decylamine (150 mg). After the gas evolution ceased, 4,6-dimethoxy-2-methylsulfonylpyrimidine (156 mg) was added. The resulting yellow suspension was stirred at 70 ° C for 4 hours. Finally, the reaction mixture was cooled to rt, diluted with EtOAc (EtOAc (EtOAc) (EtOAc) The organic layer was evaporated, and the residue was purified on a preparative tic plate (tank, 0.5 mm thick). EA: methanol: aqueous ammonia (8: 2: 1). This produces 2-phenylethanesulfonic acid {5-(2-methoxy-phenoxy)-6-[2-(4,6-di-56- this paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1298323 A7 B7 V. Description of the invention (54) Methoxy-pyrimidin-2-yloxy)-ethoxy]-2-(2-pyrimidinyl)-4-pyrimidinyl Potassiumamine, a pale yellow powder. LC-MS: tR=5.21 min, [M+l]+=662.69, [Μ-1]-=660·23. Examples 7 - 8 6 The examples shown in Tables 1 to 8 were prepared in a manner similar to that of Examples 1 - 6, using Reference Examples 1 to 2 as starting materials. -57- This paper size applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1298323 V. Description of invention (55) Table 1: A7 B7

7 1 ..σ 8 1 9 2 10 2 11 2 12 2 13 3 14 3 15 3 16 4 17 4 18 4 ..σ ..σ ,Βγ „Βγ ..σΒΓ Η Η

•IX 19 5 ry ry·· σσσ Η Η Η Η

ΒΓ

α

..IX

..IX tR = 5.41 min [Μ+ΗΓ : 570.22 [Μ-ΗΓ : 568.16 t« = 5.11 min [Μ+ΗΓ :-[Μ-Η]* :504.11 tR = 5.26 min [Μ+ΗΓ : 530.32 [Μ -ΗΓ:-tR = 5.21 min [Μ+Η]+: 647.10 [Μ-Η]": 646.54 tR = 4.84 min [Μ+ΗΓ : 583.22 [M-Η]* :581.18 tR = 4.82 min [M+ Hf : 599.34 [Μ-Η]·: 597.45 tR = 5.28 min [Μ+ΗΓ :604.11 [M-Η]·: 602.42 tR = 5.33 min [M+H]+ : 647.96 [Μ-Η+2Γ : 647.52 tR = 4.97 min [M+H]+ : 600.19 [M-Hp 598.28 tR = 5.51 min [M+H]+ : 589.97 _]·: 587.47 tR = 5.56 min [Μ+2+ΗΓ : 636.23 [Μ-ΗΓ : 632.12 tR = 5.18 min [M+H+2]+ : 587.88 [Μ-ΗΓ : 583.91 tR = 5.59 min [Μ+ΗΓ :584.10 [Μ-Η+2Γ : 583.54 This paper size applies to the Chinese National Standard (CNS) A4 size (210X 297 mm) -58- 1298323 A7 B7 V. Description of invention (56) Table 1: Continued Ex. No Ref. Ex. No R1

R2 R3 LC-MS 20 5 21 6 22 6 23 7 24 7 25 26 27 8 28 8 29 8 30 8

tR = 5.24 min Η . [Μ+ΗΓ :536.32 [Μ-ΗΓ : 534.40 •丫, tR = 5.55 min H [Μ+ΗΓ :584.18 Br [MH]* :582.12 •.丫' tR = 5.46 min H ill . [M+H]+:552.03 ^ [MH]· :550.15 〇···. 〇···· σσ

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 丫, tR = 4.47 min n J [M+H]+ : 600.95 [M-H]·: 598.84

tR = 4.97 min [M+H]+:635.16 [M-H]* : 632.99 〇·-' 〇··-

tR = 5.02 min [M+H]+ : 679.17 [MH]·:- tR = 4.68 min [M+H]+:631.30 [MH]·: 629.22 tR = 4.90 min [M+H]+ : 636.17 [MH ]*: 634.43 tR = 4.73 min [M+Hf :614.10 [MH]* : 612.15 tR = 4.68 min [M+H]+ : 632.33 [MH]': 630.00 •丫' tR = 5.08 min 11 [Μ+ΗΓ : 670.19 CF3 [MH]· :668.34 -59- 1298323 A7 B7 V. Description of invention (57) Table 1:

Ex. No Ref. Ex. No R1 R2 R3

LC-MS 31 8

32 9

〇·- . tR = 5.42 min U^nc [Μ+ΗΓ :669.05 CF3 [MH]* :666.80 •丫' tR = 4.70 min IJ [Μ+ΗΓ : 602.25 [MH]· :600.18 33 9 ..,a 34 9

35

〇·-〇··...

tR = 5.19 min [Μ+Η+2Γ : 681.96 Br [M-H]·: 678.21 tR = 4.88 min [M+H]+ : 632.24 [M-H]·: 630.35

36 10

37 10

Όσ· ..ix 38 10

39 10

40 11

H ••IX Ό 41 11

H

Br 42 11

H

tR = 5.11 min [Μ+ΗΓ : 648.57 [MH]* :646.11 tR = 5.13 min [M+H]+ : 609.31 [MH]*: 607.25 tR = 5.67 min [M+H]+ : 686.92 [MH]* : 685.02 tR = 5.30 min [M+H]+ : 639.30 [MH]-: 637.13 tR = 5.51 min [M+H]+ : 654.92 [MH]· : 653.08 tR = 4.84 min [M+Na]+ : 524.32 [MH]·: 522.00 tR = 5.38 min [M+H]+ : 601.95 [MH]· : 600.33 - tR = 5.01 min [M+H]+ : 554.14 , [MH]*: 552.03 This paper size applies to China Standard (CNS) A4 size (210X 297 mm) -60- 1298323 A7 B7 V. Description of invention (58) Table 1: continued

R3 LC-MS atR = 5.75 min * [Μ+ΗΓ : 59144 Cf=3 [M-H]* :588.99

tR = 5.52 min [M+H]+ : 687.24 [M-H]·: 685.44

tR = 5.18 min [M+H]+ : 639.32 [Μ-ΗΓ: 637.14 tR = 5.25 min [M+H]+ : 602.00 [MH]- : 599.99 tR = 4.89 min [M+H]+ : 553.98 [MH ]* :551.97 -61 -This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298323 A7 B7 V. Description of invention (59 ) Table 2 ··

48 49 50 51 52 53 54 55 56 57 58 59 14 14 14 15 15 15 15 16 16 16 17 17 ,..σ..cr

,CI ..Ο01

H H H H , H H H 〇.·····σ. •·χχ

Br

, .iX

Cl

Br

CI

Br

Br tp = 5.24 min [M+H]+ : 532.13 [Μ-ΗΓ : 530.35 tR = 5.31 min [M+H]+ : 576.07 [Μ-ΗΓ : 574.19 tR = 4.95 min [M+H]. : 528.17 [ MH]* : 526.12 tR = 5.28 min [M+H]+ : 552.39 [MH].:550.27 tR = 5.33 min [Μ+Η+2Γ : 598.29 [MH]·: 595.43 tR = 5.07 min [M+H] + : 532.29 [MH]·: 529.95 tR = 4.99 min [M+H]+ : 547.89 [MH]': 545.91 tR = 5.07 min [M+H]+:641.16 [MH]': 638.75 tR = 4.96 min [ M+H]+ : 685.12 [MH]* : 683.33 tR = 4.62 min [Μ+ΗΓ : 637.18 [MH]' : 635.04 tR = 5.56 min [M+H]+ : 693.12 [MH]· :691.31 tR = 5.21 Min [M+H]+ : 645.35 [MH]·: 643.48 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -62-1298323 A7

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298323 A7 B7 V. Invention description (61) Table 4:

R3 Ex. No Ref. Ex. No R1 R2 R3 LC-MS 62 19 63 19 64 19 65 20 66 20 67 20 68 21 69 21 -64-

〇··... 〇·-0;· σ 〇·- "0 '.·α

Br, Br tR = 4.46 min [M+H]+ : 587.43 [MH]·: 585.40 tR = 5.00 min [M+H+2f : 667.12 [M-H+2]·: 665,47 tR = 5.71 min [ Μ+Η+2Γ : 665.39 [Μ-Η+2Γ : 662.71 ······, tR = 4.43 min IJ [Μ+ΗΓ : 588.66 [MH]·: 586.33

Br

tR = 4.93 min [Μ+Η+2Γ : 668.21 [Μ-Η+2Γ : 665.81

Br

Br tR = 5.52 min [Μ+Η+2Γ : 666.29 [MH]·: 662.25 tR = 5.01 min [Μ+ΗΓ : 595.27 [MH]· :593.18 tR = 5.46 min [M+H]+:673.11 [M- H+2】· : 673.42 This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1298323 A7 B7 V. Description of invention (62) Table 5:

71 22 72 23 73 23

Ο...Ί

tR = 5.28 min [M+H+2]+ : 681.24 [M-Η]* : 677.00 tR = 4.76 min [M+H]+ : 602.20 [MH]· :600.18 tR = 5.24 min [M+H]+ : 680.13 [MH]* : 678.14 -65- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1298323 A7 B7 V. Description of invention (63) Table 6:

R2 R3 LC-MS

tR = 5.13 min [M+Hf : 506.25 [MH]*: 504.26 tR = 5.62 min [Μ+Η+2Γ : 586.33 [MH]* :582.11 tR = 4.56 min [M+H]+:615.53 [MH]' :613.40 〇.·.··

〇-〇 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

tR = 5.09 min [Μ+ΗΓ : 694.42 [MH]': 692.21 tR = 5.09 min [M+Hf : 693.22 [MH]':691.07 tR = 4.58 min [M+H]+ : 616.54 [Μ-ΗΓ : 614.29 tR = 5.20 min [M+H]+: 623.37 [Μ-ΗΓ :621.19 tR = 5.66 min [Μ+Η+2Γ : 703.51 [M-H+2]* :701.52 -66 - 1298323 A7 B7 V. Description of invention (64) Table 7 ··

82 28

83 28

0;·0;' Ό

F3 tR = 4.55 min [M+H]+ : 602.43 [Μ-ΗΓ : 600.26 tR = 5.59 min [M+H]+ : 669.49 [M-H]·: 667.40 Table 8 ··

H 84 85 86 29 29 29

H

Br, Br

H a, tR = 5.71 min [Μ+Η+2Γ : 600.18 [Μ-ΗΓ : 596.05 tR = 6.21 min [M+H+2]+ : 598.96 [MH]· : 594.67 tR = 6.16 min [M+H] +: 587.19 [MH]·: 584.74 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 dongdong) 67- 1298323

09 (above name Announcement wood % year / ^月〇日修波) is replacing page '831 3121592 A4 C4 ~ palm filled by this bureau) # m %

Book New Name 中—^英•---- Last Name 文文

Arylalkyl-sulphonamide for the treatment of diseases associated with endothelin action and pharmaceutical compositions containing the same ARYLALKANE-SULFONAMIDES FOR TREATING DISORDERS ASSOCIATED WITH A ROLE OF ENDOTHELIN AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME Place name (name) nationality

1. Thomasville Willer THOMAS WELLER 3 Christopher Perth CHRISTOPH BOSS 5 · Watt Fitzgerald WALTER FISCHLI

2. MARTIN BOLLI 4. Martin Kroz MARTINE CLOZEL Country I 4· Shi Ruijun 5· 3. .2. ^o ^ weu 1498m No. M6 58 Tete Road Street Ma Ma W Tris斯乌柏兹巴莫1欧荷市市市市尔尔*ά尔根威威Μ威尼奇奇 4 奇宾艾艾ώ 士士士士瑞瑞瑞法里 L2.3.4.5· Swiss company Aike Tailian Pharmaceutical Co., Ltd. ACTELION PHARMACEUTICALS LTD. Swiss applicants, 16 Jiva Bay Street, Aiqiwei, Switzerland

1. Cher SCHERER 2. Willer WELLER A4 specification (210X297 mm)

κ月丨1曰修(8)正换页 B7 I2983^^90121592 Patent application Chinese manual replacement page (October 96) V. Invention description (2)

Brit J Pharmacol (1992) 107:85 8). ETA and ETB receptors are structurally highly similar and belong to the superfamily of G-protein coupled receptors. Based on the increased blood and tissue levels of ET-1 in many disease states, pathophysiological effects such as hypertension, bacteremia, atherosclerosis, acute myocardial infarction, congestive heart failure, renal failure, migraine have been inferred. And asthma. Therefore, endothelin receptor antagonists have been extensively studied as potent therapeutic agents. Endothelin receptor antagonists have been shown to have preclinical and/or clinical efficacy in various diseases, such as cerebral vasospasm after subarachnoid hemorrhage, heart failure, pulmonary and systemic hypertension, neurogenic inflammation, renal failure, and myocardial infarction . Today, there are no endothelin receptor antagonists on the market, and many are still in clinical trials. However, these molecules have many weaknesses, such as complex synthesis, low solubility, high molecular weight, poor pharmacokinetics, or safety issues (such as increased liver enzymes). The inhibitory activity of a compound of formula I at the endothelin receptor can be demonstrated using the test procedures indicated below: To assess the strength and potency of the compound of formula I, the following assays were used: 1) Endothelin and human-derived ET Inhibition of cell membrane binding by receptor C: In a competitive binding study, a CHO cell membrane that expresses human recombinant sputum or purine receptors is used. Membranes from recombinant CHO cells were prepared and subjected to binding assays as previously described (Breu V., et al, FEBS Lett 1993; 334:210). The analysis was performed in 200 μl of 50 mM Tris/HCl buffer. Solution pH 7.4 73605-961019.doc - 5 - This paper scale applies to Chinese national standard (C^S) A4 specification <210X 297 mm) Ι2983^390121592 Patent application Chinese manual replacement page (October 96) Year卜月日修_正正换页•fLl_ V. Description of the invention (8) - low carbon pit group - sulfur group; aryloxy group; aryl group - low carbon alkyl group - aryl group; aryl group - low carbon alkyl group; Aryl-juvenile; heteroaryl; heteroaryl-oxy; heteroaryl-lower carbon fe-alkoxy; heteroaryl-amino; heteroaryl-loweryl-amino; Heteroaryl-thio;heteroaryl-lower alkyl-thio;heteroaryl-lower alkyl;heteroaryl-sulfinyl;heterocyclyl;heterocyclyl-lower alkyl- Oxygen;heterocyclyl-oxy;heterocyclyl-amino;heterocyclyl-lower alkyl-amino; heterocyclyl-thio;heterocyclyl-lower alkyl-sulfur;heterocyclyl- Lower alkyl; heterocyclic-sulfinyl; cycloalkyl; cycloalkyl-oxy; cycloalkyl - lower alkyl-oxygen, syl-amino, porphyrin-lower carbon fe-amino; cycloalkyl-sulfur; cycloalkyl-lower alkyl-sulfur; cycloalkyl-low carbon Alkyl; cycloalkyl-subcontinued thiol; X represents oxygen; sulfur; NH; CH2 or a bond; Y represents oxygen; sulfur or -NH-; Z represents oxygen; sulfur, -NH- or a bond; Q represents -(CH2)k-; -(CH2)m-CEC-(CH2)p-, in the case where p represents 0 (zero), Z represents a bond; -CH2-cyclopropene-CH2-; k represents a number 2,3,4,5, or 6; m represents the number 1, 2 or 3; p represents the number 0, 1, 2 or 3; η represents the number 1, 2 or 3; and its pure diastereoisomer a mixture of diastereoisomers, diastereomeric stereoisomers, diastereomeric stereoisomers, and meso-forms, and pharmaceutically acceptable Salt. In the definition of formula I - if not stated otherwise - denotes a lower alkyl or lower alkane 73605-961019.doc - 11 - This paper scale applies to the Chinese National Standard (C&S) Α4 specification (210Χ297 mm) / 3⁄43⁄43⁄4

12983 is a patent application No. 0121592. Chinese manual replacement page (96 years 1 month) 5. Inventive Note (14) wherein R1 and R2 are as defined above in Formula 1, and pharmaceutically acceptable thereof. More preferably, in the compound of formula V, wherein R2 represents a heteroaromatic. a pharmaceutically acceptable salt, including a mineral acid or an organic acid, such as hydrogen, such as hydrochloric acid or hydrogen acid; sulfuric acid minus two: bar acid, formic acid, acetic acid, Malay Acid, tartaric acid, mesonic acid, methic acid, etc., or in the compound of formula I, if its nature is acidic 01 and inorganic test, such as test or soil test, such as hydroxide 1 = _, calcium hydroxide, etc. . Jade emulsifying a compound of formula I may have more than one asymmetric carbon atom and may be an enantiomer of j, or a diastereomeric stereoisomer, a mixture of enantiomers or diastereomeric isomers, The racemic stereoisomer racemate, diastereomeric oromeromer racemate mixture, may also be in the meso-form. The present invention includes all of these types. The mixture can be isolated in a manner known per se, i.e., by column chromatography, thin layer chromatography, HPLC, crystallization, and the like. 7 Because of its ability to inhibit endothelin binding, the compounds described herein and their pharmaceutically acceptable salts are useful in the treatment of diseases associated with increased contraction, proliferation or inflammation of endothelin. Examples of this disease are: hypertensive disorders, palpitations, renal and myocardial blood stasis, renal failure, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, portal hypertension, and lung height blood pressure. It can also be used for atherosclerosis, balloon or stent angioplasty 2 to prevent restenosis, inflammation, stomach and duodenal ulcer, cancer, prostatic hypertrophy, sexual dysfunction, hearing loss, cataract, chronic bronchitis, Asthma, Gram-negative bacteremia, stroke, sickle cell anemia, glomerulonephritis, renal large intestine, glaucoma, diabetes concomitant 73605-961019.doc _17_ This paper scale applies to Chinese national standard (ClSJS) A4 specification (210X 297 public Chu)

Claims (1)

12983 Level 01 Cong No. Application - ί-Winter Shentuo Taili Range Replacement (96 years), Patent Application Scope 1. A compound of formula I, Formula I wherein R represents a phenyl group which may optionally be substituted with a Ci4 alkyl group; Or a P phenyl group; R 2 represents a phenyl group which may optionally be substituted with one yl group; a pyrimidinyl group which may optionally be selected from one or two independently selected from halo, trimethyl, ci4 k, C 〖"Substituent substitution of a group consisting of an oxy group and a C 4 ·burning group, or P is a decyl group, which may optionally be substituted with a trimethylmethyl group; R3 represents a phenyl group; or a mono- or di-substituted group a phenyl group, wherein the substituents are each independently selected from the group consisting of ci 4 alkyl, C 4 -4 alkoxy, and halogen; R 4 represents chlorine; p is a bite base; Or 福福普林基, X stands for oxygen or one bond; 73605-961019.doc This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Y represents oxygen; ζ represents oxygen; Q represents -(CH2)k-; or 6; k represents the number 2,3,4,f η represents the number 1, 2 or 3; or the pure donor of the compound of formula I Mixture, non-pf bean isomer, diastereomeric] two oilfields 乂 Bean isoform racemate, non-paired racemic mixture, meso-type: salt. 〜未子上J壬 2 . According to the patent application scope 1 oxygen · _ coin 1 member < compound of formula I, wherein x generation ^ or a compound of formula I pharmaceutically acceptable salts. 3. A compound of formula I according to claim 1 of the scope of the patent application, wherein x, γ and ; represent oxygen, Q represents -(CH; 〇k-, k = 2 or 3; and sense 3 represents phenyl or 』 Substituted phenyl: anthracene, C1-4 alkyl or (^-4 alkoxy; or a pharmaceutically acceptable salt of the compound of formula I. 4. A compound of formula I according to claim 1 of the scope of the patent application, wherein Alternate oxygen; Q represents -(CH2)k-, k = 2 or 3; R2 represents a pyrimidinyl group which may be required to be independently selected from halo, trifluoromethyl, cH- and C-alkane Substituted by a group consisting of an oxy group, or a pyridyl group, which may optionally be substituted with a trifluoromethyl group; and R3 represents phenylj or a phenyl group which is monosubstituted: _, Ci 4 alkyl or Ci 4 alkane-based; or a pharmaceutically acceptable salt of the compound of formula I. -2- 73605-961019.doc This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). A BCD 1298323 6. Patent application scope 5 · According to the compound of formula I in the scope of claim 1, wherein χ represents oxygen 'Q stands for -(CH2)2_; R2 stands for pyrimidine, which can be used as needed Or two substituents independently selected from the group consisting of halo, trifluoromethyl, C 4 alkyl and C 1 -4-alkoxy, or pyridyl, which may optionally be substituted with a trifluoromethyl group; R3 represents a phenyl group or a phenyl group which is monosubstituted: a halogen, a C 4 alkyl group or a methoxy group; or a pharmaceutically acceptable salt of the compound of the formula I. 6 · According to the scope of claim 1 a compound of formula I which is a compound of formula π Wherein R1 'R2' R3, R4, γ, Q, ζ and η are as defined in the formula I of the scope of claim i, or a pharmaceutically acceptable salt of the compound of the formula 11 / according to the scope of the patent application A compound of the formula, which is a compound of the formula 73605-961019.doc -3- 1298323 Patent application scope ABCD R \ir N R4 八Ν' Ύ I Οχ z R2 Formula III wherein R1, R2, R4, Y, Q And Z and n are as defined in Formula 1 of the patent application, or a pharmaceutically acceptable salt of the compound of Formula 111. 8. A compound of formula I according to claim 1 of the patent application, which is a compound of formula IV Formula IV -4 73605-961019.doc This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1298323 T M spear is not defined by the target field, or the pharmaceutically acceptable hoof of the compound of the formula, • according to the general formula of the patent application scope [compound, =. Compound /, 咕 is a general formula Wherein R1, R2 and η are as defined in the item i of the patent application, or a pharmaceutically acceptable salt thereof. 10. A compound according to item 9 of the scope of the patent application, wherein in the formula V, a P group, which may optionally be selected from halo, fluoromethyl, C4 alkyl and C^4 alkane, is optionally selected from one or two. A substituted earthy or azole group of the group consisting of oxy groups, which may optionally be substituted with a trifluoromethyl group; or a pharmaceutically acceptable salt thereof. 11·According to the application for patent Fanyuan! The compound of the item, which is selected from the following: 73605-961019.doc _ g ^ The paper scale is suitable for the wealth of the household scale ((10) (four) secret needle AB c D 1298323 Sixth, the patent scope 2 - phenyl-ethene {6-[2-(5-bromo-indolyl-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-ylbuminamide, 2-phenyl-ethene Acidic acid {6-[2-(5-bromo-amyl-2-yloxy)-ethoxy]-5-p-tolyl_[2,2']bipyrimidin-4-yl}- Indoleamine, 2-phenyl-ethanesulfonic acid {5-(2-decyloxy-phenoxy)-6-[2-(pyrimidin-2-yloxy)-ethoxy]-[2, 2'] bipyrimidin-4-yl oxime, 2-phenyl-ethanesulfonic acid {5-(2-decyloxy-phenoxy)-6-[2-(5-decyloxy- Pyrimidin-2-yloxy)-ethoxy]-[2,2']bipyrimidin-4-yloxime, 2-thiophenyl-2-yl-ethanesulfonic acid [6-[2- (5-Bromo-pyrimidin-2-yloxy)-ethoxy]-5-(4-chloro-phenyl)-pyrimidin-4-yl]-decylamine, 2-thiophenyl-2-yl-B Alkylsulfonic acid {5-(4-chlorophenyl)-6· [2-(5-methoxy-mouth-Butyl-2-yloxy)-ethoxy] dimethyl-4-yl}-acid amine And 2-pyridin-2-yl-ethanesulfonic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5- (2-Methoxyphenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-decylamine, or a pharmaceutically acceptable salt thereof. 12. A compound according to claim 1 It is selected from the following: 2-phenyl-ethanesulfonic acid {6-[2-(pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-P-bite- 4-based}-decylamine; 2 -benyl-ethene-reductive acid {5-p-tolyl-6-[2-(5-di-methylmethyl-p-bit-2-yloxy)- Ethoxy]methicone-4-yl}-bristamine; 2-phenyl-ethanesulfonic acid {6-[2-(4-bromo-phenoxy)-ethoxy]-5-para- Tolyl-0 butyl-4-yl}-nitramine, 73605-961019.doc - 6 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) · AB c D 1298323 VI. Patent application园2-Phenyl-ethyl benzoate {5-(2-methoxy-1-yl-phenyl)-6-[2-(p-predative 2-yloxy)-ethoxy]-[2 , 2'] dipyrimidinyl-4-ylbuminamide; 2-phenyl-ethyl benzoic acid [6 - [ 2 - ( 5 - > odorous - butyl 2-yloxy) ethoxy ]-5 -(.2-methoxy-phenoxy)-[2,2V]dimethyl benzo-4-yl]-bristamine; 2-phenyl-acetonitrile acid [6 - [ 2 - (4,6-dimethyl emulsion -p-Bite-2 -yl-based)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2']dipyrimidin-4-yl]-decylamine, 2 -Phenylethyl acid {6-[2-(5-> odor-p-melt-2-yl)-ethoxy]-5-p-tolyl-my -4-yl}- Acid amine, 2-phenyl-ethyl urate {6-[2-(5-methyl-deni-2-yl)-ethoxy]-5-p-tolyl-p-bit 4-amino}-bristamine, 2-phenyl-ethyl-calcinic acid {6-[2-(5-chloro-deni-2-yloxy)-ethoxy]-2 -p ratio bit-4 Base-5-para-methylolyl-p-biti-4-yl}-acid amine, 2-phenyl-ethene-cross-acid {6-[2-(5-> odor-mouth-dense-2 -yloxy)-ethoxylated 1yl]-2 -p than phospho-4-yl-5-p-tolyl-m--4-yl}-acid amine, 2-phenyl-ethyl benzoate { 6-[2-(5-Methyl-denid-2-yloxy)-ethoxy]-2 - p ratio-4 -yl-5-p-tolyl-p-Bite-4 }--Amine, 2-phenyl-B:fe continued acid {6-[2-(5-methoxy-rhout-2-yloxy)-ethoxy]-2-pyridin-4-yl -5-p-tolyl-pyrimidin-4-yl}-decylamine; 2-phenyl-ethanesulfonic acid {6-[2-(5-chloro-pyrimidin-2-yloxy)-ethoxyl ]]-5-p-tolyl-[2,2^]di-p-phenyl-4-yl }--N-amine, 2-phenyl-acetonitrile acid {6-[2-(5-> odor-0-melan-2-yloxy)-ethoxy] group]-5-para-toluene Base - [2,2']di-p-butyl-4-yl}-nitramine, 73605-961019.doc - 7 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 8 8 8 8 AB c D 1298323 VI. Patent Application 2 -Phenyl-ethanesulfonic acid {6-[2-(5-methoxy-pyrimidin-2-yloxy)-ethoxy]-5 -para-tolyl-[2,2']dipyrimidin-4-ylbuminamide; 2-phenyl-ethanesulfonic acid { 5 -(4-bromo-phenyl)-6 - [ 2 - (5-chloro-pyrimidin-2-yloxy)-ethoxy]-p-melt-4-yl}-acid amine; 2 -winter-ethyl-su-butic acid { 5 - (4 - > Phenyl)-6 - [ 2 - ( 5 - > odor-distillate-2 ~ yloxy)-ethoxy]-wall acyl-4-phenylphosphonium; 2-phenyl-ethane sulfonate Acid {5-(4-bromo-phenyl)-6-[2-(5-methoxy-pyrazin-2-yloxy)-ethoxy] dimethyl-4-yl}-acid amine; [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(3,4-dimethyl-phenyl)-pyrimidine 2-phenyl-ethanesulfonic acid 4-yl]-nonylamine; 2-phenyl-ethanesulfonic acid {5-(3,4-dimethyl-phenyl)-6-[2-(5- oxy-P-milyl-2-yloxy)-ethoxy] crypt-4-yl}--: amine; 2-phenyl-ethanesulfonic acid [6-[2-(5-bromo-) Pyrimidin-2-yloxy)-ethoxy]-5-(2,4-didecyl-phenyl)-dense-4-yl]-bristamine; 2-phenyl-ethanesulfonic acid { 5 - (2,4-dimethyl-phenyl)-6-[2-(5-fluorenylsulfonyl-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-ylbuminamide ; 2-phenyl-ethanesulfonic acid {5-(2-methoxy-phenoxy)-2-pyridin-4-yl-6-[2-( 口密咬-2-yl lactyl)- Ethoxy]-mercapto-4-yl}-bristamine; 2-phenyl-ethanesulfonic acid [6-[2-(5-chloro-pyrimidin-2-yloxy)-ethoxy] -5-(2-methyllate-anthracene)-2 -ρ ratio bite-4-yl-salt-4-yl]-bristamine; 2-phenyl-ethanesulfonic acid [6-[2 -(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-2-p ratio -4-yl-salt-4-yl ]--Amine; 73605-961019.doc - 8 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm). 8 8 8 8 ABCD 1298323 VI. Patent scope 2-phenyl-ethane Sulfonic acid {5-(2-methoxy-phenoxy)-6-[2-(5-methoxy-p-milyl-2-yl lactyl) -ethylidene]-2 - p-precipitate-4-yloxy-4-yl}~ decylamine; 2-phenyl-ethanesulfonic acid [6-[2-(5-chloro-pyrimidine-2- Benzyl)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2f]dipyrimidin-4-yl]-decylamine; 2-phenyl-acetonitrile {5-(2-Methyllacyl-phenyllactyl)-6-[2-(5-methyl-p-milyl-2-yllacyl)-ethoxy]-[2,2*]dian Benzyl-4-yl}bristamine; 2-phenyl-ethene-reductive acid {5-(2-methyllacyl-phenoxy)-6-[2-(5-methoxy-peri-dense- 2-yloxy)-ethoxy]-[2,21di-p-predyl-4-yl}-bristamine; 2-phenyl-ethanesulfonic acid {5-(2-methoxy-benzene) Oxy)-6-[2-(5-trifluoromethyl-pyrimidin-2-yloxy)-ethoxy]-[2,2']dipyrimidin-4-yl}-decylamine; -Phenyl-acetonitrile-acid {5-(2-methoxy-phenoxy)-6-[2-(5-tris-methyl-p-but-2-yloxy)-ethoxy ]-[2,2']di-p-butyl-4-yl}-decylamine; 2-phenyl-ethionic acid {5-(2-methoxy-phenoxy)-2-external bp Well-2 -yl_ 6-[2-( 口密咬-2-ylyl)-ethoxy] dimethyl-4-yl}-acid amine, 2-phenyl-acetonitrile acid [6- [2·(5-> Odor-But-2-yloxy)-ethoxy]-5-(2-A Benzyl-phenyl)-2-7-but-2-yl-denyl-4-yl]-bristamine; 2-phenyl-ethene-acidic acid {5-(2-oxo-anthracene) -6-[2-(5 -甲气73605-961019.doc - 9 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 8 8 8 8 A BCD 1298323 VI. Patent application ccentiment-2-yloxy)-ethoxy]-2-ptb^-2-yl-carbyl-4-yl}-decylamine; 2 - Phenyl-B: Transacid {5-(2-methoxy-phenoxy)-6-[2-(5-methyl fluorescein-carcinoma-2 -yloxy)-ethoxy! Base]-2 - p than spray-2 -yl-furan-4 · hydrazide; 2 -phenyl-ethene-cross-acid {5-(2-methoxy-phenyl-lactyl)-2 -福普-4-yl-6-[2-(molan-2-yl)-ethoxy]-feeding-4-yl}-bristamine, 2-phenyl-ethylic acid [6 -[2-(5-'/, succinyl-2-yloxy)-ethoxy]-5-(2-methoxy-phenyllactyl)-2 - phenanthyl p--4-yl-淀 -4--4-yl] 醯 醯 amine; 2 - phenyl-B: glutamic acid {5-(2-methoxy-phenoxy)-6-[2-(5-methoxy-p-dense -2-yloxy)-ethoxyl-1-yl]-2-moffin-4-yl-. Secret disease-4_ kibamine; 2-phenyl. B: glutamic acid {5-(2-methoxy-phenoxy)-6-[2-(5-methyl fluorescene-p-denyl-2-yloxy)-ethyl lactyl]- 2 - 福福. Lin-4-yl-Crypt-4-Butylamine; 2-Phenyl-B-acidic acid {5-(2-oxo-phenoxy)-6-[2-(p-bite_2 -based lactyl)-ethoxy]-. Bite-4-yl}-bristamine, 2-phenyl-ethyl benzoate [6-[2-(5-> Odor-Butyl-2-yloxy)-ethylidyl]-5-( 2-methoxy-phenoxy)-p-butyl-4-yl]-bristamine, 2-phenyl-ethyl-acid {5-(2-methoxy-phenoxy)-6-[2- (5-methoxy-p-p-po-2-yl lactyl)-ethoxyl-yl]- shouting 4-yl}-bristamine, 2-phenyl-ethyl:fe continued acid {5-( 2-methoxy-phenoxy)-6-[2-(5-difluoroindolyl-^~17-p--2-yloxy)-ethoxy]-feeding-4-yl}- Amine, 73605-961019.doc - 10 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm). 8 8 8 8 AB CD 1298323 VI. Patent application scope 2 - Phenyl-acetonitrile [6-[2-(5 -> Odor-Butyl-2-yloxy)-ethoxy]-5-(3-methoxy-phenoxy)-2-moffin-4-yl淀-4-yl]·* decylamine; 2-phenyl-ethylidene acid {5-(3-methyllacyl-phenoxy)-6-[2-(5-methoxy-p-dense -2-yloxy)-ethoxy]-2-moffufolin-4-yl-p-milyl-4-pyridinium; 2-phenyl-ethyl:feic acid [6-[2- (5-> odorin-2-yl lactyl)-ethoxy]-5-(3-methoxy-phenoxy)-p-dimethyl-4-yl]-bristamine, 2- Base-Bit pit acid {5-(3-carbomethoxy-phenoxy)-6-[2-(5-methoxy-p-melan-2-yloxy)-ethyl lactyl]-p密-4-yl}-bristamine; 2-thiophenyl-2-yl-ethyl-burning acid {6-[2-(5-chloro-mouth-bitter-2-yl aryl)~ ethoxylate] -5-p-tolyl-precipitate-4-yl}-bristamine, 2-thiophenyl-2-yl-ethylidene acid {6-[2-(5 - > stinky-mouth bite-2 -yloxy)-ethoxy]yl]-5-p-tolyl-mylidene-4-yl}-decylamine, 2-thiophenyl-2-yl-ethene-cross-acid {6-[2-( 5-methoxyl-yl-. succinyl-2-yloxy)-ethoxy]-5-p-tolyl-benzophen-4-yl}-bristamine, 2-thiophenyl-2-yl - ethanesulfonic acid { 5-(4-chloro-phenyl)-6-[2-(5-chloro-pyrazin-2-yloxy)-ethoxy] butyl-4-yl}- Amine, 2-thiophenyl-2-yl-ethene-heteroic acid [6-[2-(5-'/odor-mouth-dense-2-yl lactyl)-ethoxy]-5-(4-chloro -phenyl)-carcinogen-4-yl]-bristamine, 2-thiophenyl-2-yl-ethene-cross-acid {5-(4-chloro-phenyl)-6-[2-(5-A Base-endo-predominant-2-yl lactyl)-ethoxy]-milo-4-yl}-bristamine, 2-thiophenyl-2-yl-ethanesulfonic acid { 5-(4·chloro-benzene) Base)-6-[2-(5-methoxy-p-denid-2-yl lactyl)-ethyl lactyl] Bite-4-yl}-bristamine, 73605-961019.doc - 11 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm). 8 8 8 8 AB c D 1298323 VI. Scope of Application 2 - Sulfur Benzene-2-yl-ethyl benzoate [6-[2-(5-Chloro-oral-dense-2 -yl)-ethoxy 5-[2-methoxy-phenoxy)-2-ρ ratio -4-yl-melide-4-yl]-decylamine; 2-thiophenyl-2-yl-ethyl benzoate [6 - [ 2 - ( 5 - > Odor - . Bite - 2 -yloxy)-ethoxy]yl]-5-(2-methoxy-1-yl-phenyl)-p-precipitate -4-Mimilide-4-yl]·» decylamine; 2-thiophenyl-2-yl-ethylidene {5-(2-methoxy-phenoxyl-yl)-6-[2_ ( 5-anthoxy-precipitated-2-yloxy)-ethoxy]-2-p ratio-4*-yl-bromo-4-pyridinium; 2-thiophenyl-2-yl- Ethyl sulphate [6-[2-(5->odor-mouth-melan-2-yloxy)-ethoxy]-5-(2-methoxy-1-yl-phenoxy)-2福福琳-4-Mimimidate-4-yl]-nonylamine; 2-thiophenyl-2-yl-ethyl-fetra-acid {5-(2-methoxy-1-yl-phenyl)--6-[ 2_(5-Methyl-milk-precipitate-2·yl lactyl)-ethoxy]-2-ifolin p-lin-4-yl-melanyl-4-yl}decylamine; 2 - ρ-precipitate-2 -yl-ethene-burning acid {5-(2-methoxy-phenoxy-4-yl-6-[2-(.)-2-yloxy)-ethoxy]-mouth bite- 4-yl}-nonylamine; ' 2 - Specific bite-2-yl-ethyl-acid [6-[2-(5-> odor-. dimethyl-2-yloxy)-ethoxy]-5-(2- methoxy-phenoxy ))-2-pyridin-4-yl-pyrimidin-4-yl]-decylamine; N-{5-(2-methoxy-phenoxy)-2-pyridin-4-yl-6-[ 2-(pyrimidin-2-yllacyl)-ethoxy]-0 butyl-4-yl}-(!1-phenyl-methylpropanol, 1^-[6-[2-(5- >Smell-.Mated-2-yl-gas-based)-ethoxy]-5-(2-Mercapy 73605-961019.doc - 12 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 MM) 8 8 8 8 AB c D 1298323 VI. Scope of application for patent base - benzene gas base) - 2-7 than lake - 4 - thiophene - 4 -yl]-C-phenyl-methyl then amine; ^-[ 6-[2-(4-Bromo-phenoxy)-ethoxy]-5-(2-methoxy-phenoxy)-2 - p ratio-4 - carbyl-4-yl] -C-phenyl-methenyl, N-{5-(2-methoxy-phenoxy)-6-[2-(pyrimidin-2-yloxy)-ethoxy]-[2 , 2f]di-p-butyl-4-yl}-indole-phenyl-methyleneamine, N-[6-[2-(5-> odor-mouth-butyl-2-yloxy)-B Oxy]-5-(2-methoxy-phenoxy)-[2,2"di-feeding-4-yl]-C-phenyl-peptidylamine; !^[6-[2 -(4-bromo-phenoxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,21di-p-butyl-4-yl]-C-phenyl- N-{5-(2-methyllacyl-phenyllactyl)-2-moffin-4-yl-6-[2-(p-Bitter-2-yloxy)-B Oxy]-pyran-4-ylindole-C-phenyl-methylpropanol, N-[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5 -(2-methoxy-phenyl-lactyl)-2-isfosin-1^-lin-4-yloxy-4-yl]-C-phenyl-indole-burning amine; N-{5-(2 - Methoxy-phenyllactyl)-2-p is more than -4-yl-6-[2-(mouth-bito-2-yloxy) -ethoxy]-0 dimethyl -4-yl}-(11-p-tolyl-methyl: acetaminophen; 1^-[6-[2-(5-bromo-pyrimidin-2-yloxy) ))-ethoxy]-5-(2-methoxy-phenyl-milyl)-2 - p-precipitate-4-yl-p-[4]-yl]-C-para----- _ A: amine; N - { 5 - (2-methoxy-phenoxy)-2 - pyridin-2-yl-6-[2-(pyrimidin-2-yloxy)-ethyl milk Based on the Chinese National Standard (CNS) A4 specification (210 X 297 public). This paper scale applies to the Chinese National Standard (CNS) A4 specification (73 X 297 gong) PCT) 8 8 8 8 ABCD 1298323 VI. Patent Application N-[6-[2-(5->Smelly-mouth-Bite-2-yloxy)-ethoxy]-5-(2 - Methyl lacto-phenoxy)-2-ptb-propen-2-yl dimethyl-4-yl]-C-para-p-phenyl-methanesulfonamide; 3-phenyl-propan-l-continued acid { 6-[2-(p-Bite-2-yloxy)-ethylidyl]_ 5-p-tolyl-pyrimidin-4-yl}-decylamine; 3-phenyl-propene:fe-Ι - continued acid {6-[2-(5-> odor-m-butyl-2-yloxy)-ethylidyl]-5-p-tolyl-p-melt-4-yl}-acid amine , 3-phenyl-propion pit-1 -crossic acid {5-(2-methoxy-phenoxy)-2 -ρ than food-4_yl-6- [2-(mouth bite -2-yloxy)-ethylidyl]-mercapto-4-yl}-bristamine, 3-phenyl-propanone-1-cross-acid [6-[2-(5->淀-2-yllacyl)-ethoxy]-5-(2-methoxy-1-yl-phenyllactyl)-2-p-pyrifom-4-yl-denyl-4-yl]-acid amine; -Phenyl-propan pit-1 -crossacid {5-(2-methoxy-phenoxy)-6-[2-(. Precipitate-2-yl lactyl)-ethyl lactyl]-[2,21 bis. Dicyl-4-yl}-acid amine., 3-phenyl-propanone-1-supply acid [6-[2-(5-> odor-.-precipitate-2-yl lactyl)-B Lacto]-5-(2-methoxy-phenoxy)-[2,2']dipyrimidin-4-yl]-decylamine, 3-phenyl-propan-1 - continued acid {5 -(2-methoxy-phenoxyl-yl)-2-ifolin _ 4 -yl- 6- [2-(p-Methyl-2-yloxy)-ethoxy]-bita-4. -yl}-chatoline; 3-phenyl-propene-fe-oxime-supply acid [6-[2-(5-> odoro-2-yloxy-1-yl)-ethoxy]-5-( 2-methoxy-phenoxy 1 yl)-2 - morphine p-lin-4-yl-p-dense-4 -yl]~ decylamine; N-{5-(2-methoxy-phenoxy )-6-[3-(Pyridine-2-yloxy)-propoxy 73605-961019.doc - 14 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm). 1298323 as B8 C8 - ------ .... D8 VI. Application for patent Fanyuan-[2,2']dipyrimidinyl-4-yl]-c_phenylmethanesulfonamide; N-{5-(2_methoxy -Phenoxy)-6-[3_(5-trifluoromethyl-pyridin-2-yloxy)-propoxy-[2,2,]dipyrimidin-4-yl]-C-phenyl -methanesulfonamide·, '3-phenylpropane_丨_sulfonic acid {6_[3_(5_bromo-pyrimidin-2-yloxypropoxy-5-para-A) P-pyrimidine _ 4 _ yl] decylamine; 3 phenyl-propane-continuation acid {6_[3_(5-bromo-pyridin-2-yloxy)-propoxy b 5 -para-tolyl -pyrimidin-4 -yl} •decylamine; and 3_phenyl-propanol-busulfonic acid {5•para-tolyl_6_[3_(5-trifluoromethyl-P-bite-2-yl) Oxy)-propoxy]-carcin-4-yl}-guanamine. A pharmaceutical composition for treating disorders associated with the action of endothelin, which is selected from the group consisting of hypertension and blood. A group consisting of vasospasm, angina pectoris, and cancer, wherein the pharmaceutical composition contains a compound according to any one of claims 1 to 1 and a general carrier substance and an adjuvant. A pharmaceutical composition for a disorder associated with endothelin action, the disorder being selected from the group consisting of migraine, asthma, and inflammatory disorders, wherein the pharmaceutical composition contains · according to the scope of claims 1 to i J A compound and a general carrier material and an adjuvant thereof. The compound according to any one of claims 1 to 3, which is pharmaceutically acceptable or pharmaceutically acceptable Salt-based drugs can be used purported to treat disorders related to the role of endothelin, the group consisting of the disorder selected from the group consisting of hypertension, blood must, vasospasm, angina, cancer, migraine and inflammatory disorders. -15· 73605-961019.doc This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) AB CD 1298323 VI. Patent application scope 16. Type 1 to 1 according to the scope of application for patents Use of a compound of the formula or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of a disorder associated with the action of endothelin, which is selected from the group consisting of hypertension, blood loss, vasospasm, A group of angina and cancer. 17. The use of a compound according to any one of claims 1 to 1 or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition for the treatment of disorders associated with endothelin action The disorder is selected from the group consisting of migraine, asthma, and inflammatory disorders. 73605-961019.doc - 16 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)