CN1407973A

CN1407973A - Butyne diol derivatives

Info

Publication number: CN1407973A
Application number: CN00816718A
Authority: CN
Inventors: 马丁·博利; 克里斯托夫·博斯; 马丁内·克洛泽尔; 瓦尔特·菲施利
Original assignee: Actelion Pharmaceuticals Ltd
Current assignee: Actelion Pharmaceuticals Ltd
Priority date: 1999-12-22
Filing date: 2000-12-14
Publication date: 2003-04-02
Also published as: WO2001046156A1; KR20020068373A; NO20022971L; NO20022971D0; HUP0204168A2; IL149529A0; ZA200203796B; JP2003518102A; AU3536701A; MXPA02006250A; BR0016241A; CA2389479A1

Abstract

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

Description

Butyne diol derivatives

The present invention is about the novel butyne diol derivatives with structural formula (I) and they are as the application of activeconstituents in the preparation medicine compound preparation.The invention still further relates to the synthesis technique of this compound and comprise the medicine compound preparation that one or more have the compound of structural formula (I), especially they are as the application of the plain acceptor of oestrone in anti-.

Interior oestrone (ET-1, ET-2, ET-3) is generated by the 21-amino acid peptide, all has live (Yanagisawa M et al.:Nature (1998) 322:411) in nearly all tissue.Interior oestrone is important amboceptor potential vasoconstrictor and the heart, kidney, internal secretion and immunologic function etc.(McMillen?MA?et?al.：J?Am?CollSurg(1995)180：621)。They participate in bronchoconstriction, the secretion of regulating neurotransmitters, activation, fibrosis, cell proliferation and the cytodifferentiation (Rubanyi GM et al.:Pharmcol Rev (1994) 46:328) of inflammatory cell.

The oestrone acceptor has carried out vegetative propagation and sign (ET in two kinds in Mammals _A, ET _B) (Arail H etal.:Nature (1990) 348:730; Sakurai T et al.:Nature (1990) 348:732).ET _AAcceptor is a feature so that ET-1 and ET-2 comparison ET-3 is shown higher affinity.Show in blood vessel smooth muscles cell and in adjusting vasoconstriction and the proliferative response especially significantly (Ohlstein EH et al.:Drug Dev Res (1993) 29:108).On the contrary, ET _BAcceptor has same affinity (Ogawa Y et al.:BBRC (1991) 178:248) to the 3rd oestrone with peptide with to linear oestrone, four-propionic acid oestrone, sarafotoxin S6C.This acceptor is arranged in blood vessel endothelium and smooth muscles, is distributed in especially in a large number in lung and the brain.By interior oestrone excretory ET _BAcceptor can be regulated temporary transient vasodilation, and response ET-1 and ET-3 be by discharging carbon monoxide and/or prostacyclin, yet by the ET of smooth muscles emiocytosis _BAcceptor is carried out vasoconstriction task (Sumner MJ et al.:Brit JPharmacol (1992) 107:858).ET _AAnd ET _BAcceptor is structurally closely similar, and they belong to the superfamily of G-protein and receptors bind.

The pharmacology role of ET-1 is based under the various disease states it to blood plasma with organize the raising of level, as: hypertension, septicemia, atherosclerosis, Acute Myocardial Infarction, congestive heart failure, renal failure, migraine, asthma etc.Therefore, anti-interior oestrone is furtherd investigate as potential preparation by voxel.Oestrone is subjected to voxel to show potential and/or clinical effect in various diseases in anti-, as: the retinal hemorrhage that the brain spasm causes, heart failure, lung and system's hypertension, neuritis, renal failure, myocardial failure etc.

At present, also not anti-oestrone element is sold by voxel on the market, has several examples to use clinically.Yet these molecules have many shortcomings, as safety issues (increasing as organized enzyme) such as synthetic complexity, low-solubility, high molecular, bad drug psychosiss.In addition, different ET _A/ ET _BAcceptor blocks not clear to clinical contribution.Therefore, suitable physical chemistry and pharmacology, and be compulsory to given clinical manifestation to the selectivity of every kind of antibody.We have found a kind of novel butyne diol derivatives (its structure is as follows), find that they can meet above-mentioned butyne diol derivatives specified conditions.

Inhibition activity with internal oestrone acceptor of compound of Formula I can be demonstrated by test process described below.

In order to estimate the potential effect of compound, adopt following test with Formula I:

1) forbid that the Chinese hamster ovary celI film that carries human ET acceptor combines with interior oestrone:

For the research of competition bonding, utilize the performance mankind again in conjunction with ET _AOr ET _BThe Chinese hamster ovary celI film of acceptor.From preparing little neu in conjunction with Chinese hamster ovary celI again, bonding is chemically examined with former description (Breu V., et al.:FEBS Lett1993; 334:210).

Chemical examination (comprises 25mM Mncl in 200 microlitre 50mM Trid/HCL PH are 7.4 damping fluid ₂(manganous chloride), 1mM EDTA (ethylene dinitrilotetra-acetic acid) and 0.5% (w/v) BSA) in the polypropylene microtiter plates, carry out.The film that will contain 0.5 micrograms of protein is at 20 ℃ and 8PM[ ¹²⁵] insulation 2 hours under the condition of ET-1 (4000cpm), increase the concentration of not indicating antibody.Be maximum value and the minimum value that has detected bonding under the 100nM situation not containing ET-1 and ET-1 respectively.After 2 hours, in the filtering table that contains the GF/C filter membrane, little neu is filtered (filtering table is from the Canberra Packard company import of Zurich, SUI).To each sample, the flicker cocktail (scintillation cocktail) (microscint20 of the Canberra Packard company of Zurich, SUI) and the filtering table that add 50 microlitres are counted (TopCount, the CanberraPackard company of Zurich, SUI) in little dish counter.

In all test compounds dissolvings, dilution and adding DMSO.Chemical examination is carried out in the presence of 2.5%DMSO, does not find its remarkably influenced bonding effect.IC ₅₀Calculated as antibody concentration, this antibody suppresses with ET-1 50% of specific bonding is arranged.As the reference compound, following IC ₅₀Value is found: ET _ACell: to ET-1, IC ₅₀Value is 0.075nM (n=8), to ET-3, and IC ₅₀Value is 118nM (n=8); ET _BCell: to ET-1, IC ₅₀Value is 0.067nM (n=8), to ET-3, and IC ₅₀Value is 0.092nM (n=3).

Acquisition has the IC of the compound of Formula I ₅₀Value as shown in Table I.Table 1

Example	??IC ₅₀[nM]
	??IC ₅₀[nM]		?ET _A	?ET _B
	Example 1g	?26	?ET _A	?ET _B	?77
Example 2c	Example 1g	?26	?126	?44	?77
Example 2c	Example 3e	?22	?126	?44	?1520
Example 4d	Example 3e	?22	?53	?2030	?1520
Example 4d	Example 5b	?38	?53	?2030	?635
Example 9d	Example 5b	?38	?16	?49	?635
Example 9d	Example 11d	?49	?16	?49	?97
Example 18	Example 11d	?49	?79	?36	?97
Example 18	Example 19	?112	?79	?36	?45
Example 21	Example 19	?112	?230	?44	?45
Example 21	Example 58	?7	?230	?44	?123
Example 70	Example 58	?7	?94	?375	?123
Example 70	Example 71	?13	?94	?375	?28
Example 72	Example 71	?13	?1	?42	?28
Example 72	Example 81	?1	?1	?42	?197
Example 84	Example 81	?1	?2	?241	?197
Example 84	Example 89	?13	?2	?241	?1140
Example 94	Example 89	?13	?13	?107	?1140

2) inhibition is by the mouse artery ring specimen (ET of interior oestrone initiation _AAcceptor) contraction and mouse tracheae ring specimen (ET _BAcceptor) shrinks

The evaluation of the potential inhibit feature of oestrone element is the mouse artery ring specimen (ET that is caused by interior oestrone-1 by their inhibition in anti- _AAcceptor) the mouse tracheae ring specimen (ET that shrinks and cause by sarafotoxin S6c _BAcceptor) contraction is carried out.Become mouse to implement anesthesia, bloodletting processing to Wistar.The ring specimen that chest Aorta or tracheae be cut, dissected and be cut into the 3-5 millimeter.By the internal surface that rubs gently to remove endothelium-denuded/epithelial cell.Each ring specimen is suspended on respectively in the organic vessel of the 10ml that is full of Kerbs-Hemseleit solution, is placed in the atmosphere of 37 ℃ and 95% oxygen, 5% carbonic acid gas.(in the mM) composed as follows of Kerbs-Hemseleit solution: NaCl115, KCl4.7, MgSO ₄1.2, KH ₂PO ₄1.5, NaHCO ₃25, CaCl ₂2.5, glucose 10.Ring specimen and force transducer link, isometric(al) stress go on record (EMKA Technologies SA, Paris, France).Ring specimen is stretched to 3 gram resting tensions (to Aorta) or 2 gram resting tensions (to tracheae).Sample is cultivated after 10 minutes ET-1 (to Aorta) reagent in test compounds or its carrier or sarafotoxin S6c (to tracheae) reagent is added successively.The potential inhibit feature of test compounds is estimated by the calculating concentration rate.As the EC that causes by different test compounds concentration ₅₀Variation.EC ₅₀Be the concentration that expression reaches 50% needed interior oestrone of maximum collapse, pA ₂Be anti-in the negative logarithm of the plain concentration of oestrone (it causes EC ₅₀Value has moved two orders of magnitude).

Acquisition has the pA of the compound of Formula I ₂Be worth as shown in table 2.Table 2

Compound	pA ₂
	pA ₂		Artery goes in ring	Tracheae
	Example 4d	?7.15	Artery goes in ring	Tracheae	?5.89
Example 9d	Example 4d	?7.15	?7.11	?6.47	?5.89
Example 9d	Example 11d	?7.05	?7.11	?6.47	?7.03
Example 19	Example 11d	?7.05	?＜5	?7.62	?7.03
Example 19	Example 58	?7.57	?＜5	?7.62
Example 59	Example 58	?7.57	?7.70
Example 59	Example 72	?7.70	?7.70
Example 81	Example 72	?7.70	?7.56
Example 81	Example 84	?8.11	?7.56

Because described compound has the ability that suppresses interior oestrone bonding, so they can be owing to treatment because the relative diseases such as vasoconstriction, propagation or inflammation that interior oestrone causes.As: hypertension, coronary heart disease, cardianeuria, kidney and deficiency myocardial blood supply, renal failure, blood supply insufficiency of brain, dementia, migraine, subarachnoid hemorrhage, Reynolds (Raynaud) syndromes, portal hypertension and lung's hypertension etc.They can also be owing to the treatment arteriosclerosis, be used to prevent restenosis, inflammation, gastric duodenal ulcer, cancer, prostatomegaly, protuberance dysfunction, hearing disability, the blue or green light of reconstructing blood vessel postoperative blind, chronic bronchitis, septicemia, shock, herrik syndrome, glomus, nephralgia, glaucoma etc., the complication after treatment and prevent diabetes complication, blood vessel or heart operation complication, the organ transplantation, ring-type robe handle complication and other also the unknown now with interior oestrone diseases associated.

Modes such as this compound can be oral, injection, bowel lavage are used, for example vein, muscle, subcutaneous, intrathoracic or skin use or hypogloeeis, medicament for the eyes or use as aerosol.The example that uses has capsule, tablet, oral liquid, suppository, injection liquid, medicament for the eyes, ointment or aerosol etc.

The suggestion use-pattern is intravenous injection, intramuscular injection, oral or medicament for the eyes.Using dosage is according to given activity composition, patient's age and requirement and use kind.Usually, using dosage is per weight 0.1-50mg/kg every day.Can contain inertia or active drug excipient in the preparation of compound.For example, tablet or particle can contain wedding agent, fill vehicle, carrier or thinner.

The general Formula I of the butyne diol derivatives that this patent is relevant is as follows:

General formula I is here:

R ¹Represent phenyl; One five of forming of phenyl, halogen, hydroxyl, low-carbon alkyl, low alkenyl, low-carbon (LC) alkynyl, low-alkoxy, low alkene oxygen base, low alkynyloxy group, low alkylidene group or low alkenylene or low alkylene oxide group or low alkylene dioxo base and phenyl ring or six-ring, hydroxyl-low-carbon alkyl, hydroxyl-hang down alkenyl, hydroxyl-low-carbon (LC) alkynyl, low-alkoxy-low-carbon alkyl, low-alkoxy-low-alkoxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxyl-cycloalkyl is single, double or tri-substituted phenyl; Heterocyclic radical; Five yuan of hetero-aromatic rings that contain one or two N, S or O atom (may by halogen, low-carbon alkyl, low-alkoxy, hydroxyl-low-carbon alkyl, halogen, trifluoromethyl list or two replacement); The 2-pyridyl; The 2-pyridyl that 5-substituting group-usefulness low-carbon alkyl, low-alkoxy replace; Phenyl; Form one five or six-ring, hydroxyl-low-carbon alkyl, hydroxyl-hang down alkenyl, hydroxyl-low-carbon (LC) alkynyl, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxyl-cycloalkyl, single, double or tri-substituted phenyl with phenyl, halogen, hydroxyl, low-carbon alkyl, low alkenyl, low alkynyl, low-alkoxy, low alkene oxygen base, low alkynyloxy group, low alkylidene group or low alkenylene or low alkylene oxide group or low alkylene dioxo base and phenyl ring; Five yuan of hetero-aromatic rings that contain one or two N, S, O atom; Aromatic base; Heterocyclic aromatic base;

R ²Representation hydroxy; Low-carbon alkyl; Trifluoromethyl; One five of forming of phenyl, halogen, hydroxyl, low-carbon alkyl, low alkenyl, low-carbon (LC) alkynyl, low-alkoxy, low alkene oxygen base, low alkynyloxy group, low alkylidene group or low alkenylene or low alkylene oxide group or low alkylene dioxo base and phenyl ring or six-ring, hydroxyl-low-carbon alkyl, hydroxyl-hang down alkenyl, hydroxyl-low-carbon (LC) alkynyl, low-alkoxy-low-carbon alkyl, low-alkoxy-low-alkoxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxyl-cycloalkyl is single, double or tri-substituted phenyl; Heterocyclic radical; Five yuan of hetero-aromatic rings that contain one or two N, S or O atom (may by halogen, low-carbon alkyl, low-alkoxy list or two replacement); Phenyl; One five of forming of phenyl, halogen, hydroxyl, low-carbon alkyl, low alkenyl, low-carbon (LC) alkynyl, low-alkoxy, low alkene oxygen base, low alkynyloxy group, low alkylidene group or low alkenylene or low alkylene oxide group or low alkylene dioxo base and phenyl ring or six-ring, hydroxyl-low-carbon alkyl, hydroxyl-hang down alkenyl, hydroxyl-low-carbon (LC) alkynyl, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxyl-cycloalkyl is single, double or tri-substituted phenyl; The 2-pyrimidyl; Low-carbon alkyl, low-alkoxy, hydroxyl-low-carbon alkyl, halogen, trifluoromethyl, contain five yuan of fragrant heterocycles of one or two N, S, O atom; Aromatic base; Heteroaryl; Heterocyclic radical; Chemical formula is-C (A)-B-R ^aFunctional group of gang

Here: A represents O or S;

B represents NH or singly-bound;

R ^aRepresent low-carbon alkyl; Cycloalkyl; Trifluoromethyl; Phenyl; One five of forming of phenyl, halogen, hydroxyl, low-carbon alkyl, low alkenyl, low-carbon (LC) alkynyl, low-alkoxy, low alkene oxygen base, low alkynyloxy group, low alkylidene group or low alkenylene or low alkylene oxide group or low alkylene dioxo base and phenyl ring or six-ring, hydroxyl-low-carbon alkyl, hydroxyl-hang down alkenyl, hydroxyl-low-carbon (LC) alkynyl, low-alkoxy-low-carbon alkyl, low-alkoxy-low-alkoxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxyl-cycloalkyl is single, double or tri-substituted phenyl; Heterocyclic radical; Five yuan of hetero-aromatic rings that contain one or two N, S or O atom (may by halogen, low-carbon alkyl, low-alkoxy, trifluoromethyl, trifluoromethoxy list or two replacement); The hexa-member heterocycle that contains one or two N atom (may by halogen, low-carbon alkyl, low-alkoxy, trifluoromethyl, list or two replacement); )

R ³Representation hydroxy, low-carbon alkyl, phenyl; Low-carbon alkyl, low alkenyl, low-carbon (LC) alkynyl, low-alkoxy, amino, low alkylamino, amino-low-carbon alkyl, trifluoromethyl, trifluoromethoxy, halogen, sulfo-low-carbon alkyl, hydroxyl, hydroxyl-low-carbon alkyl, cyano group, carbonyl, lower alkanes acyl group, formyl radical is single, double or tri-substituted phenyl; The benzene furyl; Heteroaryl; Low-carbon alkyl, low alkenyl, low-carbon (LC) alkynyl, low-alkoxy, amino, low alkylamino, trifluoromethyl, halogen, hydroxyl, hydroxyl-low-carbon alkyl, cyano group, carbonyl list or two three substituted heteroaryls;

R ⁴Representation hydroxy, halogen, trifluoromethyl, low-carbon alkyl, low cycloalkyl, low-alkoxy, low cycloalkyloxy, sulfo-low-carbon alkyl, sulfo-low-carbon alkyl-low-carbon alkyl, hydroxyl-low-carbon alkyl, low-carbon alkyl-oxygen-low-carbon alkyl, hydroxyl-low-carbon alkyl-oxygen-low-carbon alkyl, amino-low-carbon alkyl, low-carbon alkyl-amino-low-carbon alkyl, amino, low-carbon alkyl amino, two low-carbon alkyl amino; Phenyl; One five of forming of phenyl, halogen, hydroxyl, low-carbon alkyl, low-alkoxy, low alkylidene group or low alkenylene or low alkylene oxide group or low alkylene dioxo base and phenyl ring or six-ring, low alkenyl, hang down alkenyloxy, trifluoromethyl, cycloalkyl, hydroxyl-cycloalkyl is single, double or tri-substituted phenyl; Aromatic base; Aromatic base-amino; The sulfo-low-carbon alkyl; Virtue epoxy group(ing), aromatic base-low-carbon alkyl; Heteroaryl; Heterocyclic radical;

X represents Q, S, NH or singly-bound;

Mixture with acceptable salt etc. on mixture, racemize diastereomer and the pharmacology of pure enantiomer, diastereomer, diastereomer and racemize diastereomer.

In the definition to Formula I, unless otherwise noted, low expression contains the straight or branched group of 1 to 7 carbon atom, refers in particular to 1 to 4 carbon atom.For example low-carbon alkyl and low-carbon alkoxy are meant methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl, heptyl, methoxyl group, oxyethyl group, propoxy-, butoxy, isobutoxy, sec-butoxy, tert.-butoxy.Low-carbon (LC) dioxy base refers to methylene radical dioxy base, ethylidene dioxy base, propylidene dioxy base, butylidene dioxy base.The lower alkanes acyl group is meant ethanoyl, propionyl, butyryl radicals.Low alkenyl and low-carbon (LC) alkynyl are meant vinyl, propenyl, butenyl, three butylene (2-methyl-propyl group) and ethynyl, proyl, butynyl, pentynyl, 2-methyl-prop alkynyl.Low alkenyloxy is meant allyloxy, vinyloxy group, propenyloxy group etc.Cycloalkyl is the saturated cyclic alkyls that expression contains the 3-6 carbon atom, and as cyclopropane, tetramethylene, pentamethylene, hexanaphthene, they can be replaced by low-carbon alkyl, hydroxyl low-carbon alkyl, amino low-carbon alkyl, low-alkoxy low-carbon alkyl, the low alkenyl of alkynyl.Heterocyclic radical is meant that saturated or unsaturated (but non-aromatic ring) contains 5,6,7 yuan of identical or different rings such as one or two nitrogen, oxygen or sulphur, this heterocycle can be replaced by low-carbon alkyl, amino, halogen, nitrogen, hydrogen, low-alkoxy, as pyridyl, morpholinyl, piperazinyl, THP trtrahydropyranyl, dihydro pyranyl, 1, the replacement that 4-dioxazines base, pyridinoline base, tetrahydrofuran base, pyrrolin, glyoxalidine, pyrazoline, pyrazolidyl etc. are derived from by these heterocyclic substituted as mentioned above.Heteroaryl is meant and contains a hexa-atomic aromatic nucleus to four nitrogen-atoms, contain a hexa-atomic aromatic nucleus of the benzo to three nitrogen-atoms, the 5-membered aromatic ring that contains a Sauerstoffatom or a nitrogen-atoms or a sulphur atom, five yuan of benzo aromatic nucleus that contain a Sauerstoffatom or a nitrogen-atoms or a sulphur atom, the 5-membered aromatic ring and the benzo derivative that contain a Sauerstoffatom or a nitrogen-atoms, the 5-membered aromatic ring and the benzo derivative that contain a nitrogen-atoms or a sulphur atom, the 5-membered aromatic ring and benzo derivative or the tetrazolium basic ring that contain three nitrogen-atoms.As: furfuryl group, thienyl, pyrryl, pyrimidyl, indyl, quinolyl, isoquinolyl, imidazolyl, triazinyl, thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, oxazolyl, isoxazolyl etc.These rings can be by low-carbon alkyl, amino, amino-low-carbon alkyl, halogen, hydroxyl, low-carbon alkoxy, three fluoro methoxyl groups, three fluoro methyl substituted simultaneously.Aryl is represented by 1,2, the aromatic nucleus of 36 to 10 carbon atoms that replace as: phenyl or naphthyl, they can be by aryl, halogen, hydroxyl, low-carbon alkoxy, low-carbon alkyl, trifluoromethyl, low carbene oxygen base, trifluoromethoxy, cyclopropyl, hydroxyl-cyclopropyl, low-carbon (LC) alkylene oxide group or low-carbon (LC) alkylene dioxo base simultaneously.

The compound that the acceptable salt comprises inorganic salt or organic salt such as haloid acid (hydrogenchloride, hydrogen bromide), sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetate, toxilic acid, tartrate, methylsulphonic acid, tosic acid or the like or has a Chemical formula 1 on the pharmacology has inorganic group such as alkali or native alkali etc. in essence, for example sodium hydroxide, potassium hydroxide, calcium hydroxide etc. are tart.

Therefore compound with Chemical formula 1 has one or more unsymmetrical carbons, can be pure enantiomer or pure diastereomer or both mixtures, pure racemize diastereomer or racemize non-enantiomer mixture.The present invention includes all these structures.Mixture can with known to method separate, as column chromatography, layer chromatography, high pressure lipuid chromatography (HPLC), Crystallization Separation etc.

Because they have the ability that suppresses interior oestrone bonding, therefore describe compound and on pharmacology, can be used for the treatment of the relative diseases such as vasoconstriction, propagation or inflammation that cause by interior oestrone by received salt with them with Chemical formula 1.As: hypertension, coronary heart disease, cardianeuria, kidney and deficiency myocardial blood supply, renal failure, blood supply insufficiency of brain, dementia, migraine, subarachnoid hemorrhage, Reynolds (Raynaud) syndromes, portal hypertension and lung's hypertension etc.They can also be used for the treatment of arteriosclerosis, be used to prevent restenosis, inflammation, gastric duodenal ulcer, cancer, prostatomegaly, protuberance dysfunction, hearing disability, the blue or green light of reconstructing blood vessel postoperative blind, chronic bronchitis, septicemia, shock, drepanocytemia, glomus, nephralgia, glaucoma etc., the complication after treatment and prevent diabetes complication, blood vessel or heart operation complication, the organ transplantation, ring-type robe handle complication and other also the unknown now with interior oestrone diseases associated.

This compound formulation can external application or oral, as tablet, sugar-pill, capsule, emulsion, solution or suspension, can make aerosol or directly uses with the form of suppository nasal cavity.These preparations can also use with injection solution forms such as intramuscular injection, intravenous injections.

These medicine compound preparations contain compound and their acceptable salts on pharmacology of Chemical formula 1, and these salts combine with inorganic and/or organic excipients.Usually the vehicle of usefulness has lactose, corn or their growth, talcum, stearic acid or stearate in pharmaceutical industry.

The preparation capsule can utilize vegetables oil, wax, fat, liquid or semiliquid polyol.Preparation solution and syrup can utilize water, polyol, sucrose, glucose etc.The preparation injection liquid can water, polyol, alcohol, glycerine, vegetables oil, Yelkin TTS, liposome etc.Preparation suppository can be with natural or hydrogenant oil, wax, lipid acid, liquid or semiliquid polyol etc.

Compound formulation may contain sanitas, stablizer, the improvement of interpolation or regulate viscosity agent, chaotropic agent, sweeting agent, siccative, taste conditioning agent, the salt that changes osmotic pressure, buffer reagent, oxidation inhibitor etc.

Compound with Chemical formula 1 can use together in conjunction with one or more other the useful material of treatment, and as the alpha block medicine, β-blocking agent resembles fragrant appropriate amine, phenoxybenzamine, atropic peace, Propranololum, timolol, metoprolol, carteolol etc.; Vasodilator resembles hydralazine, U-10858, diazoxide, Manoplas etc.Anticalcification agent such as diltiazem, nicardipine, nimodipine, verapamil, nifedipine etc.ACE inhibitor Yipingshu, the how general riel of Kapp, enalapril, lisin etc.The potassium promoting agent as than that ground you etc.

The anti-agent of angiotensin II: diuretic(s) such as hydrochlorothiazide, chlorothiazide, ethanamide, bumetanide, furosemide, methaqualone, chlorothiazide etc.Sympatholytic such as methyldopa, clonidine catapresan, guanabenz, serpentine etc.; Other medicine is applied to hypertension or cardiac disorders.

Dosage can change in wide scope, but should be suitable for particular case.Usually, be 70 kilograms of grownups for body weight, oral dosage should be between 3mg-3g every day, and preferable is between 10mg-1g, the most preferably between 5mg-300mg, should divide every day and take by aliquot for 1-3 time.For children, should adapt with body weight and age, take low dose.

The chemical formula of suggestion compound is expression formula I

Here R ¹, R ², R ⁴Definition the same;

R3 represents phenyl; The phenyl that low-carbon alkyl, low-carbon alkoxy, trifluoromethyl, trifluoromethoxy, halogen replace;

X represents O or singly-bound;

With acceptable salt on the pharmacology.

The structural formula of the compound of another kind of suggestion is a Formulae II: Formulae II is R wherein ², R ³, R ⁴With the same Formula I of the definition of X, R ⁵Acceptable salt on expression low-carbon alkyl and the pharmacology.The compound structure of another kind of suggestion is Formulae II I:

R wherein ¹, R ³, R ⁴With the same Formula I of the definition of X, R ⁶, R ⁷And R ⁸Represent hydroxyl, low-carbon alkyl, low-carbon alkyl, low alkenyl, low-carbon (LC) alkynyl, low-alkoxy, low alkene oxygen base, low alkynyloxy group, halogen, trifluoromethyl, trifluoromethoxy or sulfo-low-carbon alkyl respectively;

With acceptable salt on the pharmacology.

The chemical formula of also advising compound is expression formula IV:

Here R ¹, R ³, R ⁴, R ^aIdentical with the definition of X with Chemical formula 1

With acceptable salt on the pharmacology.

The compound structure of another kind of suggestion is Formula I, wherein R ¹, R ³, R ⁴Identical with the definition of X with Formula I, R ²Be low-carbon alkyl;

With acceptable salt on the pharmacology.

Acceptable salt on the compound of another kind of suggestion the finished product that to be example 1 given below describe to the example 96 and the pharmacology.

Structure is that the compound of Formula I is that the compound of chemical formula V is a raw material with the structure, by a kind of the making in two kinds of methods that describe below.Compound VI and compound R ²-Y (Y represents a reactive leavings group such as chlorine, bromine, sulfone, vitriol etc. here) reaction or work as R ²Be formula C (A)-NH-R ^aCompound the time and compound R ^a-N=C=A (R ^aDefine same general formula I with A) reaction.

Structure is that the compound of chemical formula VII utilizes 2-butyl-1,4-glycol and R ²-Y in the presence of alkali, react (as alkali hydroxide metal, alkali metal alcoholates, sodium hydride etc.) in solvent as DMSO, DMF, THF, pyrimidine, water etc. (as Tetrahedron Letters 38 (1997), 7887-7890; Bull.Chem.Socc.Jpn.28 (1995), 80-82; J.Org.Chem.188 (1953), 1601-1606).Structure is that the compound of chemical formula VII can also be with the 1-chloro-4=hydroxyl-2-butane and the pure reactant salt of suitable hydroxyl protection, then as document description, separate blocking group (as Bull.Chem.Soc.1955,502; J.Org.Chem.USSR (Engl.Transl.) 12 (1976), 505-507; J.Org.Chem.63 (1998), 4291-4298).

Compound V prepares (Bioorg.Med.Chem.Letters7 (1997) .2223-2228, Chimia50 (1996), 519-524, and the reference of quoting) here by corresponding compound of dichloro VIII.

At room temperature, with excessive sulfanilamide (SN) sylvite have or alkali-free in the presence of in solvent (as DMF, DMSO), handle compound VIII and prepare desired compounds V.The preparation of sulfanilamide (SN) sylvite can be with reference to pertinent literature, as Bioorg.Med.Chem.Letters7 (1997) .2223-2228.

Under (30-120 ℃) condition of intensification, with chlorizating agent such as POCl ₃, PCl ₅Or their mixture, having or alkali-free (as N, N-dialkyl aniline or benzyl triethyl ammonium ammonia chloride) processing Compound I X (or its tautomer) preparation compound VIII respectively.(Bioorg.Med.Chem.Letters7(1997).2223-2228；J.Med.Chem.，41(1998)，3793-3803；J.Chem.Soc.1959，2214；Bull.Soc.Chim.Fr.1959，741-742)。

In the standard method that Pinner describes (in order to be familiar with, please see example: Pyrimidines, by D.J.Brown, Wiley Interscience, New York1970) at room temperature, with suitable propylene diester derivative in the presence of alcoxyl sodium, in solvent (as methyl alcohol, ethanol etc.), concentrate corresponding X amidine (isolating hydrochloric acid salt) and obtain compounds X I (as Bull.Soc.Chim.Fr.1960,1648)

In methyl alcohol, make the X amidine or in Virahol, add hydrochloric acid (Advanced Organic Chemistry, by J.March, 3 afterwards with hexamethyldisilazane processing XII nitrile compound with adding ammonia chloride after the sodium methylate processing XII nitrile compound ^RdEdtion, Wiley1985, p.803 and references citd therein).

Propylene diester derivative XI can buy, and also can prepare according to the step of document description (as J.Am.Chem.Soc.62 (1940), 1154,1155; Ibid.74 (1952), 4466; J.Chem.Soc.Perkin 1,1979,2383-2386; Collect.Czech.Chem.Comm.55 (1990), 1278-1289; J.med.Chem.Chim.Ther.26 (1991) .599-604; Bull.Soc.Chim.Fr.1973,2065-2071)

May be the compound that will have one or more optical activity carbon atoms as an example with the mode of generally acknowledging be dissolved in the pure enantiomer, in the pure diastereomer, in the two the mixture, in the outward turning diastereomer or in the mixture of outward turning diastereomer, if wish, the compound that synthetic is had a Formula I in the mode of generally acknowledging changes into the acceptable salt on the pharmacology.The compound that will have one or more optical activity carbon atoms with the mode of generally acknowledging be dissolved in the pure enantiomer, in the pure diastereomer, in the two the mixture, in the outward turning diastereomer or in the inward turning diastereomer.Embodiment:

Following Example has illustrated the present invention, but is not confined in such scope.All temperature are all ℃ being unit.

The step of compound as described above given below prepares.All compounds are used ¹H-NMR (300MHz) characterizes, the usefulness that has ¹³C-NMR (75MHz) characterizes (Varian Oxford, 300MHz; Chemically relevant with solution variation is represented with ppm; Diversity: s=is single, and d=is two, and t=three, and m=is many), characterize (Waters Micromass by liquid chromatograph mass spectrography; ZMD-platform with ESI-probe withAlliance2790HT; Pillar: 2X3mm, Gromsil ODS4,3um, 120A; Composition: 0-100% acetonitrile in water, 6 minutes, use 0.05% formic acid, flow: 0.45ml/min; t _fMinute to provide, at t _fThe time the molecular mass mark), characterize by tlc TLC that (Merck produces thin-layer chromatography dish, silica gel 60F ₂₅₄); Have very little by measuring the fusing point sign.Abbreviation: DCM=methylene dichloride, MeOH=methyl alcohol, DMF=N, the N dimethyl formamide, THF=tetrahydrofuran (THF), DMSO=dimethyl sulfoxide (DMSO), DMPU=1,3-dimethyl-3,4,5,6-tetrahydroxy-2 (1 hydrogen)-pyrimidone, DMAP=4-dimethylamino yl pyrimidines, DBU=1,8=diazabicyclo [5.4.0] 11-7-alkene, min=minute, h=hour.Example 1

A) 0.23g sodium is put into methyl alcohol and is made solution, at room temperature, and toward the 4-cyanopyrimidine that wherein adds 10.62g.Continuously stirring 6 hours, the ammonia chloride that adds 5.9g afterwards be continuously stirring 10 hours again.The diethyl ether that then adds 120ml after 30 minutes filters out throw out, at every turn with the washing of 20ml diethyl ether.Product is dry under high vacuum.Obtain white powder 4-amino-pyrimidine ammonia chloride of 14.95g.

B) 70.8g salt of wormwood is put into 480ml acetone and is mixed with suspension, 48ml2-methoxyl group-phenol is slowly added in the suspension of stirring, is heated to 45 ℃ afterwards.Then 63.2ml dimethyl chloride propanedioic acid being added the solution that obtains in the acetone added in 20 minutes.Reaction mixture was by adverse current heating 16 hours.The vapourisation under reduced pressure solvent, resistates is put into water, distills with DCM.With the dry and evaporation on sodium sulfate of bonded organic layer.Oily matter is crystallized out from methyl-3-butyl-ether.Obtain 86g dimethyl-(neighbour-methoxyphenol) propanedioic acid.

C) the 9.7g sodium methylate is put into 100ml methyl alcohol and is made solution, 21.7g dimethyl-(neighbour-methoxyphenol) propanedioic acid is put into 50ml methyl alcohol and is made solution, the latter was added in 15 minutes in the former solution that stirs, and continuously stirring 30 minutes, add 15g4-amino-pyrimidine ammonia chloride afterwards, then continuously stirring 20 hours at room temperature.Reaction mixture concentrates under vacuum.Solid residue stirs with ether.The powdery substance that obtains is filtered out, be dissolved in the 300ml water.Add acetate to PH=4.To precipitate product and filter out, wash with water and down dry in 50 ℃ in a vacuum.Obtain 20.1g white powder material 5-(neighbour-methoxyphenol)-4, and 6-dihydroxyl-2-(4-pyridyl)-pyrimidine (also may be its tautomer 5-(neighbour-methoxyphenol)-4,6-dihydroxyl-2-(4-pyridyl)-tetrahydropyrimidine-4,6-diketone.

D) 10g5-(neighbour-methoxyphenol)-4,6-dihydroxyl-2-(4-pyridyl)-pyrimidine, the 11.2gN-ethyl diisopropyl amine, 11g tetraethyl-ammonia chloride and 13.8g phosphorus pentachloride are dissolved in the 25ml phosphorus oxychloride, and adverse current heated 3 hours.The vaporising under vacuum mixture adds toluene, and evaporating mixture once more.Resistates is put into DCM, be poured on ice/waterborne.Demixing phenomenon takes place, and the oily layer washes with water, dry evaporation on sodium sulfate.From acetone, behind the recrystallization, obtain 6.52g 4,6-two chloro-5-(neighbour-methoxyphenol)-2-(4-pyridyl)-pyrimidines.

E) according to patent EP 0713875 A1 and Bioorganic ﹠amp; Medicinal Chemistry Letters, 7 (1997), the step of introducing among the 2223-2228 prepares 5-sec.-propyl pyrimidine-2-sulfanilamide (SN).

F) 1g 4, and 6-two chloro-5-(neighbour-methoxyphenol)-2-(4-pyridyl)-pyrimidines and 1.43g5-sec.-propyl pyrimidine-2-sulfanilamide (SN) sylvite are suspended among the 20ml exsiccant DMF.Mixture at room temperature stirs in argon gas, becomes clear in several hours.After at room temperature 16 hours, most of solvent is removed in evaporation under low pressure.20ml water is put in the resistates taking-up, and the acetate that adds about 1ml is regulated PH to 4-5.Form throw out, it is filtered out, wash drying with water.On silica gel, be further purified yellow powder with the column chromatography, at first use hexane: ethyl acetate=washing in 1: 1, then use DCM: methyl alcohol=washing in 10: 1.Obtain 1.43g pale yellow powder 5-sec.-propyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-4-pyrimidine]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.00min，[M+1] ⁺＝512.19，[M-1] ^-＝510.26。

G) the 0.7g sodium hydride puts into that 30ml does DMF and 5ml DMPU is configured to soup compound, and under 0-5 ℃, with 5.04g2-butyl-1, the 4-diketone adds in the soup compound that is stirring in batches.Continuously stirring is evaporated totally until gas.At room temperature, in the suspension that obtains, add 1.5g5-sec.-propyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-4-pyrimidine]-2-pyrimidine sulfanilamide (SN), under 95 ℃, stirred the mixture 24 hours.At last, soup compound is cooled to room temperature, then is poured on the aqueous citric acid solution of 100ml10%, uses twice of 150ml ethyl acetate extraction.In conjunction with organic layer 50ml water washing twice, dry evaporation on sal epsom.Remaining dark-brown oily matter washs with the DCM that contains 0-5% methyl alcohol on 80g silica gel with the column chromatography.Obtain light yellow solid thing 5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-4-pyrimidine of 0.82g]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.39min，[M+1] ⁺＝562.29，[M-1] ^-＝560.41。Example 2

A) 15.2g4-tributyl phenyl sulfonyl chlorine is dissolved among the 150ml THF, with the cooling of ice groove.25% ammonia soln of 15.2ml is splashed into.After adding finishes, at room temperature dry 15 minutes.Under vacuum, remove and desolvate.Resistates washes with water twice in being dissolved in ethyl acetate.Organic phase is dry on sodium sulfate, evaporation.The 14.8g white powder that obtains is dissolved in the 75ml methyl alcohol, adds 7.5g tributyl potassium.At room temperature, stir a little and evaporate.The resistates that obtains is carefully dry, obtain 16.3g4-tributyl phenyl sulfonyl sylvite.

B) 6.1g4,6-two chloro-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-pyrimidine (see example 1 a) to d)) be dissolved in 100ml and do among the DMF, add 8.8g4-tributyl phenyl sulfonyl sylvite under the room temperature.Solution is joined in the mixed solution of 150ml water and 100ml ethyl diacetate, add acetate and regulate PH to 5.Collect the throw out that forms.Water and ethyl diacetate washing.The powder suspension that obtains is in the ebullient ethyl acetic acid.In the ice groove, cool off.At last, the solid state material that collect, drying obtains obtains 6.6g beige crystals 4-tributyl-N-[6-chloro--5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-pyrimidine phenyl sulfanilamide (SN).LC-MS：t _R＝5.80min，[m+1] ⁺＝525.31，[m-1] ^-＝523.48。

C) the 0.96g sodium hydride is put into 25ml and is done DMF and 5ml and do DMPU and be configured to soup compound, and at room temperature, with 6.9g2-butyl-1, the 4-diketone adds in the soup compound that is stirring in batches.Continuously stirring is evaporated totally until gas.At room temperature, in the suspension that obtains, add 2.1g4-tributyl-N-[6-chloro-5-(neighbour-methoxyphenol)-2-(4-pyridyl)-4-pyrimidine]-phenyl sulfanilamide (SN), under 90 ℃, stirred the mixture 48 hours.At last, evaporating solvent under low pressure, remaining oily matter is handled with the 150ml10% acetic acid aqueous solution.Dark solvent extracts with 150ml DCM.Organic layer washes with water, dry on sal epsom, evaporation.Obtain dark-brown oily matter and further on silica gel, carry out purifying, use toluene: ethyl acetate=washing in 4: 1 to 1: 4 with the column chromatography.Obtain cream-coloured foam 1.28g4-tributyl-N-[6-(hydroxyl-2 butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-pyrimidine] phenyl sulfanilamide (SN).LC-MS：t _R＝4.87min，[M+1] ⁺＝575.32，[M-1] ^-＝573.45。Example 3

A) under the room temperature, the 200ml25% hydrochloride aqueous solution is joined in the suspension that 70g2-bromo-5-methylpyrimidine makes in 500ml water.In limpid solution, add the 68g thiocarbamide, the adverse current heated mixt.Add the 34g thiocarbamide after 4 hours in addition, add the 17g thiocarbamide after 18 hours again.After 24 hours, solution cools off on the ice groove, adds the sodium hydroxide solution of 360ml4N.Add the 600ml DCM throw out of solution formation again.Separate organic layer, use the 500ml water washing.With spirit of salt aqueous phase as acidified is arrived PH=3, extract repeatedly with DCM., evaporation under low pressure dry on sal epsom in conjunction with organic layer.Recrystallization goes out the 46.9g yellow solid from ebullient ethanol, obtains the block 5-methyl of 37.6g-2-sulphur-pyrimidine, and it softens at 168 ℃, 179-190 ℃ of fusing gradually. ¹H-NMR(CDCl ₃，300MHz)：2.17(s，3H)；7.24(dd，J＝2.0，8.8，1H)；7.41(t，J＝1.0，1H)；7.47(d，J＝8.8，1H)；14.03(sbr，1H)。

B) in the mixed solution of the 100ml25% spirit of salt aqueous solution and 250mlDCM, add 18g5-methyl-2-sulphur-pyrimidine.In the vigorous stirring mixture, remain on-10 ℃ of careful aqueous solution that contain 13% clorox that add.After adding finishes, continuously stirring 10 minutes.Separate organic layer.In water layer, add 250ml DCM, use the further treating mixture of 250ml SYNTHETIC OPTICAL WHITNER as previously mentioned.With 200ml DCM extraction 5 times.Collected organic layer, dry on sal epsom, evaporation.The oily matter that obtains is dissolved in 125ml reaches among the THF, be cooled to-20 ℃.Slowly add the saturated ammonia soln of 25ml.Add in the spirit of salt and excess of ammonia, under vacuum, remove THF.150ml ethyl acetate extraction three times of the remaining aqueous solution.Dry on sal epsom in conjunction with organic layer, solvent is evaporated.Recrystallize goes out remaining solids from the ebullient ethyl acetate, obtains 13.35g beige crystals 5-methyl-2--pyrimidine-thiamines. ¹H-NMR(D6-DMSO，300MHz)：2.17(s，3H)；7.36(s，2H)；7.78-7.85(m，2H)；8.53(s，1H)；LC-MS：t _R＝2.32min，[M+1] ⁺＝173.04，[M-1] ^-＝171.10。

C) 18.54g5-methyl-2--pyrimidine-thiamines is dissolved in the 400ml methyl alcohol, and 12.08g tributyl potassium adds wherein.At room temperature stirred solution is 5 minutes, under low pressure removes solvent, and residue drying in high vacuum obtains 22.64g beige solid 5-methyl-2--pyrimidine-sulfanilamide (SN) sylvite.

D) in argon gas atmosphere,, 6-two chloro-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridine)-pyrimidine (see example 1 a) to d)) be dissolved in 40ml and do among the DMF, after the 2.95mlHunig base, add 3.62g5-methyl-2--pyrimidine-sulfanilamide (SN) sylvite 4 of 4g.Dark solution at room temperature stirred 22 hours.Add 0.75g5-methyl-2--pyrimidine-sulfanilamide (SN) sylvite again, continuously stirring 18 hours.Reaction mixture is poured on the aqueous citric acid solution of 150ml10%, uses 150ml ethyl acetate extraction 4 times.The bonded organic phase washes with water, dry on sal epsom, evaporation.The resistates that obtains is suspended on 20ml methyl alcohol and the 20ml acetone.Collecting precipitation thing methyl alcohol: the solution washing of ethyl diacetate=1: 1.Obtain 4.56g cream-coloured powder 5-methyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-pyrimidine]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.38min，[M+1] ⁺＝484.58，[M-1] ^-＝482.51。

E) the 0.99g sodium hydride puts into that 25ml does DMF and 5mlDMPU is configured to soup compound, and at room temperature, with 8.0g2-butyl-1, the 4-diketone adds in the soup compound that is stirring in batches.Continuously stirring is evaporated totally until gas.At room temperature, in the suspension that obtains, add 2.0g4-sec.-propyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-4-pyrimidine]-phenyl sulfanilamide (SN), under 90 ℃, stirred the mixture 16 hours.At last, soup compound is cooled to room temperature, then is poured on the mixed solution that the aqueous citric acid solution of 200ml10% and 200ml ethyl acetate form.Form thin throw out.Elimination throw out, water and ethyl acetate washing.Separate organic layer, use twice of ethyl acetate extraction water layer.The bonded organic layer is dry on sal epsom, and solvent is removed general 10ml.Collect the thin throw out that forms, with the ethyl acetate washing, in conjunction with the throw out of from water layer, separating.Obtain buff powder 5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-4-pyrimidine of 1.65g]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝3.81min，[M+1] ⁺＝534.63，[M-1] ^-＝532.54。Example 4

A) 4,6-dihydroxyl-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-pyrimidine (or its tautomer 5-(neighbour-methoxyl group phenoxy group)--2-(2-pyrimidyl)-tetrahydropyrimidine-4, the 6-diketone is made by 2-amidine-pyrimidine and dimethyl-(neighbour-methoxyl group phenoxy group) propanedioic acid according to the description of patent EP 0 526 708 A1.

B) 4,6-two chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-pyrimidine according to the description of patent EP 0 526 708A1 by 4,6-dihydroxyl-5-(neighbour-methoxyphenol)-2-(2-pyrimidyl)-pyrimidine (or its tautomer 5-(neighbour-methoxyphenol)--2-(2-pyrimidyl)-tetrahydropyrimidine-4,6-diketone) makes.

C) 3.5g4,6-two chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-pyrimidine and 4.98g5-sec.-propyl-2-Sulphapyridine sylvite are dissolved among the 40ml DMSO, at room temperature stir 4 hours.Mixture is poured on waterborne, uses the ethyl diacetate extracting twice.Water layer acetate acidifying.Collect the throw out that forms, water and ethyl diacetate washing, drying obtains 5.1g white solid 5-sec.-propyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidine]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.87min，[M+1] ⁺＝513.32，[M-1] ^-＝511.26。

D) from 600ml5-sec.-propyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidine]-2-pyrimidine sulfanilamide (SN) prepares 273ml5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidine by the step of routine 1g]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.31min，[M+1] ⁺＝563.71，[M-1] ^-＝561.59。Example 5

A) 4-tributyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidine]-step that phenyl sulfanilamide (SN) is described according to patent EP 0 526 708 A1 is by 4, and 6-two chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-pyrimidine and right-tributyl phenyl sulfanilamide (SN) sylvite make.LC-MS：t _R＝5.50min，[M+1] ⁺＝526.29，[M-1] ^-＝524.43。

B) the cream-coloured foam-like material 4-of 295mg tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidine]-phenyl sulfanilamide (SN) is by 1.4g4-tributyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidine]-phenyl sulfanilamide (SN) is by the step preparation of routine 1g.LC-MS：t _R＝5.06min，[M+1] ⁺＝576.36，[M-1] ^-＝574.45。Example 6

A) 4, form suspension among 6-two chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-pyrimidine (routine 4b) and 2.65g5-methyl-2--pyrimidine-sulfanilamide (SN) sylvite (routine 3c) adding 40ml DMF, toward wherein adding 10mlDMSO.It is limpid that mixture becomes, and at room temperature continuously stirring is 16 hours.Mixture is poured on the aqueous citric acid solution of 50ml10%, forms white depositions.The collecting precipitation thing, water and ethyl acetate washing, drying.Obtain 2.67g white powder 5-methyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl]-the 2-Sulphapyridine.LC-MS：t _R＝4.23min，[M+1] ⁺＝485.56，[M-1] ^-＝483.48。

B) 347mg weak yellow foam shape material 5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl]-the 2-Sulphapyridine is by 1g 5-methyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl]-the 2-Sulphapyridine makes according to the step of routine 1g.LC-MS：t _R＝3.90min，[M+1] ⁺＝535.66，[M-1] ^-＝533.55。Example 7

A) make solution in 10g dimethyl-dried methyl alcohol of (neighbour-methoxyl group phenoxy group) propanedioic acid (routine 1b) adding 80g, be cooled to 0 ℃.Add the 6.71g sodium methylate in batches.Add 2.84g acetone amidine hydrogenchloride again, at room temperature stir the mixture on the whole night.Under low pressure remove solvent, residue is suspended in the 100ml ethyl diacetate, be dissolved in the 50ml water.The acetate adjusting PH that adds 25ml ice is 4.Filter the white depositions that forms, wash drying with water and obtain 5.17g white powder 5-(neighbour-methoxyl group phenoxy group)-4,6-dihydroxyl-2-methyl-pyrimidine (or tautomer).

B) 5-of 10.9g (neighbour-methoxyl group phenoxy group)-4,6-dihydroxyl-2-methyl-pyrimidine (or tautomer) adds 150ml POCl ₃Make solution, stirred 72 hours down at 50 ℃.With excessive POCl ₃Evaporation, the POCl of adding toluene coevaporation trace ₃At last, the careful ice that adds in the residue: water mixture, regulate PH to 8 with the sodium hydroxide solution of 3N.With the further diluted mixture thing of 300ml water, extract with 500mlDCM.Separate organic layer, use the 300ml water washing, dry evaporation on sodium sulfate.Residue is dissolved among the DCM once more, by a slice filtered through silica gel, washs with DCM.Under vacuum, remove and desolvate.The residue dried that obtains is obtained 8.7g cream-coloured powder 4,6-two chloro-5-(neighbour-methoxyl group phenoxy group)-2-methyl-pyrimidine.

C) 2.15g4 makes solution among 6-two chloro-5-(neighbour-methoxyl group phenoxy group)-2-methyl-pyrimidine adding 40mlDMSO, toward wherein adding 3.59g5-sec.-propyl-2-Sulphapyridine salt.At room temperature stirred 72 hours.With 350ml water diluting soln, with 200ml ethyl diacetate extracting twice.Being acidified to PH in conjunction with water layer with 5ml acetate is 4, uses the DCM extracting twice.Wash organic layer with water, dry on sodium sulfate.Use activated carbon treatment, on Celite, filter, evaporate.Resistates is suspended in the 30ml ethyl diacetate, and filtration, drying obtain the light cream-coloured powder 5-sec.-propyl of 3.15g-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl]-the 2-Sulphapyridine.LC-MS：t _R＝5.18min，[M+1] ⁺＝49.25，[M-1] ^-＝447.31。

D) the cream-coloured foam-like material 5-of 440mg sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl]-the 2-Sulphapyridine is by 600mg5-sec.-propyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl]-the 2-Sulphapyridine is according to the step preparation of routine 1g, but reaction mixture stirred 48 hours at 95 ℃.LC-MS：t _R＝4.74min，[M+1] ⁺＝449.25，[M-1] ^-＝497.33。Example 8

A) 2g4,6-two chloro-5-(neighbour-methoxyl group phenoxy group)-2-methyl-pyrimidine (routine 7b) is dissolved among the 30mlDMSO, at room temperature, toward wherein adding 2.95g5-methyl-2--pyrimidine-sulfanilamide (SN) sylvite (routine 3c).At room temperature stirred 48 hours, and be poured on waterborne then.Aqueous solution 200ml ethyl diacetate extracting twice.Extraction of organic layer water and water layer are 4 in conjunction be acidified to PH with 3ml acetate.Add the saturated sodium-chlor of 100ml and make that throw out increases in the product, mixture is cooled to 0 ℃.At last, throw out is filtered out, use cold water washing, drying obtains 2.26g cream-coloured powder 5-methyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl under high vacuum]-the 2-Sulphapyridine.LC-MS：t _R＝4.79min，[M+1] ⁺＝421.42，[M-1] ^-＝519.46。

B) 584mg cream-coloured powder 5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl]-the 2-Sulphapyridine is by 950mg5-methyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl]-the 2-Sulphapyridine is according to the step preparation of routine 1g, but reaction mixture stirred 72 hours at 95 ℃.LC-MS：t _R＝4.32min，[M+1] ⁺＝471.57，[M-1] ^-＝469.40。Example 9

A) 32.75g dimethyl-(neighbour-methoxyl group phenoxy group) propanedioic acid (routine 1b) is dissolved in the 250ml methyl alcohol and makes solution, is cooled to 0 ℃.Add the 20.0g sodium methylate in batches, wait add finish after, at room temperature stirred 6 hours.Add 25.0g morpholine carbonamidine hydrogen bromide then, continuously stirring 72 hours.Evaporate the solvent of cream-coloured suspension, with 150ml ethyl diacetate washed twice residue.Remaining powder is dissolved in the 200ml water.Regulate PH to 4 with 50ml acetate, form throw out.The collecting precipitation thing washes with water, and drying obtains the light cream-coloured powder 5-of 17.07g (neighbour-methoxyl group phenoxy group)-4,6-dihydroxyl-2-(N-morpholinyl)-pyrimidine (or tautomer) under vacuum.

B) under 0 ℃ with 50ml POCl ₃Carefully join in the H ü nig alkali of 27.5ml.Toward wherein add 17g5-(neighbour-methoxyl group phenoxy group)-4,6-dihydroxyl-2-(N-morpholinyl)-pyrimidine in batches.The mixture that obtains is stirred under 130 ℃ whole night.With excessive reagent evaporation, remove the POCl of trace with the toluene coevaporation ₃The residue of black 50mlDCM and 50ml water: ice mixture process.Stir after 15 minutes, with 400ml water and 400mlDCM purging compound.Separate organic layer, use the 300ml water washing.Use the 400mlDCM aqueous layer extracted.Dry on sodium sulfate in conjunction with the DCM layer.Removing solvent to volume is about 100ml.Remaining solvent filters on 50g silica gel and washs with DCM.The evaporation filtrate.The resistates that obtains is suspended on the 50ml ethyl diacetate.Filter out solids, drying obtains 13.85g white crystal sprills 4,6-two chloro-5-(neighbour-methoxyl group phenoxy group)-2-(N-morpholinyl)-pyrimidine.

C) 4g4 makes suspension among 6-two chloro-5-(neighbour-methoxyl group phenoxy group)-2-(N-morpholinyl)-pyrimidine adding 60mlDMSO.Toward wherein adding 5.32g5-sec.-propyl-2-pyridine-sulfanilamide (SN) sylvite (routine 3c) and 0.98ml Hunig alkali.Mixture was stirred 72 hours down at 65 ℃.It is waterborne that dark solution is poured on 500ml, filters rapidly by celite.Filtrate extracts with 500ml and 250ml ethyl diacetate.Organic layer is washed with 100ml.Water layer is combined, with the acidifying of 3.5ml acetate, is cooled to 0 ℃.The throw out that forms is collected, use cold water washing, drying under high vacuum obtains brown ceramic powder 5-sec.-propyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(N-morpholine)-4-pyrimidine pyridine base of 4.94g]-the 2-Sulphapyridine.LC-MS：t _R＝5.46min，[M+1] ⁺＝520.22，[M-1] ^-＝518.36。

D) the 0.55g sodium hydride puts into that 30ml does DMF and 7mlDMPU is configured to soup compound, and under 0-5 ℃, with 3.97g2-butyl-1, the 4-diketone adds in the soup compound that is stirring in batches.Continuously stirring is evaporated totally until gas.At room temperature, in the suspension that obtains, add 1.2g5-sec.-propyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(N-morpholine)-4-pyrimidine]-the 2-Sulphapyridine, under 95 ℃, stirred the mixture 6 days.At last, soup compound is cooled to room temperature, then is poured on the aqueous citric acid solution of 100ml10%, uses twice of 150ml ethyl acetate extraction., dry on sal epsom in conjunction with organic layer with 75ml water washing twice, evaporation.Remaining brown oil is used the DCM purifying that contains 0-2% methyl alcohol with the column chromatography on 120g silica gel.The fragment that collect, evaporation contains target compound, use ethyl diacetate: the hexane recrystallize is further purified residue.Obtain clear crystal (fusing point is 196-197.5 ℃) 5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(N-morpholine)-4-pyrimidine of 327mg]-the 2-Sulphapyridine.LC-MS：t _R＝4.89min，[M+1] ⁺＝570.30，[M-1] ^-＝568.43。In addition, the 494mg initial feed reverts to cream-coloured foam-like material.Example 10

A) make solution in 18.9g dimethyl-(neighbour-methoxyl group phenoxy group) propanedioic acid (routine 1b) adding 450ml methyl alcohol, under 5 ℃, toward wherein adding the 12.7g sodium methylate.After interpolation was finished, at room temperature continuously stirring was 30 minutes, adds 6g carbonamidine hydrogenchloride afterwards.At room temperature the continuously stirring mixture is 72 hours.Under low pressure remove at last and desolvate, resistates is suspended on the ethyl diacetate.Filter out solid matter, be dissolved in the 100ml water.With dense spirit of salt souring soln.Form white depositions.The collecting precipitation thing washes with water, and drying obtains white powder 15.1g5-(neighbour-methoxyl group phenoxy group)-4,6-dihydroxyl-pyrimidine (or tautomer).

B) 7.5g5-(neighbour-methoxyl group phenoxy group)-4,6-dihydroxyl-pyrimidine adds 90ml POCl ₃In make solution, toward wherein adding 24ml N, accelerine.Mixture heating up to 160 ℃ stirred 25 hours.With excessive POCl ₃Under low pressure distill, with toluene and trace P OCl ₃Coevaporation.Use ice: water mixture is handled remaining oily matter, with the spirit of salt acidifying of 1N, and uses the ethyl diacetate extracting twice.The bonded organic layer spirit of salt solution washing twice of dilution, dry evaporation on sal epsom.Residue is with formaldehyde washing, drying.Obtain 4.75g pale yellow powder 4,6-two chloro-5-(neighbour-methoxyl group phenoxy group)-pyrimidine.

C) 2g4 makes solution among 6-two chloro-5-(neighbour-methoxyl group phenoxy group)-pyrimidine adding 40mlDMSO, toward wherein adding 3.7g 4-tributyl phenyl sulfanilamide (SN) sylvite.At room temperature stirred 20 hours.At last, mixture to waterborne at 400ml, is used 200ml ethyl diacetate washed twice.Organic layer extracts with 200ml water.In conjunction with water layer concentrated hydrochloric acid acidifying.Mixture is cooled to 0 ℃, adds 100ml salt solution.Collect the throw out, the drying that form and obtain 2.7g white powder 4-tributyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-4-pyrimidyl]-phenyl sulfanilamide (SN).LC-MS：t _R＝5.80min，[M+1] ⁺＝448.17，[M-1] ^-＝46.21。

D) 0.7 9g sodium hydride is put into 45mlDMF and 15mlDMPU is configured to soup compound, and under 10 ℃, with 5.68g 2-butyl-1, the 4-diketone adds in the soup compound.Continuously stirring is evaporated totally until gas.At room temperature, toward wherein adding 1.48g4-tributyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-4-pyrimidine]-phenyl sulfanilamide (SN), under 90 ℃, stirred the mixture 72 hours.Under vacuum, remove and desolvate, take out the acetic acid aqueous solution that residue is placed on 150ml10%.Mixture 150ml ethyl acetate extraction three times.In conjunction with organic layer water and salt water washing, dry on sal epsom, evaporation.The brown oil that obtains is used hexane with the column chromatography on silica gel: ethyl acetate is the elution purifying from 3: 1 to 1: 1.Obtain light brown foam-like material 4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-4-pyrimidine of 320mg]-phenyl sulfanilamide (SN).LC-MS：t _R＝5.21min，[M+1] ⁺＝498.35，[M-1] ^-＝496.49。Example 11

A) make solution in the 6.8g sodium methylate adding 200ml methyl alcohol, it is cooled to 0 ℃.10.3g slowly adding in the 50ml methyl alcohol, diethyl-2 (right-tolyl)-propanedioic acid makes solution.After interpolation is finished,, add 7.57g 4-amino-pyrimidine ammonia chloride (routine 1a) with the solution cool to room temperature.Mixture at room temperature stirred 16 hours.At last, under low pressure remove solvent, residue is dissolved in the 2M spirit of salt.With the ethyl diacetate extraction, adding 10M sodium hydroxide adjusting PH is 5.The throw out that collect to form is used cold water washing, under high vacuum in 60 ℃ of dryings.Obtain 8.77g safran crystal 4,6-dihydroxyl-2-(4-pyridine)-5-(right-tolyl)-pyrimidine (or its tautomer).

B) under the room temperature, to 8.0g 5-(right-tolyl)-4,6-dihydroxyl--pyrimidine and 100mlPOCl ₃Mixture in add the 25ml diethylamide.Under 60 ℃, stirred the mixture 16 hours.Excessive POCl ₃Distillation is under low pressure removed.Residual oily matter is dissolved among the 300mlDCM, uses the 300ml water treatment.Separating water layer extracts three times with DCM.Be suspended in the Virahol in conjunction with organic layer water and salt water washing, residue dry on sal epsom, that evaporation obtains.Collect solids, obtain 7.2g white crystalline powder 4,6-two chloro-2-(4-pyridine)-5-(right-tolyl)-pyrimidine with Virahol and ethyl diacetate washing, drying.

C) 654mg4, the mixture of 6-two chloro-2-(4-pyridine)-5-(right-tolyl)-pyrimidine and 1051mg5-sec.-propyl 2-pyrimidine sulfanilamide (SN) sylvite (routine 1e) is put into 20ml DMF and was at room temperature stirred 16 hours.At last, distillation under low pressure removes desolvates, and obtains residue and handles with 100ml 10% acetic acid aqueous solution and 100ml DCM.Demixing phenomenon appears.With DCM aqueous layer extracted least twice.Wash dry on sal epsom, evaporation with water.Remaining residue is from Virahol: crystallization is separated out the ethyl diacetate.Collect yellow crystals, wash with cold Virahol and ethyl diacetate, drying obtains 870mg 5-sec.-propyl-N-[6-chloro-5-(right-tolyl)-2-(4-pyridine)-4-pyrimidine under high vacuum]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.06min，[M+1] ⁺＝480.40，[M-1] ^-＝478.48。

D) the 0.34g sodium hydride is put into 15mlDMF and 4mlDMPU is configured to soup compound, and at room temperature, with 2.4g 2-butyl-1, the 4-diketone adds in the soup compound.Continuously stirring is evaporated totally until gas.At room temperature, toward wherein adding 0.67g 5-sec.-propyl-N-[6-chloro-5-(right-tolyl)-2-(4-pyridine)-4-pyrimidine]-2-pyrimidine sulfanilamide (SN), under 90 ℃, stirred the mixture 48 hours.Under vacuum, remove and desolvate, take out residue and be placed in the acetic acid aqueous solution of 100ml 10%.In conjunction with organic layer water and salt water washing, dry on sal epsom, evaporation.The brown oil that obtains is used the methyl alcohol elution that contains 4-10%DCM with the column chromatography on silica gel.From DCM: recrystallization obtains about on a small quantity 43mg light yellow crystal 5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-tolyl)-2-(4-pyridine)-4-pyrimidine the ethyl acetate]-2-pyrimidine sulfanilamide (SN).Obtain light brown foam-like material 5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-tolyl)-2-(4-pyridine)-4-pyrimidine of the brown oil 456mg of another part purity about 90%]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.53min，[M+1] ⁺＝530.23，[M-1] ^-＝528.21。Example 12

A) under 0 ℃, 14.2g diethyl 2-(right-tolyl)-propanedioic acid adds in the 50ml methyl alcohol makes solution, is dissolved in the solution that disposes in the 300ml methyl alcohol toward wherein slowly adding by the 9.4g sodium methylate.After adding is finished,, add 5.4g carbonamidine hydrogenchloride again with the mixture slightly heated.At room temperature stirred the mixture 16 hours.Under low pressure remove and desolvate, resistates is handled with the spirit of salt of 150ml2N.Stirred suspension 0.5 hour.Regulate PH to 4 at 0-5 ℃ of careful sodium hydroxide solution with 10N.The collecting precipitation thing with cold water, Virahol and ethyl diacetate washing, obtains the white powder 4 of 11.2g, 6-dihydroxyl-5-(right-tolyl)-pyrimidine (or its tautomer) in 65 ℃ of dryings under high vacuum.

B) under the room temperature, to 5.1g 4,6-dihydroxyl-5-(right-tolyl)-pyrimidine and 75ml POCl ₃Mixture in add 10mlN, accelerine.Under 70 ℃, stirred the mixture 16 hours.Excessive POCl ₃Distillation is under low pressure removed.Residual oily matter is with icing: water mixture is handled, with ethyl diacetate extraction three times.In conjunction with organic layer with the 1N spirit of salt aqueous solution and salt water washing, dry on sal epsom, evaporation.Residual brown oil crystallizes out from Virahol.Collect light yellow crystal, with cold washed with isopropyl alcohol, drying obtains 4.1g 4 under high vacuum, 6-two chloro-5-(right-tolyl)-pyrimidine.

C) 0.8g4,6-two chloro-5-(right-tolyl)-pyrimidine and 1.68g 4-tributyl phenyl sulfonyl sylvite (routine 2a) form in 20ml DMSO and reach mixture and at room temperature stirred 24 hours.It is waterborne that mixture is poured on 200ml, with 100ml ethyl diacetate extracting twice.In conjunction with organic layer 50ml water extracting twice.In conjunction with water layer spirit of salt acidifying.Obtain thin suspension for twice with ethyl acetate extraction., evaporation dry on sodium sulfate in conjunction with organic layer.Residue drying under high vacuum obtains 1.34g white powder 4-tributyl-N-[6-chloro-5-(right-tolyl)-4-pyrimidine]-phenyl sulfanilamide (SN).LC-MS：t _R＝5.92min，[M+1] ⁺＝416.20，[M-1] ^-＝414.24。

D) 700mg brown glass shape material 4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-tolyl)-4-pyrimidine]-phenyl sulfanilamide (SN) is by 1.45g 4-tributyl-N-[6-chloro-5-(right-tolyl)-4-pyrimidine]-phenyl sulfanilamide (SN) makes according to the step that routine 10d describes.LC-MS：t _R＝5.38min，[M+1] ⁺＝466.24，[M-1] ^-＝464.32。Example 13

A) 2.71g 4, and the mixture of 6-dichloro--5-(right-the methoxyl group phenoxy group)-pyrimidine (routine 10b) and 5.0g5-sec.-propyl pyrimidine 2-sulfanilamide (SN) sylvite (routine 1e) is put into 50ml DMF and at room temperature stirred 20 hours.Remove in a vacuum and desolvate, will obtain residue and put into 200ml 10% acetic acid aqueous solution, use ethyl acetate extraction three times.In conjunction with organic layer water and salt water washing, dry on sal epsom, evaporation.Raw product crystallization from 2-propyl alcohol and ethyl diacetate is separated out.Collect xln, wash with cold 2-propyl alcohol and ethyl diacetate, drying obtains 2.8g white crystal 5-sec.-propyl-N-[6-chloro-5-(right-the methoxyl group phenoxy group)-4-pyrimidine]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.99min，[M+1] ⁺＝435.25，[M-1] ^-＝433.28。

B) 11.02g 2-butyl-1, the 4-diketone puts into 100mlDMF and 30mlDMPU disposes solution, toward 2.8g sodium hydride in batches wherein.After adding was finished, continuously stirring 1.5 hours was afterwards toward wherein adding 2.78g 5-sec.-propyl-N-[6-chloro-5-(right-the methoxyl group phenoxy group)-4-pyrimidine]-2-pyrimidine sulfanilamide (SN).Mixture heating up to 95 ℃ stirred 65 hours.Under vacuum, remove and desolvate, take out residue and be placed in the aqueous citric acid solution of 250ml10%, use twice of 250ml ethyl acetate extraction.In conjunction with organic layer water and salt water washing, dry on sal epsom, evaporation.Thick product with the column chromatography on silica gel with containing hexane: ethyl acetate elution from 1: 1 to 1: 4.Obtain 1.27g brown solid 5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-4-pyrimidine]-2-pyrimidine sulfanilamide (SN).In order to analyze, crystallization goes out a part of beige crystals from the 2-propyl alcohol.LC-MS：t _R＝4.50min，[M+1] ⁺＝485.27，[M-1] ^-＝483.41。Example 14

A) 15.2g 4-three-butyl phenyl alkylsulfonyl chlorine is dissolved among the 150ml THF, with the cooling of ice groove.25% ammonia soln of 15.2ml is splashed into.After adding finishes, at room temperature dry 15 minutes.Under vacuum, remove and desolvate.Resistates is dissolved in the ethyl acetate again, washes with water twice.Organic phase is dry on sodium sulfate, evaporation.The 14.8g white powder that obtains is dissolved in the 75ml methyl alcohol, adds 7.5g tributyl potassium.At room temperature, stir a little and evaporate.The resistates that obtains is carefully dry, obtain 16.3g4-tributyl phenyl sulfonyl sylvite.

B) 2.0g4,6-two chloro-5-(2-methoxyl group phenoxy group)-2-(N-morpholine)-pyrimidine (routine 9b) and 2.96g 4-tributyl benzene sulfanilamide (SN) sylvite are put into 30mlDMF and were at room temperature stirred 24 hours.1g4-tributyl benzene sulfanilamide (SN) sylvite add finish after, at room temperature continuously stirring 24 hours again stirred 16 hours down at 55 ℃ afterwards.At last, mixture is poured in 350ml water and the 350ml acetate.By adding the acetate acidifying mixture.Forming white viscous precipitate thing generates.Stirred throw out 1 hour at 0 ℃.Filter throw out, water and acetate washing are dissolved in the ethyl acetate again.Remove under vacuum and desolvate, remaining solids is suspended in the 100ml ethyl diacetate.Filter out solids, add the ethyl diacetate washing again, drying obtains 2.57g white powder 4-tributyl-N-[6-chloro-5-(2-methoxyl group phenoxy group)-2-morpholine-4-pyrimidine-4-yl]-benzene sulfanilamide (SN).LC-MS：t _R＝5.98min，[M+1] ⁺＝533.29，[M-1] ^-＝531.41。

C) the 675mg sodium hydride is put into 45mlDMF and 5ml DMPU is configured to suspension, and with 4.85g2-butyl-1, the 4-diketone adds wherein.At room temperature, continuously stirring is evaporated totally until gas.Then toward wherein adding 1.5g4-tributyl-N-[6-chloro-5-(2-methoxyl group phenoxy group)-2-morpholine-4-pyrimidine-4-yl]-benzene sulfanilamide (SN), with under the mixture heating up to 95 that obtains ℃, and stirred 5 days.At last, mixture is poured in the acetate of 150ml10%, uses 150ml ethyl acetate extraction three times.Organic layer water and salt water washing, dry on sal epsom, evaporation.The residue that obtains is used hexane with the column chromatography on silica gel: ethyl acetate=elution in 1: 1 obtains the cream-coloured foam-like material of 265mg.Obtain light brown foam-like material 4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-morpholine-4-pyrimidine-4-yl of the brown oil 456mg of another part purity about 90%]-benzene sulfanilamide (SN) and 1.13g initiator 4-tributyl-N-[6-chloro-5-(2-o-methoxyl group phenoxy group)-2-morpholine-4-pyrimidine-4-yl]-benzene sulfanilamide (SN).LC-MS：t _R＝5.39min，[M+1] ⁺＝583.41，[M-1] ^-＝581.35。Example 15

A) 4g4,6-two chloro-5-(2-methoxyl group phenoxy group)-2-(N-morpholine)-pyrimidine (routine 9b) is put into 20ml DMSO and is made suspension, toward wherein adding 4.72g5-methyl-2-pyrimidine sulfanilamide (SN) sylvite (routine 3c).Mixture stirred 17 hours at 55 ℃.Dark solution is poured in the 500ml water, filtered by celite rapidly.Filtrate extracts with 500ml and 250ml ethyl diacetate.Organic layer extracts with 100ml water.Collect water layer,, and be cooled to 0 ℃ with the acidifying of 3.5ml acetate.Collect the throw out that forms, dry under high vacuum with cold water washing, obtain 4.42g brown ceramic powder 5-methyl-N-[6-chloro-5-(2-methoxyl group phenoxy group)-2-(N-morpholine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.80min，[M+1] ⁺＝492.31，[M-1] ^-＝490.37。

B) the 712mg sodium hydride is put into 30mlDMF and 7ml DMPU is configured to suspension, and with 5.11g2-butyl-1, the 4-diketone adds wherein.At room temperature, continuously stirring is evaporated totally until gas.Then toward wherein adding 1.45g5-methyl-N-[6-chloro-5-(2-methoxyl group phenoxy group)-2-(N-morpholine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN), with under the mixture heating up to 95 that obtains ℃, and stirred 4 days.At last, mixture is poured in the acetate of 200ml10%, uses 200ml ethyl acetate extraction three times.Organic layer water and salt water washing, dry on sal epsom, evaporation.The residue that obtains is used hexane with the column chromatography on silica gel: ethyl acetate=elution in 1: 1 obtains 470mg cream-coloured powder 5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-(N-morpholine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN).With 660mg initiator 5-methyl-N-[6-chloro-5-(2-methoxyl group phenoxy group)-2-(N-morpholine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.33min，[M+1] ⁺＝542.35，[M-1] ^-＝540.32。Example 16

A) 10g4, the mixture of 6-two chloro-5-(right-tolyl)-pyrimidine (routine 12b) and 4.8g5-sec.-propyl pyrimidine 2-sulfanilamide (SN) sylvite (routine 1e) is put into 100mlDMF and was at room temperature stirred 72 hours.Remove partial solvent under vacuum, mixture is handled with the 50ml ethyl diacetate afterwards.Add 10% acetic acid aqueous solution under the vigorous stirring and regulate PH to 3.10 ℃ of following continuously stirring 15 minutes.Collect the throw out that forms, water and ethyl diacetate washing obtain 7.67g white powder 5-sec.-propyl-N-[6-chloro-5-(right-tolyl) 4-pyrimidine in 50 ℃ of dryings under high vacuum]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.13min，[M+1] ⁺＝403.24，[M-1] ^-＝401.28。

B) 21.5g2-butyl-1, the 4-diketone puts into 200mlDMF and 50mlDMPU disposes solution, is 55% solution toward wherein add concentration that the 5.5g sodium hydride forms in mineral oil in batches.After retort gas is overflowed, toward wherein adding 5.04g5-sec.-propyl-N-[6-chloro-5-(right-tolyl)-4-pyrimidine]-2-pyrimidine sulfanilamide (SN), stirred the mixture 80 hours at 90 ℃.Remove under vacuum and desolvate, residue is placed on respectively in the aqueous citric acid solution and 300ml ethyl acetate of 300ml10%.Water layer is with ethyl acetate extraction at least twice.In conjunction with organic layer water and salt water washing, dry on sal epsom, evaporation.Thick product with the column chromatography on silica gel with containing hexane: ethyl acetate is the elution purifying from 1: 1 to 1: 4.Obtain 2.0g brown solid 5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-tolyl)-4-pyrimidine]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.64min，[M+1] ⁺＝453.28，[M-1] ^-＝451.40。Example 17

To the sodium hydride of 14mg55% be dispersed in the mineral oil in 2ml do DMF and 2ml do in the suspension that THF forms add 80mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 1g).Stir after 10 minutes, add 41mg2-chloro-pyrimidine.70 ℃ of following continuously stirring 1 hour.Reaction mixture is poured on the aqueous citric acid solution of 50ml10%.With twice of 50ml ethyl acetate extraction.Wash dry evaporation on sal epsom with water in conjunction with organic layer.Remaining residue is used the DCM elution purifying that contains 0-2% methyl alcohol with the column chromatography on silica gel.Obtain 72mg colourless foam shape material 5-sec.-propyl-N-[6-(4-(2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.74min，[M+1] ⁺＝640.35，[M-1] ^-＝638.49。Example 18

80mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidine]-2-pyrimidine sulfanilamide (SN) (routine 1g) and 78mg4,6-dimethoxy-2-methyl-sulphonyl pyrimidine makes 88mg faint yellow solid 5-sec.-propyl-N-[6-(4-(4,6-dimethoxy-2-2-pyrimidinyl oxy)-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidine according to the step of example 17]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.34min，[M+1] ⁺＝700.42，[M-1] ^-＝698.52。Example 19

Sodium hydride to 76mg55% is dispersed in adding 403mg4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl in the suspension that forms in the mineral oil in the dried THF of 15ml]-phenyl sulfanilamide (SN) (routine 2c).Stir after 2 hours, add 91mg2-chloro-pyrimidine.At room temperature continuously stirring is 42 hours.Distillation removes and desolvates, and residue is put into acetic acid aqueous solution and the 50ml ethyl acetate of 50ml10% respectively.Separate organic layer, water layer 50ml ethyl acetate extraction at least twice.Wash dry evaporation on sal epsom with water in conjunction with organic layer.Remaining residue is used the DCM elution purifying that contains 5-10% methyl alcohol with the column chromatography on silica gel.Obtain 256mg colourless foam shape material 4-tributyl-N-[6-(4-(2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-phenyl sulfanilamide (SN).LC-MS：t _R＝5.21min，[M+1] ⁺＝653.69，[M-1] ^-＝651.78。Example 20

By 196mg4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-phenyl sulfanilamide (SN) (routine 2c) and 73mg5-bromo-2-chloropyrimide make 200mg beige crystals 4-tributyl-N-[6-(4-(5-bromo-2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl according to the step of example 19]-phenyl sulfanilamide (SN).LC-MS：t _R＝5.63min，[M+1] ⁺＝731.65，[M-1] ^-＝729.66。Example 21

400mg4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-phenyl sulfanilamide (SN) (routine 2c), 116mg4,6-dimethoxy-2-methyl-sulphonyl pyrimidine and 147mg salt of wormwood add among the 15ml DMF makes suspension, and this suspension was stirred 16 hours down at 90 ℃.Add 42mg4 again, 6-dimethoxy-2-methyl-sulphonyl pyrimidine continues down to stir 24 hours at 90 ℃.At last, remove under vacuum and desolvate, remaining residue is put into acetic acid aqueous solution and the 50ml DCM of 50ml5% respectively.Separate organic layer, with 50ml DCM aqueous layer extracted at least twice.Wash in conjunction with organic layer dry evaporation on sal epsom with water.Residual oily matter is with using toluene with the column chromatography on silica gel: ethyl acetate is purifying from 4: 1 to 1: 1.From ethyl acetate: recrystallize obtains white crystal product 76mg4-tributyl-N-[6-(4-(4,6-dimethoxy-2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl the ethyl diacetate]-phenyl sulfanilamide (SN).LC-MS：t _R＝5.84min，[M+1] ⁺＝713.35，[M-1] ^-＝711.45。Example 22

Sodium hydride to 41mg55% is dispersed in adding 200mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl in the suspension that forms in the mineral oil in dried DMF of 5ml and the dried THF of 5ml]-2-pyrimidine sulfanilamide (SN) (routine 3e).Stir after 10 minutes, add 47mg2-chloro-pyrimidine.At room temperature continuously stirring is 20 hours.And then adding 20mg2-chloro-pyrimidine, continuously stirring 24 hours.At last, reaction mixture is poured in the aqueous citric acid solution of 50ml10%.With 50ml ethyl acetate extraction at least twice.Wash twice dry evaporation on sal epsom with water in conjunction with organic layer.Remaining residue is used the DCM elution purifying that contains 0-3% methyl alcohol with the column chromatography on silica gel.Obtain 147mg pale yellow powder 5-methyl-N-[6-(4-(2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.26min，[M+1] ⁺＝612.29，[M-1] ^-＝610.43。Example 23

By 100mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 3e) and 44mg5-bromo-2-chloropyrimide make 65mg faint yellow solid 5-methyl-N-[6-(4-(5-bromo-2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl according to the step of example 22]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.77min，[M+1] ⁺＝690.22，[M-1] ^-＝688.36。Example 24

By 100mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 3e) and 82mg4,6-dimethoxy-2-sulfonyloxy methyl pyrimidine makes 91mg faint yellow solid 5-methyl-N-[6-(4-(4,6-dimethoxy-2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl according to the step of example 22]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.80min，[M+1] ⁺＝672.32，[M-1] ^-＝670.46。Example 25

By 80mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 3e) and 70mg4,6-dimethyl-2-sulfonyloxy methyl pyrimidine makes 72mg faint yellow solid 5-methyl-N-[6-(4-(4,6-dimethyl-2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl according to the step of example 22]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.68min，[M+1] ⁺＝640.32，[M-1] ^-＝638.39。Example 26

By 80mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-pyrimidine sulfanilamide (SN) (routine 4d) and 33mg2-chloropyrimide make the cream-coloured foam-like material 5-of 59mg sec.-propyl-N-[6-(4-(2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl according to the step of example 22]-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4-55min，[M+1] ⁺＝641.63，[M-1] ^-＝639.47。Example 27

By 80mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 4d) and 55mg5-bromine 2-chloropyrimide make the cream-coloured foam-like material 5-of 65mg sec.-propyl N-[6-(4-(5-bromine 2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl according to the step of example 22]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.99min，[M+1] ⁺＝719.56，[M-1] ^-＝717.28。Example 28

By 75mg4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl]-phenyl sulfanilamide (SN) (routine 5b) and 103mg5-bromine 2-chloropyrimide make the cream-coloured foam-like material 4-of 65mg tributyl-N-[6-(4-(5-bromine 2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl according to the step of example 22]-phenyl sulfanilamide (SN).LC-MS：t _R＝5.83min，[M+1] ⁺＝732.31，[M-1] ^-＝730.36。Example 29

By 75mg4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl]-phenyl sulfanilamide (SN) (routine 5b) and 140mg4,6-dimethoxy-2-sulfonyloxy methyl pyrimidine makes 71mg colourless foam shape material 4-tributyl-N-[6-(4-(4,6-dimethoxy 2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl according to the step of example 22]-phenyl sulfanilamide (SN).LC-MS：t _R＝5.92min，[M+1] ⁺＝714.42，[M-1] ^-＝712.50。Example 30

By 60mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 6b) and 36mg2-chloropyrimide make 20mg colourless foam shape material 5-methyl-N-[6-(4-(2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl according to the step of example 22]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.37min，[M+1] ⁺＝613.29，[M-1] ^-＝611.45。Example 31

By 80mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 6b) and 120mg5-bromo-2 chloropyrimide make 75mg colourless powder 5-methyl-N-[6-(4-(5-bromo-2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl according to the step of example 22]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.64min，[M+1] ⁺＝691.64，[M-1] ^-＝689.45。Example 32

By 80mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 6b) and 120mg5-bromo-2 chloropyrimide make 75mg colourless powder 5-methyl-N-[6-(4-(5-bromo-2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-the methoxyl group phenoxy group)-2-(2-pyrimidyl)-4-pyrimidyl according to the step of example 22]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.72min，[M+1] ⁺＝673.70，[M-1] ^-＝671.53。Example 33

By 80mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 7d) and 46mg2 chloropyrimide make 73mg colourless foam shape material 5-sec.-propyl-N-[6-(4-(2-2-pyrimidinyl oxy)-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl according to the step of example 17]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.18min，[M+1] ⁺＝577.27，[M-1] ^-＝575.36。Example 34

By 80mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 7d) and 88mg4,6-dimethoxy-2 sulfonyloxy methyl pyrimidine makes 75mg colourless foam shape material 5-sec.-propyl-N-[6-(4-(4,6-dimethoxy-2-2-pyrimidinyl oxy)-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl according to the step of example 17]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.80min，[M+1] ⁺＝637.31，[M-1] ^-＝635.40。Example 35

By 80mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 7d) and 75mg4,6-dimethyl-2 sulfonyloxy methyl pyrimidine makes 76mg colourless foam shape material 5-sec.-propyl-N-[6-(4-(4,6-dimethyl-2-2-pyrimidinyl oxy)-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl according to the step of example 17]-2-pyrimidine sulfanilamide (SN).LC-MS：T _R＝5.51min，[M+1] ⁺＝605.35，[M-1] ^-＝603.43。Example 36

By 80mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 8b) and 96mg 5-bromo-2-chloropyrimide make 98mg colourless foam shape material 5-methyl-N-[6-(4-(5-bromo-2-2-pyrimidinyl oxy)-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl according to the step of example 22]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.33mim，[M+1] ⁺＝627.20，[M-1] ^-＝625.27。Example 37

By 80mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 8b) and 74mg4,6-dimethoxy-2-sulfonyloxy methyl pyrimidine makes 80mg colourless foam shape material 5-methyl-N-[6-(4-(4,6-dimethoxy-2-2-pyrimidinyl oxy)-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl according to the step of example 22]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.46min，[M+1] ⁺＝609.31，[M-1] ^-＝607.38。Example 38

By 80mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 8b) and 79mg4,6-dimethyl-2-sulfonyloxy methyl pyrimidine makes 80mg colourless foam shape material 5-methyl-N-[6-(4-(4,6-dimethyl-2-2-pyrimidinyl oxy)-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl according to the step of example 22]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.10min，[M+1] ⁺＝577.30，[M-1] ^-＝571.41。Example 39

Sodium hydride to 58mg55% is dispersed in adding 280mg4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-tolyl)-4-pyrimidyl in the suspension that forms in the mineral oil in the dried THF of 15ml]-phenyl sulfanilamide (SN) (example 12).Stir after 1 hour, add 144mg4,6-dimethoxy-2-sulfonyloxy methyl pyrimidine.Continuously stirring is 12 hours under adverse current.At last, evaporating solvent, remaining residue are put into aqueous citric acid solution and the 50ml ethyl acetate of 50ml10% respectively.Separate organic layer, water layer 50ml ethyl acetate extracting twice at least.In conjunction with organic layer water and salt water washing, dry evaporation on sal epsom.Remaining residue with the column chromatography on the silica gel with containing 10-20% ethyl acetate elution purifying in toluene.The yellow foam-like material of separating is further purified on ready silica gel dish, obtain 91mg colourless foam shape material 4-tributyl-N-[6-(4-(4,6-dimethoxy-2-2-pyrimidinyl oxy)-2-butoxy)-5-(p-dimethylbenzene)-4-pyrimidyl]-phenyl sulfanilamide (SN).LC-MS：t _R＝6.32min，[M+1] ⁺＝604.31，[M-1] ^-＝602.43。Example 40

Sodium hydride to 88mg55% is dispersed in adding 375mg4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-tolyl)-4-pyrimidyl in the suspension that forms in the mineral oil in the dried THF of 15ml]-phenyl sulfanilamide (SN) (example 12).Stir after 1 hour, add 170mg5-bromo-2-chloropyrimide.40 ℃ of following continuously stirring 60 hours.At last, evaporating solvent, remaining residue are put into aqueous citric acid solution and the 50ml ethyl acetate of 50ml10% respectively.Separate organic layer, water layer 50ml ethyl acetate extracting twice at least.In conjunction with organic layer water and salt water washing, dry evaporation on sal epsom.Raw product crystallizes out from the 2-propyl alcohol that contains a small amount of ethyl diacetate, obtains 168mg beige crystals 4-tributyl-N-[6-(4-(5-bromo-2-2-pyrimidinyl oxy)-butoxy)-5-(right-tolyl)-4-pyrimidyl]-phenyl sulfanilamide (SN).LC-MS：t _R＝6.22min，[M+1] ⁺＝624.28。Example 41

Sodium hydride to 29mg55% is dispersed in adding 150mg4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-4-pyrimidyl in the suspension that forms in the mineral oil in the dried THF of 15ml]-phenyl sulfanilamide (SN) (example 10).Stir after 0.5 hour, add 64mg5-bromo-2-chloropyrimide.40 ℃ of following continuously stirring 40 hours.At last, evaporating solvent, remaining residue are put into aqueous citric acid solution and the 50ml ethyl acetate of 50ml10% respectively.Separate organic layer, water layer 50ml ethyl acetate extracting twice at least.In conjunction with organic layer water and salt water washing, dry evaporation on sal epsom.Raw product crystallizes out from the 2-propyl alcohol, obtains 126mg beige crystals 4-tributyl-N-[6-(4-(5-bromo-2-2-pyrimidinyl oxy)-butoxy)-5-(neighbour-methoxyl group phenoxy group)-4-pyrimidyl]-phenyl sulfanilamide (SN).LC-MS：t _R＝6.07min，[M+1] ⁺＝656.24，[M-1] ⁺＝654.34。Example 42

By 150mg4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-4-pyrimidyl]-phenyl sulfanilamide (SN) (example 10) and 72mg4,6-dimethyl-2-sulfonyloxy methyl pyrimidine makes 126mg colourless foam shape material 4-tributyl-N-[6-(4-(4,6-dimethoxy-2-2-pyrimidinyl oxy)-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-4-pyrimidyl according to the step of example 41]-phenyl sulfanilamide (SN).LC-MS：t _R＝6.13min，[M+1] ⁺＝635.81，[M-1] ^-＝633.77。Example 43

Do adding 450mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-tolyl)-2-(4-pyridyl)-4-pyrimidyl in the suspension that forms among the THF to 243mg salt of wormwood at 15ml]-2-pyrimidine sulfanilamide (SN) (example 11).After stirring 0.5 hour under 90 ℃, add 192mg4,6-dimethoxy-2-sulfonyloxy methyl pyrimidine.90 ℃ of following continuously stirring 16 hours.At last, evaporating solvent, remaining residue are put into aqueous citric acid solution and the 50mlDCM of 50ml10% respectively.Separate organic layer, water layer is with 50mlDCM extracting twice at least.In conjunction with organic layer water and salt water washing, dry evaporation on sal epsom.Raw product is used DCM with the column chromatography on silica gel: methyl alcohol=20: 1 elution purifying, obtain the cream-coloured foam-like material 5-of 98mg sec.-propyl-N-[6-(4-(4,6-dimethoxy-2-2-pyrimidinyl oxy)-butoxy)-5-(right-tolyl)-2-(4-pyridyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.54min，[M+1] ⁺＝668.38，[M-1] ^-＝666.39。Example 44

By 250mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 13) and 194mg5-bromo-2-chloropyrimide make 186mg beige crystals 5-sec.-propyl-N-[6-(4-(5-bromo-2-2-pyrimidinyl oxy)-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-4-pyrimidyl according to the step of example 41]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.43min，[M+1] ⁺＝643.18，[M-1] ^-＝641.29。Example 45

To 250mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-4-pyrimidyl]-add the 450mg sodium hydride in the solution that 2-pyrimidine sulfanilamide (SN) (example 13) forms in 15ml does THF.After mixture at room temperature stirs 2 hours, add 120mg4,6-dimethoxy-2-sulfonyloxy methyl pyrimidine.Another mistake stream continuously stirring 16 hours.At last, evaporating solvent, remaining residue are put into aqueous citric acid solution and the 50ml ethyl acetate of 50ml10% respectively.Separate organic layer, water layer 50ml ethyl acetate extracting twice at least.In conjunction with organic layer water and salt water washing, dry evaporation on sal epsom.Raw product is used acetate with the column chromatography on silica gel: methyl alcohol: the amine salt aqueous solution=8: 2: 1 elution purifying, obtain the cream-coloured foam-like material 5-of 71mg sec.-propyl-N-[6-(4-(4,6-dimethoxy-2-2-pyrimidinyl oxy)-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.50min，[M+1] ⁺＝623.29，[M-1] ^-＝621.40。Example 46

Sodium hydride to 9mg55% is dispersed in adding 50mg4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-morpholinyl-4-base-pyrimidine-4-yl in the suspension that forms in the mineral oil in dried DMF: the THF (1: 1) of 4ml]-phenyl sulfanilamide (SN) (example 14).After the whole effusions of gas, add 42mg5-bromo-2-chloropyrimide.Under 65 ℃, stirred the mixture 1 hour, and diluted with aqueous citric acid solution and the 50ml ethyl acetate of 50ml10% afterwards.Separate organic layer, use the 50ml water washing, dry evaporation on sal epsom.Raw product is used hexane with the column chromatography on silica gel: ethyl acetate=3: 2 elution purifying obtains 60mg colourless foam shape material 4-tributyl-N-[6-(4-(5-bromo-2-2-pyrimidinyl oxy)-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-morpholinyl-4-base-pyrimidine-4-yl]-phenyl sulfanilamide (SN).LC-MS：t _R＝6.14min，[M+1] ⁺＝739.18，[M-1] ⁺＝741.32。Example 47

By 50mg4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-morpholinyl-4-base-pyrimidine-4-yl]-phenyl sulfanilamide (SN) (example 14) and 47mg4,6-dimethoxy-2-sulfonyloxy methyl pyrimidine makes 48mg colourless foam shape material 4-tributyl-N-[6-(4-(4,6-dimethoxy-2-2-pyrimidinyl oxy)-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-morpholinyl-4-base-pyrimidine-4-yl according to the step of example 46]-phenyl sulfanilamide (SN).LC-MS：t _R＝6.21min，[M+1] ⁺＝721.44，[M-1] ⁺＝719.35。Example 48

By 50mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-(N-morpholinyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 15) and 45mg5-bromo-2-chloropyrimide make 37mg cream-coloured powder 5-methyl-N-[6-(4-(5-bromo-2-2-pyrimidinyl oxy)-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-(N-morpholinyl)-4-pyrimidyl according to the step of example 46]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.31min，[M+1] ⁺＝700.34，[M-1] ⁺＝698.24。Example 49

By 50mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-(N-morpholinyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 15) and 50mg4,6-dimethoxy-2-sulfonyloxy methyl pyrimidine makes 48mg colorless solid 5-methyl-N-[6-(4-(4,6-dimethoxy-2-2-pyrimidinyl oxy)-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-(N-morpholinyl)-4-pyrimidyl according to the step of example 46]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.42min，[M+1] ⁺＝680.43，[M-1] ⁺＝678.36。Example 50

By 230mg5-sec.-propyl N-[6-(4-hydroxyl-2-butoxy)-5-(right-tolyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 16) and 194mg5-bromo-2-chloropyrimide make the cream-coloured foam-like material 5-of 128mg sec.-propyl-N-[6-(4-(5-bromo-2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-tolyl)-4-pyrimidyl according to the step of example 45]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.49min，[M+1] ⁺＝611.25，[M-1] ⁺＝609.39。Example 51

By 230mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-tolyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 16) and 120mg4,6-dimethoxy-2-sulfonyloxy methyl pyrimidine makes the cream-coloured foam-like material 5-of 68mg sec.-propyl-N-[6-(4-(4,6-dimethoxy-2-2-pyrimidinyl oxy)-2-butoxy)-5-(right-tolyl)-4-pyrimidyl according to the step of example 45]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.60min，[M+1] ⁺＝591.21，[M-1] ⁺＝589.24。Example 52

At room temperature, to 50mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-4-pyrimidyl]-add 25 μ ln-butyl isocyanate in the solution that 2-pyrimidine sulfanilamide (SN) (routine 1g) and 10mg4-dimethylamino yl pyrimidines form in the dried chloroform of 5ml.After mixture heating up to 65 ℃ stirred 42 hours.In the time of 6 hours, 18 hours, 28 hours, add another part 25 μ ln-butyl isocyanate respectively.At last, mixture dilutes with the 50ml ethyl acetate.Twice of 20ml water washing of solution.Water layer with ethyl acetate extraction once.In conjunction with organic layer dry evaporation on sal epsom.Residue is at first used hexane with the column chromatography on silica gel: ethyl acetate=elution in 1: 1, with the DCM washing that contains 4% methyl alcohol, obtain 39mg weak yellow foam shape material n-butyl-carboxylamine 4-[6-(5-sec.-propyl-pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-pyrimidine-4-base-pyrimidyl-4 oxygen base again]-butyl-2-alkynes ester.LC-MS：t _R＝5.17min，[M+1] ⁺＝661.37，[M-1] ^-＝659.51。Example 53

At room temperature, to 50mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-4-pyrimidyl]-add 25 μ l phenyl isocyanate in the solution that 2-pyrimidine sulfanilamide (SN) (routine 1g) and 10mg4-dimethylamino yl pyrimidines form in the dried chloroform of 5ml.After mixture heating up to 65 ℃ stirred 4 hours.At last, mixture dilutes with the 50ml ethyl acetate.Twice of 20ml water washing of solution.Water layer with ethyl acetate extraction once.In conjunction with organic layer dry evaporation on sal epsom.Residue is at first used hexane with the column chromatography on silica gel: ethyl acetate=elution in 1: 1, with the DCM washing that contains 4% methyl alcohol, obtain 40mg white solid (fusing point is 153-164 ℃) phenyl-carboxylamine 4-[6-(5-sec.-propyl-pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-pyrimidine-4-base-pyrimidyl-4 oxygen base again]-butyl-2-alkynes ester.LC-MS：t _R＝5.15min，[M+1] ⁺＝681.36，[M-1] ^-＝679.51。Example 54

By 50mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 1g) and 25ul4-p-methoxy-phenyl isocyanate make 45mg weak yellow foam shape material (4-p-methoxy-phenyl)-carboxylamine 4-[6-(5-sec.-propyl-pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-pyrimidine-4-base-pyrimidyl-4-oxygen base according to the step of example 53]-butyl-2-alkynes ester.LC-MS：t _R＝5.33min，[M+1] ⁺＝695.98，[M-1] ^-＝693.53。Example 56

By 50mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 1g) and 25ul2-p-methoxy-phenyl isocyanate make 27mg weak yellow foam shape material (2-p-methoxy-phenyl)-carboxylamine 4-[6-(5-sec.-propyl-pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-pyrimidine-4-base-pyrimidyl-4 oxygen base according to the step of example 53]-butyl-2-alkynes ester.LC-MS：t _R＝5.30min，[M+1] ⁺＝711.36，[M-1] ^-＝709.49。Example 57

By 50mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 1g) and 12mg 2-fluorophenyl isocyanate make 36mg white solid (2-fluorophenyl)-carboxylamine 4-[6-(5-sec.-propyl-pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-pyrimidine-4-base-pyrimidyl-4 oxygen base according to the step of example 53]-butyl-2-alkynes ester.LC-MS：t _R＝5.16min，[M+1] ⁺＝699.36，[M-1] ^-＝697.28。Example 58

50mg2-pyridine carboxylic acid trinitride (being prepared according to Chem.Pharm.Bull.25 (1997) 1651-1657 by the 2-pyridine carboxylic acid) and 10mg DMAP add the 8ml chloroform and make solution, stir this solution down after 1 hour at 75 ℃.Add 50mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridyl)-4-pyrimidyl earlier]-2-pyrimidine sulfanilamide (SN) (routine 1g), add 3ml DMF afterwards again.The limpid solution that obtains was stirred 16 hours at 75 ℃.Mixture dilutes with the 50ml ethyl acetate, uses the solution washing of 50ml10% citric acid again, uses the 50ml water washing afterwards again.The organic layer evaporation.Raw product is at first used methylene dichloride with the column chromatography on chromatographic sheet: methyl alcohol is 10: 1 purifying, to 41mg white solid 2-pyrimidyl-carboxylamine 4-[6-(5-sec.-propyl-pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-pyrimidine-4-base-pyrimidyl-4 oxygen base]-butyl-2-alkynes ester.LC-MS：t _R＝4.74min，[M+1] ⁺＝682.47，[M-1] ^-＝680.41。Example 59

By 300mg5-sec.-propyl-N-[6-, (4-hydroxyl-2-butoxy)-5-, (neighbour-methoxyl group phenoxy group)-2-, (4-pyridyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN), (routine 1g) and 199mg pyrazine-2-carbonyl nitride, (by pyrazine-2-carboxylamine according to Chem.Pharm.Bull.25, (1997) 1651-1657 preparation) step according to example 58 makes 271mg white powder 2-pyrazine-carboxylamine 4-[6-, (5-sec.-propyl-pyrimidine-2-sulfonamido)-5-, (2-methoxyl group phenoxy group)-2-pyrimidine-4-base-pyrimidyl-4 oxygen base]-butyl-2-alkynes ester.LC-MS：t _R＝4.73min，[M+1] ⁺＝683.44，[M-1] ^-＝681.37。Example 60

Under argon gas atmosphere, 50mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 3), be made into suspension among 10mg DMAP and 25ul hexamethylene isocyanate adding 4ml chloroform and the 3ml DMF, stirred 72 hours down at 70 ℃.Mixture dilutes with the 50ml ethyl acetate, uses the solution washing of 50ml10% citric acid again, uses twice of 50ml water washing afterwards again.Organic layer is dry on sal epsom, evaporation.Raw product is used hexane with the column chromatography on silica gel: ethyl acetate be 1: 1 to pure ethyl acetate purifying, again with the DCM purifying that contains 4% methyl alcohol, to the cream-coloured foam-like material hexamethylene of 38mg carbonic acid 4-[6-(5-methyl-pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-pyrimidine-4-base-pyrimidyl-4 oxygen base]-butyl-2-alkynes ester.LC-MS：t _R＝4.89min，[M+1] ⁺＝659.33，[M-1] ^-＝627.25。Example 61

50mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 3), be made into suspension in 10mg DMAP and the 25ul phenyl isocyanate adding 5ml chloroform, adverse current stirred 15 minutes under argon gas atmosphere.Add 1.5ml DMF, continuously stirring is 16 hours under heating.Limpid solution dilutes with the 50ml ethyl acetate, uses the solution washing of 50ml10% citric acid again, uses twice of 50ml water washing afterwards again.Organic layer is dry on sal epsom, evaporation.Raw product is used hexane with the column chromatography on silica gel: ethyl acetate is 1: 1 purifying, again with the DCM purifying that contains 4% methyl alcohol, to 47mg light yellow solid phenyl-carbonic acid 4-[6-(5-methyl-pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-pyrimidine-4-base-pyrimidyl-4 oxygen base]-butyl-2-alkynes ester.LC-MS：t _R＝4.80min，[M+1] ⁺＝653.37，[M-1] ^-＝651.33。Example 62

By 50mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 3) and 25ul 3-aminomethyl phenyl isocyanate make 37mg yellow solid (3-aminomethyl phenyl)-carboxylamine 4-[6-(5-methyl-pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-pyrimidine-4-base-pyrimidyl-4 oxygen base according to the step of example 61]-butyl-2-alkynes ester.LC-MS：t _R＝4.95min，[M+1] ⁺＝667.42，[M-1] ^-＝665.30。Example 63

By 50mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 3) and 25ul2-fluorophenyl isocyanate make 38mg white foam shape material (2-fluorophenyl)-carboxylamine 4-[6-(5-methyl-pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-pyrimidine-4-base-pyrimidyl-4 oxygen base according to the step of example 61]-butyl-2-alkynes ester.LC-MS：t _R＝4.79min，[M+1] ⁺＝671.34，[M-1] ^-＝669.28。Example 64

By 50mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 3) and 25ul4-fluorophenyl isocyanate make 42mg white foam shape material (4-fluorophenyl)-carboxylamine 4-[6-(5-methyl-pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-pyrimidine-4-base-pyrimidyl-4 oxygen base according to the step of example 61]-butyl-2-alkynes ester.LC-MS：t _R＝4.89min，[M+1] ⁺＝671.34，[M-1] ^-＝669.28。Example 65

By 50mg5-methyl-N-[6-, (4-hydroxyl-2-butoxy)-5-, (neighbour-methoxyl group phenoxy group)-2-, (4-pyridine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN), (example 3) and 50mg2-pyridine carboxylic acid trinitride, (by the 2-pyridine carboxylic acid according to Chem.Pharm.Bull.25, (1997) 1651-1657 preparation) step according to example 58 makes 38mg white powder 2-pyrimidine-carboxylamine 4-[6-, (5-methyl-pyrimidine-2-sulfonamido)-5-, (2-methoxyl group phenoxy group)-2-pyrimidine-4-base-pyrimidyl-4 oxygen base]-butyl-2-alkynes ester.LC-MS：t _R＝4.32min，[M+1] ⁺＝654.39，[M-1] ^-＝652.33。Example 66

By 50mg5-sec.-propyl-N-[6-, (4-hydroxyl-2-butoxy)-5-, (neighbour-methoxyl group phenoxy group)-2-, (2-pyrimidyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN), (example 4) and 28mg2-pyridine carboxylic acid trinitride, (by the 2-pyridine carboxylic acid according to Chem.Pharm.Bull.25, (1997) 1651-1657 preparation) step according to example 58 makes 18mg white solid 2-pyrimidine-carboxylamine 4-[6-, (5-sec.-propyl-pyrimidine-2-sulfonamido)-5-, (2-methoxyl group phenoxy group)-2-, (2-pyrimidyl)-pyrimidine-4-oxygen base]-butyl-2-alkynes ester.LC-MS：t _R＝4.84min，[M+1] ⁺＝683.41。Example 67

By 50mg5-sec.-propyl-N-[6-, (4-hydroxyl-2-butoxy)-5-, (neighbour-methoxyl group phenoxy group)-2-, (2-pyrimidyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN), (example 4) and 50mg pyrazine-2-carbonyl nitride, (by pyrazine-2-carboxylamine according to Chem.Pharm.Bull.25, (1997) 1651-1657 preparation) step according to example 58 makes 28mg light yellow solid 2-pyrazine-carboxylamine 4-[6-, (5-sec.-propyl-pyrimidine-2-sulfonamido)-5-, (2-methoxyl group phenoxy group)-2-, (2-pyrimidyl)-pyrimidine-4-oxygen base]-butyl-2-alkynes ester.LC-MS：t _R＝4.67min，[M+1] ⁺＝684.42，[M-1] ^-＝682.39。Example 68

By 50mg4-tributyl-N-[6-, (4-hydroxyl-2-butoxy)-5-, (neighbour-methoxyl group phenoxy group)-2-, (2-pyrimidyl)-4-pyrimidyl]-phenyl sulfanilamide (SN), (example 5) and 50mg2-pyridine carboxylic acid trinitride, (by the 2-pyridine carboxylic acid according to Chem.Pharm.Bull.25, (1997) 1651-1657 preparation) step according to example 58 makes 24mg light yellow solid 2-pyrimidine-carboxylamine 4-[6-, (4-tributyl phenyl-sulfonamido)-5-, (2-methoxyl group phenoxy group)-2-, (2-pyrimidyl)-pyrimidine-4-oxygen base]-butyl-2-alkynes ester.LC-MS：t _R＝5.44min，[M+1] ⁺＝696.43，[M-1] ^-＝694.35。Example 69

By 50mg4-tributyl-N-[6-, (4-hydroxyl-2-butoxy)-5-, (neighbour-methoxyl group phenoxy group)-2-, (2-pyrimidyl)-4-pyrimidyl]-phenyl sulfanilamide (SN), (example 5) and 50mg pyrazine-2-carbonyl nitride, (by pyrazine-2-carboxylamine according to Chem.Pharm.Bull.25, (1997) 1651-1657 preparation) step according to example 58 makes 39mg light yellow solid 2-pyrazine-carboxylamine 4-[6-, (4-tributyl phenyl-sulfonamido)-5-, (2-methoxyl group phenoxy group)-2-, (2-pyrimidyl)-pyrimidine-4-oxygen base]-butyl-2-alkynes ester.LC-MS：t _R＝5.25min，[M+1] ⁺＝697.44，[M-1] ^-＝695.355。Example 70

50mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-methyl-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 7d) adds wiring solution-forming in the dried chloroform of 5ml, to wherein adding 25ul phenyl isocyanate, add 20mg DMAP solution afterwards and stirred 3 hours down earlier at 65 ℃.Under low pressure remove part solution, rest solution is used hexane with the column chromatography on silica gel: ethyl acetate is 2: 1 purifying, obtains 35mg colourless foam shape material phenyl-carbonic acid 4-[6-(5-sec.-propyl-pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-methyl-pyrimidyl-4 oxygen base]-butyl-2-alkynes ester.LC-MS：t _R＝5.62min，[M+1] ⁺＝618.33，[M-1] ^-＝616.45。Example 71

By 50mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(N-morpholinyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 9) and 30ul phenyl isocyanate make 43mg white foam shape material Ben Ji-carboxylamine 4-[6-(5-sec.-propyl pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-morpholine-4-base-pyrimidine-4-oxygen base according to the step of example 53]-butyl-2-alkynes ester.LC-MS：t _R＝5.57min，[M+1] ⁺＝689.38，[M-1] ^-＝687.49。Example 72

By 150mg5-sec.-propyl-N-[6-, (4-hydroxyl-2-butoxy)-5-, (neighbour-methoxyl group phenoxy group)-2-, (N-morpholinyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN), (example 9) and 100mg2-pyridine carboxylic acid trinitride, (by the 2-pyridine carboxylic acid according to Chem.Pharm.Bull.25, (1997) 1651-1657 preparation) step according to example 58 makes 142mg colourless foam shape material 2-pyrimidine-carboxylamine 4-[6-, (5-sec.-propyl pyrimidine-2-sulfonamido)-5-, (2-methoxyl group phenoxy group)-2-, (N-morpholine)-4-pyrimidine-oxygen base]-butyl-2-alkynes ester.LC-MS：t _R＝5.37min，[M+1] ⁺＝690.53，[M-1] ^-＝688.38。Example 73

570mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(N-morpholine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 9) adds wiring solution-forming among the 15mlDCM, to the catalyzer and the 70ul morpholine-4-carbonyl chloride that wherein add 0.73mlDBU and be complementary with it.Under adverse current, stirred the mixture 16 hours, then evaporating solvent.Residue is placed on respectively in the aqueous citric acid solution and 75ml ethyl acetate of 75ml10%.Water is with ethyl acetate extraction at least twice, and in conjunction with organic layer water and salt water washing, drying is evaporated on sal epsom.Raw product is used toluene on the thin-film chromatography dish: ethyl acetate is 1: 1 purifying, obtains the cream-coloured foam-like material morpholine of 152mg-4-carboxylamine 4-[6-(5-sec.-propyl-pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-(N-morpholine)-pyrimidyl-4 oxygen base]-butyl-2-alkynes ester.LC-MS：t _R＝5.26min，[M+1] ⁺＝683.43，[M-1] ^-＝681.57。Example 74

By 570mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-(N-morpholinyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 9) and 52ul dimethyl carbonyl chloride make 170mg white crystal dimethyl-carboxylamine 4-[6-(5-sec.-propyl pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-(N-morpholine)-4-pyrimidine-oxygen base according to the step (crystallizing out) of example 73 from 2-propyl alcohol/methyl alcohol]-butyl-2-alkynes ester.LC-MS：t _R＝5.29min，[M+1] ⁺＝641.41，[M-1] ^-＝639.56。Example 75

By 40mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 13) and 50ul phenyl isocyanate make 39mg colourless foam shape material phenyl-carboxylamine 4-[6-(5-sec.-propyl pyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-pyrimidine-4-oxygen base according to the step of example 53]-butyl-2-alkynes ester.LC-MS：t _R＝5.38min，[M+1] ⁺＝604.32，[M-1] ^-＝602.25。Example 76

By 50mg4-tributyl-N-[6-(4-hydroxyl-2-butoxy)-5-(neighbour-methoxyl group phenoxy group)-2-morpholine-4-base-pyrimidine-4-yl]-phenyl sulfanilamide (SN) (example 14) and 50ul phenyl isocyanate make 50mg colourless foam shape material phenyl-carboxylamine 4-[6-(4-tributyl-phenyl-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-morpholine-4-base-pyrimidine-4-oxygen base according to the step of example 53]-butyl-2-alkynes ester.LC-MS：t _R＝6.07min，[M+1] ⁺＝702.50，[M-1] ^-＝700.40。Example 77

By 50mg4-tributyl-N-[6-, (4-hydroxyl-2-butoxy)-5-, (neighbour-methoxyl group phenoxy group)-2-, (N-morpholine)-pyrimidine-4-yl]-phenyl sulfanilamide (SN), (example 14) and 50mg2-pyridine carboxylic acid trinitride, (by the 2-pyridine carboxylic acid according to Chem.Pharm.Bull.25, (1997) 1651-1657 preparation) step according to example 58 makes 39mg colourless foam shape material 2-pyrimidine-carboxylamine 4-[6-, (4-tributyl-phenyl-sulfonamido)-5-, (2-methoxyl group phenoxy group)-2-morpholine--pyrimidine-4-oxygen base]-butyl-2-alkynes ester.MS：t _R＝5.63min，[M+1] ⁺＝703.46，[M-1] ^-＝701.38。Example 78

By 50mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-(N-morpholine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 15) and 50ul n-butyl isocyanate make 44mg white solid n-butyl-carboxylamine 4-[6-(5-methylpyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-(N-morpholine)-pyrimidine-4-oxygen base according to the step of example 53]-butyl-2-alkynes ester.MS：t _R＝5.24min，[M+1] ⁺＝641.47，[M-1] ^-＝639.39。Example 79

By 50mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-(4-morpholine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 15) and 100ul hexamethylene isocyanate make 53mg colourless foam shape material cyclohexyl-carboxylamine 4-[6-(5-methylpyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-(4-morpholine)-pyrimidine-4-oxygen base according to the step of example 53]-butyl-2-alkynes ester.MS：t _R＝5.32min，[M+1] ⁺＝667.48，[M-1] ^-＝665.41。Example 80

By 50mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-(4-morpholine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 15) and 50ul phenyl isocyanate make 54mg colourless foam shape material phenyl-carboxylamine 4-[6-(5-methylpyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-(4-morpholine)-pyrimidine-4-oxygen base according to the step of example 53]-butyl-2-alkynes ester.MS：t _R＝5.32min，[M+1] ⁺＝661.43，[M-1] ^-＝659.38。Example 81

By 50mg5-methyl-N-[6-, (4-hydroxyl-2-butoxy)-5-, (2-methoxyl group phenoxy group)-2-, (4-morpholine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN), (example 15) and 50mg2-pyridine carboxylic acid trinitride, (by the 2-pyridine carboxylic acid according to Chem.Pharm.Bull.25, (1997) 1651-1657 preparation) step according to example 58 makes 36mg white powder 2-pyrimidine-carboxylamine 4-[6-, (5-methylpyrimidine-2-sulfonamido)-5-, (2-methoxyl group phenoxy group)-2-, (4-morpholine)-pyrimidine-4-oxygen base]-butyl-2-alkynes ester.MS：t _R＝4.90min，[M+1] ⁺＝662.17，[M-1] ^-＝660.12。Example 82

By 50mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-(4-morpholine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 15) and 50mg nicotinic acid nitride (by nicotinic acid according to Chem.Pham.Bull.25 (1997) 1651-1657 preparation) make 40mg white powder 3-pyrimidine-carboxylamine 4-[6-(5-methylpyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-(4-morpholine)-pyrimidine-4-oxygen base according to the step of example 58]-butyl-2-alkynes ester.MS：t _R＝4.19min，[M+1] ⁺＝662.39，[M-1] ^-＝660.59。Example 83

By 50mg5-methyl-N-[6-(4-hydroxyl-2-butoxy)-5-(2-methoxyl group phenoxy group)-2-(4-morpholine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 15) and 50mg Yi Yansuan nitride (by Yi Yansuan according to Chem.Pharm.Bull.25 (1997) 1651-1657 preparation) make 7mg white solid 4-pyrimidine-carboxylamine 4-[6-(5-methylpyrimidine-2-sulfonamido)-5-(2-methoxyl group phenoxy group)-2-(4-morpholine)-pyrimidine-4-oxygen base according to the step of example 58]-butyl-2-alkynes ester.MS：t _R＝3.89min，[M+1] ⁺＝662.39，[M-1] ^-＝660.33。Example 84

By 50mg5-methyl-N-[6-, (4-hydroxyl-2-butoxy)-5-, (2-methoxyl group phenoxy group)-2-, (4-morpholine)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN), (example 15) and 50mg pyrazine-2-carboxylamine trinitride, (by pyrazine-2-carboxylamine according to Chem.Pharm.Bull.25, (1997) 1651-1657 preparation) step according to example 58 makes 204mg white powder 4-pyrazine-carboxylamine 4-[6-, (5-methylpyrimidine-2-sulfonamido)-5-, (2-methoxyl group phenoxy group)-2-, (4-morpholine)-pyrimidine-4-oxygen base]-butyl-2-alkynes ester.MS：t _R＝4.80min，[M+1] ⁺＝663.43，[M-1] ^-＝661.36。Example 85

By 50mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-tolyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 16) and 50ul phenyl isocyanate make 36mg white foam shape material phenyl-carboxylamine 4-[6-(5-sec.-propyl-pyrimidine-2-sulfonamido)-5-(right-tolyl)-pyrimidine-4-oxygen base according to the step of example 53]-butyl-2-alkynes ester.MS：t _R＝5.50min，[M+1] ⁺＝572.36，[M-1] ^-＝570.30。Example 86

By 50mg5-sec.-propyl-N-[6-(4-hydroxyl-2-butoxy)-5-(right-tolyl)-4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (example 16) and 95mgN-methyl-N-phenyl-carbamic acid chloride make the cream-coloured foam-like material N-methyl of 79mg-N-phenyl-carboxylamine 4-[6-(5-sec.-propyl-pyrimidine-2-sulfonamido)-5-(right-tolyl)-pyrimidine-4-oxygen base according to the step of example 72]-butyl-2-alkynes ester.LC-MS：t _R＝5.44min，[M+1] ⁺＝586.33，[M-1] ^-＝584.50。Example 87

300mg5-sec.-propyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridine) 4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 1f) and 1.47g4-methoxyl group butyral be (according to Bull.Chem.Soc.Japan 28 (1955), the step of describing among the 80-83 is by 2-butyl-1,4-two pure and mild Dimethylsulfates are prepared from) be dissolved among the 15ml DMF and be mixed with solution, to wherein adding the 234mg55% sodium hydride in mineral oil.At room temperature stir brown solution 24 hours, and added the 120mg55% sodium hydride afterwards again in mineral oil.Continuously stirring 24 hours.Mixture is used 50ml ethyl acetate extraction four times with the aqueous citric acid solution dilution of 100ml10%.In conjunction with organic phase 50ml water washing twice, dry evaporation on sal epsom.Raw product obtains 154mg yellow solid 5-sec.-propyl-N-[6-(4-methoxyl group-butyl-2-oxygen base)-5-(2-methoxyl group-phenoxy group)-2-pyrimidine-4-base-pyrimidine-4-yl with ethyl acetate elution purifying with the column chromatography on silica gel]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝4.84min，[M+1] ⁺＝576.42，[M-1] ^-＝574.37。Example 88

300mg5-sec.-propyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(4-pyridine) 4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 1f) and 502mg4-phenoxy group-2-butyne-1-alcohol is (according to J.Chem.Soc.Perkin Trans.1,1991, the step of describing among the 1721-1727 is prepared from by phenyl-proparylether and PARA FORMALDEHYDE PRILLS(91,95)) be dissolved among the 15ml THF and be mixed with solution, to wherein adding 228mg55% sodium hydride mineral oil.At room temperature stirred orange suspension 1 hour, the aqueous citric acid solution with 100ml10% dilutes afterwards.Mixture 50ml ethyl acetate extraction three times.In conjunction with organic layer 50ml water washing twice, dry evaporation on sal epsom.Raw product is used ethyl acetate with the column chromatography on ready thin-film chromatography dish: methyl alcohol: ammoniated brine solution=the elution purifying obtained the light yellow foam-like material 5-of 241mg sec.-propyl-N-[6-(4-methoxyl group-butyl-2-oxygen base)-5-(2-methoxyl group-phenoxy group)-2-pyrimidine-4-base-pyrimidine-4-yl in 8: 2: 1]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.95min，[M+1] ⁺＝666.58，[M-1] ^-＝664.62。Example 89

250mg4-tributyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidine) 4-pyrimidyl]-phenyl sulfanilamide (SN) (routine 5a) and 1.11g4-methoxyl group-2-butyne be (according to Bull.Chem.Soc.Japan28 (1955), the step of describing among the 80-83 is by 2-butyl-1,4-two pure and mild Dimethylsulfates are prepared from) add among the 15mlTHF and form mixture, to wherein adding 177mg55% sodium hydride mineral oil.Adverse current stirred suspension 16 hours.Reaction mixture with the aqueous citric acid solution dilution of 100ml10%, is used 50ml ethyl acetate extraction four times.In conjunction with organic phase 50ml water washing twice, dry evaporation on sal epsom.Raw product is used ethyl acetate with the column chromatography on ready thin-film chromatography dish: methyl alcohol: ammoniated brine solution=the elution purifying obtained the light yellow foam-like material 4-of 116mg tributyl-N-[6-(4-methoxyl group--2-butoxy)-5-(neighbour-methoxyl group-phenoxy group)-2-(2-pyrimidine)-4-pyrimidyl in 8: 2: 1]-phenyl sulfanilamide (SN).LC-MS：t _R＝5.19min，[M+1] ⁺＝590.40，[M-1] ^-＝588.39。Example 90

260mg4-tributyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidine) 4-pyrimidyl]-phenyl sulfanilamide (SN) (routine 5a) and 1.50g4-phenoxy group-2-butyne-1-alcohol is (according to J.Chem.Soc.Perkin Trans.1,1991, the step of describing among the 1721-1727 is prepared from by phenyl-proparylether and PARA FORMALDEHYDE PRILLS(91,95)) add among the 15mlTHF and form mixture, to wherein adding 184mg55% sodium hydride mineral oil.Adverse current stirred suspension 1 hour.Reaction mixture with the aqueous citric acid solution dilution of 100ml10%, is used 50ml ethyl acetate extraction four times.In conjunction with organic phase 50ml water washing twice, dry evaporation on sal epsom.Raw product is used ethyl acetate with the column chromatography on ready thin-film chromatography dish: methyl alcohol: ammoniated brine solution=the elution purifying obtained the light yellow foam-like material 4-of 116mg tributyl-N-[6-(4-phenoxy group--2-butoxy)-5-(neighbour-methoxyl group-phenoxy group)-2-(2-pyrimidine)-4-pyrimidyl in 8: 2: 1]-phenyl sulfanilamide (SN).LC-MS：t _R＝5.60min，[M+1] ⁺＝652.63，[M-1] ^-＝650.58。Example 91

390mg4-phenoxy group-2-butyne-1-alcohol is (according to Tetrahedron Lett.38 (1997), the step of describing among the 7887-7890 is by 2-butyne-1,4-two pure and mild phenyl-bromide things are prepared from) 4-tributyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidine) 4-pyrimidyl]-phenyl sulfanilamide (SN) (routine 5a) adding 5ml DMF: THF=1: be mixed with solution in 1, to wherein adding 97mg55% sodium hydride mineral oil.After the whole effusions of gas, add 250mg4-tributyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidine) 4-pyrimidyl]-phenyl sulfanilamide (SN) (routine 5a), under 50 ℃, stirred the mixture 20 hours, afterwards with the dilution of 75ml ethyl acetate.With 75ml10% aqueous citric acid solution and 75ml water washing mixture, and evaporating solvent.Raw product is used ethyl acetate with the column chromatography on ready thin-film chromatography dish: methyl alcohol: ammoniated brine solution=the elution purifying obtained the yellow foam-like material 4-tributyl-N-[6-(4-phenoxy group--2-butoxy) of 125mg-5-(neighbour-methoxyl group-phenoxy group)-2-(2-pyrimidine)-4-pyrimidyl in 10: 2: 1]-phenyl sulfanilamide (SN).LC-MS：t _R＝5.93min，[M+1] ⁺＝66647，[M-1] ^-＝664.63。Example 92

250mg4-tributyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidine) 4-pyrimidyl]-phenyl sulfanilamide (SN) (routine 5a) and 421mg4-(4-methylphenoxy)-2-butyne-1-alcohol is (according to TetrahedronLett.38 (1997), the step of describing among the 7887-7890 is by 2-butyne-1, and 4-two pure and mild 4-aminomethyl phenyl bromides are prepared from) step described according to example 91 makes the yellow foam-like material 4-tributyl-N-[6-(4-(4-methylphenoxy--2-butoxy)-5-(neighbour-methoxyl group-phenoxy group)-2-(2-pyrimidine)-4-pyrimidyl) of 184mg-phenyl sulfanilamide (SN).LC-MS：t _R＝6.11min，[M+1] ⁺＝680.51，[M-1] ^-＝679.61。Example 93

300mg4-tributyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(2-pyrimidine) 4-pyrimidyl]-phenyl sulfanilamide (SN) (routine 5a) and 1096mg4-(3-methoxyl group phenoxy group)-2-butyne-1-alcohol is (according to TetrahedronLett.38 (1997), the step of describing among the 7887-7890 is by 2-butyne-1, and 4-two pure and mild 3-p-methoxy-phenyl bromides are prepared from) step described according to example 91 makes raw product 4-tributyl-N-[6-(4-(3-methoxyl group phenoxy group-2-butoxy)-5-(o-methoxyl group-phenoxy group)-2-(2-pyrimidine)-4-pyrimidyl)-phenyl sulfanilamide (SN).Compound is used the DCM elution that contains 0-2.5% methyl alcohol with the column chromatography on silica gel, and then usefulness contains 5% DCM elution on the thin-film chromatography dish.The oily matter that obtains is dissolved in the 10ml ethyl diacetate, handles with pentane.Collecting precipitation thing, drying obtain 102mg near-white powder 4-tributyl-N-[6-(4-(3-methoxyl group phenoxy group-2-butoxy)-5-(neighbour-methoxyl group-phenoxy group)-2-(2-pyrimidine)-4-pyrimidyl)-phenyl sulfanilamide (SN).LC-MS：t _R＝5.74min，[M+1] ⁺＝696.40，[M-1] ^-＝694.32。Example 94

To 250mg5-sec.-propyl-N-[6-chloro-5-(neighbour-methoxyl group phenoxy group)-2-(N-morpholine) 4-pyrimidyl]-2-pyrimidine sulfanilamide (SN) (routine 9c) and 1.2g 4-methoxyl group-2-butyne-1-alcohol is (according to Bull.Chem.Soc.Japan28 (1955), the step of describing among the 80-83 is by 2-butyl-1, and 4-two pure and mild Dimethylsulfates are prepared from) mixture in add 192mg55% sodium hydride mineral oil.After the whole effusions of gas, adverse current stirred brown suspension 16 hours.Add 96mg55% sodium hydride mineral oil again, heating, continuously stirring 3 hours.Cooling mixture with the aqueous citric acid solution dilution of 50ml10%, is used 50ml ethyl acetate extraction four times.In conjunction with organic phase 50ml water washing, dry evaporation on sal epsom.Raw product is used hexane with the column chromatography on silica gel: ethyl acetate=1: 3 elution purifying is settled out 114mg white powder 5-sec.-propyl-N-[6-(4-methoxyl group--2-butoxy)-5-(neighbour-methoxyl group-phenoxy group)-2-(N-morpholine)-4-pyrimidyl from ethyl diacetate]-2-pyrimidine sulfanilamide (SN).LC-MS：t _R＝5.19min，[M+1] ⁺＝584.46，[M-1] ^-＝583.38。Example 95

To 300mg4-tributyl-N-[6-chloro-5-(right-tolyl)-4-pyrimidyl]-phenyl sulfanilamide (SN) (routine 12c) and 1.8g4-methoxyl group-2-butyne-1-alcohol is (according to Bull.Chem.Soc.Japan28 (1955), the step of describing among the 80-83 is by 2-butyl-1, and 4-two pure and mild Dimethylsulfates are prepared from) mixture in add 288mg55% sodium hydride mineral oil.After the whole effusions of gas, at room temperature stirred brown suspension 24 hours.Add 288mg55% sodium hydride mineral oil again, stirred 18 hours down at 60 ℃.Cooling mixture with the aqueous citric acid solution dilution of 50ml10%, is used 50ml ethyl acetate extraction four times.Wash dry evaporation on sal epsom with water in conjunction with organic phase.Raw product is used hexane with the column chromatography on silica gel: ethyl acetate=1: 1 elution purifying is settled out 213mg white powder 4-tributyl-N-[6-(4-methoxyl group--2-butoxy)-5-(right-tolyl)-4-pyrimidyl from ethyl diacetate]-phenyl sulfanilamide (SN).LC-MS：t _R＝5.61min，[M+1] ⁺＝480.30，[M-1] ^-＝478.39。Example 96

To 282mg4-tributyl-N-[6-chloro-5-(right-tolyl)-4-pyrimidyl]-phenyl sulfanilamide (SN) (routine 12c) and 1.10g4-phenoxy group-2-butyne-1-alcohol is (according to J.Chem.Soc.Perkin Trans.1,1991, the step of describing among the 1721-1727 is prepared from by phenyl-proparylether and PARA FORMALDEHYDE PRILLS(91,95)) add among the 15ml THF and form mixture, to wherein adding 271mg55% sodium hydride mineral oil.Stirred suspension is 4 hours under adverse current.Reaction mixture with the aqueous citric acid solution dilution of 100ml10%, is used 50ml ethyl acetate extraction four times.Wash dry evaporation on sal epsom with water in conjunction with organic phase.Raw product is used heptane with the column chromatography on silica gel: ethyl acetate=1: 1 elution purifying is settled out 151mg white powder 4-tributyl-N-[6-(4-phenoxy group--2-butoxy)-5-(right-tolyl)-4-pyrimidyl from ethyl acetate]-phenyl sulphur.LC-MS：t _R＝6.34min，[M+1] ⁺＝542.48，[M-1] ^-＝540.15。

Claims

1. chemical formula is the compound of general formula I.

General formula I

Here:

R ¹Represent phenyl; One five of forming of phenyl, halogen, hydroxyl, low-carbon alkyl, low alkenyl, low-carbon (LC) alkynyl, low-alkoxy, low alkene oxygen base, low alkynyloxy group, low alkylidene group or low alkenylene or low alkylene oxide group or low alkylene dioxo base and phenyl ring or six-ring, hydroxyl-low-carbon alkyl, hydroxyl hang down alkenyl, hydroxyl low-carbon (LC) alkynyl, low-alkoxy low-carbon alkyl, low-alkoxy-low-alkoxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxyl-cycloalkyl is single, double or tri-substituted phenyl; Heterocyclic radical; Five yuan of hetero-aromatic rings that contain one or two N, S or O atom (may by halogen, low-carbon alkyl, low-alkoxy, hydroxyl-low-carbon alkyl, halogen, trifluoromethyl list or two replacement); The 2-pyridyl; The 2-pyridyl that 5-substituting group-usefulness low-carbon alkyl, low-alkoxy replace; Phenyl; Form one five or six-ring, hydroxyl-low-carbon alkyl, hydroxyl-hang down alkenyl, hydroxyl-low-carbon (LC) alkynyl, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxyl-cycloalkyl, single, double or tri-substituted phenyl with phenyl, halogen, hydroxyl, low-carbon alkyl, low alkenyl, low alkynyl, low-alkoxy, low alkene oxygen base, low alkynyloxy group, low alkylidene group or low alkenylene or low alkylene oxide group or low alkylene dioxo base and phenyl ring; Five yuan of hetero-aromatic rings that contain one or two N, S, O atom; Aromatic base; Heterocyclic aromatic base;

R ²Representation hydroxy; Low-carbon alkyl; Trifluoromethyl; One five of forming of phenyl, halogen, hydroxyl, low-carbon alkyl, low alkenyl, low-carbon (LC) alkynyl, low-alkoxy, low alkene oxygen base, low alkynyloxy group, low alkylidene group or low alkenylene or low alkylene oxide group or low alkylene dioxo base and phenyl ring or six-ring, hydroxyl-low-carbon alkyl, hydroxyl-hang down alkenyl, hydroxyl-low-carbon (LC) alkynyl, low-alkoxy-low-carbon alkyl, low-alkoxy-low-alkoxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxyl-cycloalkyl is single, double or tri-substituted phenyl; Heterocyclic radical; Five yuan of hetero-aromatic rings that contain one or two N, S or O atom (may by halogen, low-carbon alkyl, low-alkoxy list or two replacement); Phenyl; One five of forming of phenyl, halogen, hydroxyl, low-carbon alkyl, low alkenyl, low-carbon (LC) alkynyl, low-alkoxy, low alkene oxygen base, low alkynyloxy group, low alkylidene group or low alkenylene or low alkylene oxide group or low alkylene dioxo base and phenyl ring or six-ring, hydroxyl-low-carbon alkyl, hydroxyl-hang down alkenyl, hydroxyl-low-carbon (LC) alkynyl, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxyl-cycloalkyl is single, double or tri-substituted phenyl; The 2-pyrimidyl; Low-carbon alkyl, low-alkoxy, hydroxyl-low-carbon alkyl, halogen, trifluoromethyl, contain five yuan of fragrant heterocycles of one or two N, S, O atom; Aromatic base; Heteroaryl; Heterocyclic radical;

Chemical formula is-C (A)-B-R ^aFunctional group of gang

Here: A represents O or S;

B represents NH or key;

X represents O, S, NH or key; The mixture of acceptable salt etc. on the mixture of pure enantiomer, diastereomer, diastereomer and racemize diastereomer, racemize diastereomer and the pharmacology.

2. chemical formula is the compound of expression formula I, R here ¹, R ², R ⁴Definition the same;

X represents O or singly-bound;

With acceptable salt on the pharmacology.

3. chemical formula is the compound of expression formula II, Formulae II

R wherein ², R ³, R ⁴With the definition of X with Formula I in the claim 1, R ⁵Acceptable salt on expression low-carbon alkyl and the pharmacology.

4. chemical formula is the compound of expression formula III,

With acceptable salt on the pharmacology.

5. chemical formula is the compound of expression formula IV,

With acceptable salt on the pharmacology.

6. structure is the compound of Formula I, wherein R ¹, R ³, R ⁴Identical with the definition of X with Chemical formula 1, R ²Be low-carbon alkyl;

With acceptable salt on the pharmacology.

7. as the compound that arbitrary final product is described among the routine 1-96.

8. the medicine compound preparation that is used for the treatment of the disease that is caused by interior oestrone, the particularly recycle system are disorderly disorderly as cancer as hypertension, vasospasm, stenocardia and propagation, comprise the arbitrary compound of claim 1-7 and general carrier and secondary material.

9. the medicine compound preparation that is used for the treatment of the disease that is caused by interior oestrone, for example migraine, asthma, inflammation comprises the arbitrary compound of claim 1-7 and general carrier and secondary material.

10. disease, the especially recycle system that oestrone caused in the arbitrary compound that requires among the claim 1-7 was used for treating is disorderly disorderly as cancer, migraine, inflammation as hypertension, local asphyxia, vasospasm, stenocardia and propagation.

11. blended ET is handled in disease that oestrone caused in the arbitrary compound that requires among the claim 1-7 was used for treating and requirement _AAnd ET _BBlock.

Disease that oestrone caused in 12. the arbitrary compound that requires among the claim 1-7 was used for treating and the ET that requires processing selecting _ABlock.

Disease that oestrone caused in 13. the arbitrary compound that requires among the claim 1-7 was used for treating and the ET that requires processing selecting _BBlock.

14. utilize arbitrary compound of requiring among the claim 1-7 be used for the treatment of as the activeconstituents of compound in the oestrone disease, the especially recycle system that cause disorderly as hypertension, local asphyxia, vasospasm, stenocardia and propagation disorder as cancer.

15. utilize arbitrary compound of requiring among the claim 1-7 be used for the treatment of as the activeconstituents of compound in the disease that causes of oestrone activity, as migraine, asthma or inflammation.

16. the preparation technology of compound, the disease that oestrone caused in it was used for the treatment of, wherein contain arbitrary compound of requiring among one or more claims 1-7 as activeconstituents, these technologies comprise with the method for generally acknowledging with one or more activeconstituentss of acceptable mixed with excipients on the pharmacology.

17. invention described above.