CN100591671C - Heteroarylcarbamoylbenzene derivative - Google Patents
Heteroarylcarbamoylbenzene derivative Download PDFInfo
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- CN100591671C CN100591671C CN200480010759A CN200480010759A CN100591671C CN 100591671 C CN100591671 C CN 100591671C CN 200480010759 A CN200480010759 A CN 200480010759A CN 200480010759 A CN200480010759 A CN 200480010759A CN 100591671 C CN100591671 C CN 100591671C
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Abstract
The compound and salt function to activate glucokinase and are useful as a therapeutic agent for diabetes. The compound represented by the following formula (I): (I) [wherein X<1> represents oxygen, etc.; X<2> represents oxygen, etc.; R<1> represents an alkylsulfonyl or another group on the ring A; R<2> represents, e.g., C3-7 cyclic alkyl optionally substituted by halogeno, etc.; R<3> represents asubstituent on the ring B, e.g., lower alkyl; the formula (II) [Chemical formula 1] (II) represents 6- to 10-membered aryl, etc.; and the formula (III) [Chemical formula 1] (III) represents a mono- or bicyclic heteroaryl which optionally has a substituent represented by the R<3> in the ring B and in which the carbon atom bonded to the nitrogen atom of the amide group in the formula (I) forms C=Nin cooperation with the nitrogen atom of the ring] or a pharmaceutically acceptable salt of the compound.
Description
Technical field
The present invention relates to contain the activators of glucokinase of Heteroarylcarbamoylbderivative derivative as effective constituent.Further relate to new Heteroarylcarbamoylbderivative derivative.
Background technology
(ATP:D-hexose 6-phosphotransferase EC2.7.1.1) is one of mammiferous four kinds of hexokinase (hexokinase IV) to glucokinase (GK).Hexokinase is the enzyme of the earliest stages of glycolysis-system, the reaction of catalysis from glucose to glucose 6-phosphoric acid.Glucokinase mainly is confined to express in liver and pancreatic beta cell, and the rate-limiting step of the glucose metabolism by controlling these cells plays an important role in the general carbohydrate metabolism.The glucokinase of liver and pancreatic beta cell is 15 aminoacid sequence differences of N-terminal owing to the different of montage respectively, but zymologic property is identical.3 kinds of hexokinase (I, II, III) beyond the glucokinase, its enzymic activity promptly reaches capacity under the glucose concn below the 1mM, and relative therewith, glucokinase then approaches the physiology blood glucose value with respect to the Km of glucose, is 8mM.Therefore, via glucokinase, glucose metabolism is to arrive the form generation hypermetabolism of the change of blood sugar of blood sugar rising (10-15mM) after meal in the cell corresponding to euglycemia (5mM).
Approximately before 10 years, someone has proposed the hypothesis (work such as Garfinkel D that glucokinase works as pancreatic beta cell or liver sugar transmitter, " Computer modelingidentifies glucokinase as glucose sensor of pancreatic beta-cells (microcomputer modelling is identified the glucokinase as the glucose sensor of pancreatic beta cell) ", AmericanJournal Physiology, the 247th volume (3Pt2), 1984, P527-536).
By the result of nearest glucokinase genetic manipulation mouse as can be known, in fact glucokinase is being brought into play important effect aspect the glucose homeostasis of whole body.The glucokinase gene suffers that the destructive mouse is (" Transgenicknockouts reveal a critical requirement for pancreatic beta cellglucokinase in maintaining glucose homeostasis (transgenosis knocks out demonstration pancreatic beta cell glucokinase and keeping keying action in the glucose homeostasis) " of work such as Grupe A for example promptly dead soon after the birth, Cell, the 83rd volume, nineteen ninety-five, P69-78), the blood glucose value of the normal and diabetic mice of glucokinase overexpression is then reduced (" Correction of diabeticalterations by glucokinase (the correcting the diabetic change) " of work such as Ferre T for example by glucokinase, Proceedings of the National Academy of Sciences of the U.S.A., the 93rd volume, 1996, P7225-7230).Along with glucose concn rises, pancreatic beta cell is different with hepatocellular reaction, but all corresponding to the direction that blood sugar is reduced.Pancreatic beta cell is secreted more Regular Insulin, and liver discharges sugar and reduces when picked-up sugar stores as glycogen.
Like this, the variation of glucokinase enzymic activity is being brought into play important effect for mammals via the glucose homeostasis of liver and pancreatic beta cell.In the youth who is called MODY2 (young ripening stage demblee form diabetes) in the case of onset diabetes, discovery has the sudden change of glucokinase gene, the reason that glucokinase active reduction becoming blood sugar rises (" the Nonsense mutation in the glucokinase gene causes early-onsetnon-insulin-dependent diabetes mellitus (nonsense mutation in the glucokinase gene causes the initial in early days of non-insulin-dependent diabetes mellitus (NIDDM)) " of work such as Vionnet N for example, Nature Genetics, the 356th volume, 1992, P721-722).
On the other hand, also found to have the family that makes the active sudden change of rising of glucokinase, these people demonstrate hypoglycemia symptom (" Familial hyperinsulinismcaused by an activating glucokinase mutation (the familial hyperinsulinemia that the sudden change of reactivity glucokinase causes) " of work such as Glaser B for example, New England Journal Medicine, the 338th volume, 1998, P226-230).
Hence one can see that, and glucokinase also is to play a role as glucose sensor for the mankind, has vital role for the glucose homeostasis.On the other hand, can expect that most type ii diabetes patients might utilize the glucokinase sensor systems to carry out blood glucose regulation.Because glucokinase-activating substance is expected to have the effect that promotes the pancreatic beta cell excreting insulin and the liver Sugar intake is hyperfunction and suppress the effect that sugar discharges, thereby can consider the medicine used as the type ii diabetes patient.
In recent years, known that pancreatic beta cell type glucokinase is in the brain of rat, be confined to that (ventromedial hypothalamic Ventromedial hypothalamus VMH) expresses at feeding center especially.About 2 one-tenth neurocyte is called as glucose responsiveness neurone among the VMH, and they are considered to that always management of body weight is had vital role.When giving glucose in rat brain, the food-intake of rat reduces, and relative therewith, gives the glucalogue glucosamine in brain, when suppressing glucose metabolism with this, and the excessive feed of rat.By the electrophysiology experiment as can be known, glucose responsiveness neurone changes (5-20mM) with the physiological glucose concn and echoes mutually and be activated, and its activity is suppressed because of inhibition glucose metabolisms such as glucosamines.The glucose concn sensory perceptual system that can infer VHM have insulin secretion with pancreatic beta cell the same by glucokinase mediated mechanism.Therefore, except that liver, pancreatic beta cell, carry out glucokinase activatory material among the VHM and not only have blood sugar correction effect, and for bringing the obesity of puzzlement also may have role of correcting for most type ii diabetes patients.
As shown in the above, compound with glucokinase activation can be used as treatment of diabetes medicine and/or prophylactic agent, perhaps, also can be used as the fat medicine that treats and/or prevents as the medicine that treats and/or prevents of chronic complicating diseases of diabetes such as retinopathy, ephrosis, neurosis, ischemic heart disease, arteriosclerosis.
On 3 and 5 of phenyl ring, have substituent compound as the same, disclose following structural formula (IV) with Heteroarylcarbamoylbderivative derivative (I) involved in the present invention
Shown in compound.This compound is all to be the tertiary butyl on 3 and 5 of Heteroarylcarbamoylbderivative ring, does not have the situation that has alkyl on 3 and 5 of The compounds of this invention.In addition; though have the imidazo [1 that links to each other with the nitrogen-atoms of formamyl; 2-a] pyridine; but this imidazo [1; 2-a] position of contained N and the relative position relation of formamyl in the pyridine ring of pyridyl, the relative position relation different (for example flat 11-505524 communiques of Japanese Unexamined Patent Application Publication) of the nitrogen-atoms that formamyl and heteroaryl had that is had with The compounds of this invention.
And then, as have two substituent compounds on the phenyl ring of Heteroarylcarbamoylbderivative derivative, time formula V is disclosed
Shown in compound (for example Japanese Unexamined Patent Application Publication 2001-526255 communique).
In two substituting groups of the compound of being put down in writing in the above-mentioned patent documentation 2, one is trifluoromethyl amino, and this trifluoromethyl amino is included in the X of The compounds of this invention
1-A ring-R
1In; and as the group that links to each other with the nitrogen-atoms of formamyl; contain pyridine ring; the part-structure of this point and The compounds of this invention is common; but with the position of nitrogen-atoms in the continuous pyridine ring of the nitrogen-atoms of formamyl then is different; in the The compounds of this invention be with pyridine ring that the nitrogen-atoms of formamyl links to each other in the ortho position of carbon atom; and in the compound that above-mentioned patent documentation 2 is put down in writing; with carbon atom in the pyridine ring that the nitrogen-atoms of formamyl links to each other also at interval a carbon atom just link to each other with nitrogen-atoms; both are different on this point, and the link position of methoxyl group is also different with the link position of The compounds of this invention.
Formula (VI) is also disclosed
Shown in compound (for example special table 2002-509536 communique).
The compound of being put down in writing in the above-mentioned patent documentation 3; in two substituting groups on its phenyl ring; one has 2-methyl-4-iodo-phenyl amino; and the ortho position at the carbon atom that links to each other with the nitrogen-atoms of formamyl has nitrogen-atoms; the structure of this point and The compounds of this invention is common; but this 2-methyl-4-iodo-phenyl amino is different with the position relation of formamyl and the position relation in the The compounds of this invention; in addition; on the phenyl ring in two substituting groups another has the fluoro base; and the substituting group on the The compounds of this invention phenyl ring does not conform to halogen atom, and this point also is different.
Summary of the invention
The inventor develops can have by the effect different with above-mentioned existing medicine than the drug effect of existing Rezulin object height and the novel diabetes medicament with new drug effect, further investigate, found that compound has the glucokinase activation shown in the formula (I), thereby finished the present invention.
That is, the present invention relates to
(1) compound or its pharmacy acceptable salt shown in the formula (I),
X in the formula
1Expression Sauerstoffatom, sulphur atom or NH, X
2Expression Sauerstoffatom, sulphur atom or CH
2, R
1Expression is selected from 1 or 2 substituting groups that can have of alkyl sulphonyl, alkyloyl, low alkyl group, hydroxyalkyl, hydroxyl, alkyl-carbamoyl, alkylsulfamoyl group, dialkyl sulfamine, alkylthio, alkoxyl group, dialkyl amido formyl radical, alkoxycarbonyl amino, alkoxy carbonyl, halogen atom, alkanoylamino alkyl, alkoxycarbonyl amino alkyl, alkyl sulfonyl-amino alkyl, cyano group and trifluoromethyl, R on the A ring
2Expression can have the cyclic alkyl that the substituent carbonatoms that is selected from halogen atom, carboxyl, alkoxy carbonyl, hydroxyl, amino (this amino can be further replaced by 1 or 2 alkyloyls or low alkyl group), alkoxyl group and N-alkyl-carbamoyl is 3-7, and (carbon atom that constitutes this ring (constitutes in the carbon atom of this ring and X
2Except the carbon atom that links to each other) can be by Sauerstoffatom, NH, N-alkyloyl or CONH displacement), straight or branched low alkyl group or low-grade alkenyl, R
3Expression is selected from 1 or 2 substituting groups that can have of low alkyl group, alkoxyl group, alkylamino, lower dialkyl amino, halogen atom, trifluoromethyl, hydroxyalkyl (hydrogen atom of hydroxyl can be replaced by low alkyl group in this hydroxyalkyl), aminoalkyl group, alkyloyl, carboxyl, alkoxy carbonyl and cyano group, formula (II) on the B ring
Can have 1 or 2 above-mentioned R on the representative ring
1Shown in substituent 6-10 unit's aryl or 5-7 unit heteroaryl, formula (III)
Expression B can have 1 or 2 above-mentioned R on the ring
3Shown in the carbon atom that links to each other with the nitrogen-atoms of the amido of formula (I) in the substituting group, this B ring and this ring nitrogen form monocycle or the bicyclic heteroaryl of C=N;
(2) compound of record, wherein X in above-mentioned (1)
1Be O or S, and X
2Be O or CH
2
(3) compound of record in above-mentioned (2), wherein the A ring is the heteroaryl of phenyl or 5-6 unit;
(4) compound of record in above-mentioned (2), wherein the A ring is phenyl;
(5) compound of record in above-mentioned (2), wherein the A ring is the heteroaryl of 5-6 unit;
(6) each compound of putting down in writing, wherein R of above-mentioned (4) or (5)
1Be hydrogen atom, alkyl sulphonyl, alkyloyl, hydroxyalkyl, alkyl-carbamoyl, alkylsulfamoyl group, dialkyl sulfamine, dialkyl amido formyl radical, alkoxycarbonyl amino, halogen atom, alkanoylamino alkyl, alkyl sulfonyl-amino alkyl, alkoxycarbonyl amino alkyl;
(7) compound of record, wherein R in above-mentioned (4)
1Be alkyl sulphonyl, alkyloyl, hydroxyalkyl, alkanoylamino alkyl, alkyl sulfonyl-amino alkyl, alkoxycarbonyl amino alkyl;
(8) compound of record, wherein R in above-mentioned (4)
1Be alkyl sulphonyl, alkyloyl, hydroxyalkyl;
(9) compound that above-mentioned (3)-(8) are put down in writing, its Chinese style (III) is for having 1 or 2 above-mentioned R on the B ring
3Shown in form the monocycle of C=N or bicyclic heteroaryl (this heteroaryl be the situation of 5-alkoxy carbonyl-pyridine-2-base or 5-carboxyl-pyridine-2-base except) with the continuous carbon atom of the nitrogen-atoms of interior the amido of formula (I) and this ring nitrogen in the substituting group, this B ring;
(10) above-mentioned (7) compound of being put down in writing, wherein the B ring forms the nitrogen-atoms of C=N except the continuous carbon atom of the nitrogen-atoms of the amido of cotype (I) in this ring, also has the heteroatoms that at least one is selected from nitrogen-atoms, sulphur atom and Sauerstoffatom in the B ring;
(11) each compound of putting down in writing, wherein R of above-mentioned (1)-(10)
2For can by halogen atom, carboxyl, alkoxy carbonyl, hydroxyl, amino (this amino can be further replaced by 1 or 2 low alkyl groups), alkoxyl group and N-alkyl-carbamoyl or alkanoylamino replaces and carbonatoms is cyclic alkyl (carbon atom that constitutes this ring can be by Sauerstoffatom, NH or the displacement of N-alkyloyl), straight or branched low alkyl group or the low-grade alkenyl of 3-7;
(12) each compound of putting down in writing of above-mentioned (1)-(11), wherein the B ring is thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl group, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrimidyl, pyrido thiazolyl or benzothiazolyl;
(13) each compound of putting down in writing, wherein R of above-mentioned (1)-(12)
3Be low alkyl group, alkoxyl group, halogen atom, hydroxyalkyl (hydrogen atom of hydroxyl can be replaced by low alkyl group in this hydroxyalkyl), aminoalkyl group or alkyloyl;
(14) each compound of putting down in writing, wherein R of above-mentioned (1)-(12)
3Be low alkyl group, hydroxyalkyl (hydrogen atom of the hydroxyl in this hydroxyalkyl can be replaced by low alkyl group);
(15) compound shown in the formula (I), each mark is identical with above-mentioned definition in the formula (I),
Described compound is following compounds or its pharmacy acceptable salt:
1) 5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-N-(4-methylthiazol-2-yl)-benzamide,
2) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide,
3) 5-oxyethyl group-3-(4-methylsulfonyl phenoxy group)-N-(4-methoxymethyl-thiazol-2-yl) benzamide,
4) 5-cyclopentyloxy-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide,
5) 3-(4-methylsulfonyl phenoxy group)-5-(tetrahydrofuran (THF)-3-base oxygen base)-N-thiazol-2-yl-benzamide,
6) 3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-1-methyl-oxyethyl group)-N-thiazol-2-yl-benzamide,
7) 3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-1-methoxymethyl-oxyethyl group)-N-thiazol-2-yl-benzamide,
8) 3-(2-fluoro-4-methylsulfonyl phenoxy group)-5-isopropoxy-N-thiazol-2-yl-benzamide,
9) 3-(4-methylsulfonyl phenoxy group)-5-(1-methoxymethyl-propoxy-)-N-(4-methyl-thiazol-2-yl)-benzamide,
10) 5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-N-pyrazole-3-yl-benzamide,
11) 5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-N-pyrazine-2-base-benzamide,
12) 3-(4-methylsulfonyl phenoxy group)-5-(3-methoxyl group-1-methyl-propoxy-)-N-thiazol-2-yl-benzamide,
13) 5-(3-hydroxyl-1-methyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide,
14) 5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-N-pyrimidine-4-base-benzamide,
15) 5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-N-(pyrimidine-2-base)-benzamide,
16) N-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-benzamide,
17) N-(isoxazole-3-base)-3-(4-methylsulfonyl phenoxy group)-5-(1-methoxymethyl-propoxy-)-benzamide,
18) 3-(4-methylsulfonyl phenoxy group)-5-(1-methoxymethyl-third oxygen oxygen base)-[1,3,4] thiadiazoles-2-base-benzamide,
19) 5-(1-hydroxymethyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-(4-methyl-thiazol-2-yl)-benzamide,
20) N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methylsulfonyl phenoxy group)-5-(1-methoxymethyl-propoxy-)-benzamide,
21) 5-(2-amino-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide,
22) 5-(2-dimethylamino-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide,
23) 5-(2-hydroxyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-(4-methyl-thiazol-2-yl)-benzamide,
24) 3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-propoxy-)-N-(4-methyl-thiazol-2-yl)-benzamide,
25) 5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-N-(thiazole is [5,4-b] pyridine-2-yl also)-benzamide,
26) 5-(2-hydroxymethyl-allyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide,
27) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazole also [5,4-b] pyridine-2-base-benzamide,
28) 5-(3-hydroxy-2-methyl-propyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide,
29) 3-(4-methylsulfonyl phenoxy group)-N-(4-methyl-thiazol-2-yl)-5-(piperidin-4-yl-oxygen base)-benzamide hydrochloride salt,
30) 5-(1-ethanoyl-piperidin-4-yl oxygen base)-3-(4-methylsulfonyl phenoxy group)-N-(4-methyl-thiazol-2-yl)-benzamide,
31) 2-[3-(4-methylsulfonyl phenoxy group)-5-(4-methyl-thiazol-2-yl-formamyl)-phenoxy group] propionic acid,
32) 5-(3-hydroxyl-1-methyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide,
33) 3-(4-methylsulfonyl phenoxy group)-5-(1-methylamino formyl radical-oxyethyl group)-N-(4-methyl-thiazol-2-yl)-benzamide,
34) 5-(2-acetylamino-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide,
35) N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-benzamide,
36) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-pyridine-2-base-benzamide,
37) 5-(2-hydroxyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide,
38) 5-(2-hydroxyl-cyclopentyloxy)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide,
39) N-(4-ethanoyl-thiazol-2-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-benzamide,
40) 5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methylsulfonyl phenoxy group)-benzamide,
41) N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-benzamide,
42) 3-(3-fluoro-4-methylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-thiazol-2-yl-benzamide,
43) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(5-methyl-thiazol-2-yl) benzamide,
44) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-([1,2,4] thiadiazoles-5-yl)-benzamide,
45) N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-1-methyl-oxyethyl group)-benzamide,
46) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(5-methoxycarbonyl-pyridine-2-yl)-benzamide,
47) 6-[5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-benzoyl-amido] nicotinic acid,
48) 5-(2-hydroxyl-1-methyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide,
49) 5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(isoxazole-3-base)-3-(4-methylsulfonyl phenoxy group)-benzamide,
50) N-(5-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-benzamide,
51) N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-1-methyl-oxyethyl group)-benzamide,
52) N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methylsulfonyl phenoxy group)-5-(tetrahydrofuran (THF)-3-base-oxygen base)-benzamide,
53) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(2-methylthiazol-4-yl)-benzamide,
54) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(4-methoxymethyl-thiazol-2-yl)-benzamide,
55) N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-1-methyl-oxyethyl group)-benzamide,
56) N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-3-(4-methylsulfonyl phenoxy group)-5-(tetrahydrofuran (THF)-3-base-oxygen base)-benzamide,
57) N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-3-(4-methylsulfonyl phenoxy group)-5-(tetrahydrofuran (THF)-3-base-oxygen base)-benzamide,
58) N-(2,5-dimethylthiazole-4-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-benzamide,
59) 5-isopropoxy-3-(4-methoxycarbonyl amino methyl phenoxy group)-N-thiazol-2-yl-benzamide,
60) 5-isopropoxy-3-(4-methylamino formyl radical-phenoxy group)-N-thiazol-2-yl-benzamide,
61) 3-(4-formyl-dimethylamino-phenoxy group)-5-isopropoxy-N-thiazol-2-yl-benzamide,
62) 5-isopropoxy-3-(4-methyl carbonylamino methyl-phenoxy group)-N-thiazol-2-yl-benzamide,
63) 5-isopropoxy-3-(4-methylsulfonyl amino methyl-phenoxy group)-N-thiazol-2-yl-benzamide,
64) 3-[4-(1-hydroxyl-propyl group)-phenoxy group]-5-isopropoxy-N-thiazol-2-yl-benzamide,
65) 6-[3-isopropoxy-5-(thiazol-2-yl formamyl)-phenoxy group]-the nicotinic acid methyl ester,
66) 3-(5-hydroxymethyl-pyridine-2-base-oxygen base)-5-isopropoxy-N-thiazol-2-yl-benzamide,
67) 5-isopropoxy-3-(5-methylsulfonyl pyridine-2-yl)-N-thiazol-2-yl-benzamide,
68) 3-(5-ethanoyl-pyridine-2-base-oxygen base)-5-isopropoxy-N-thiazol-2-yl-benzamide,
69) 5-isopropoxy-3-(5-methoxycarbonyl-pyrazine-2-base-oxygen base)-N-thiazol-2-yl-benzamide,
70) 3-(5-cyano group-pyridine-2-base-oxygen base)-5-isopropoxy-N-thiazol-2-yl-benzamide,
71) 5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-4-yl-oxygen base)-N-thiazol-2-yl-benzamide,
72) 5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxygen base)-N-thiazol-2-yl-benzamide,
73) 5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxygen base)-N-thiazole also [5,4-b] pyridine-2-base-benzamide,
74) 5-isopropoxy-3-([1,3,4] thiadiazoles-2-base sulfenyl)-N-thiazole also [5,4-b]-pyridine-2-base-benzamide,
75) 5-isopropoxy-3-(4-methyl-[1,2,4] triazole-3-base sulfenyl)-N-thiazol-2-yl-benzamide,
76) 5-isopropoxy-3-thiazol-2-yl sulfenyl-N-thiazol-2-yl-benzamide,
77) 5-isopropoxy-3-(4H-[1,2,4] triazole-3-base sulfenyl)-N-thiazol-2-yl-benzamide,
78) 5-isopropoxy-3-([1,3,4] thiadiazoles-2-base sulfenyl)-N-thiazol-2-yl-benzamide,
79) 5-isopropoxy-3-(5-methyl sulfenyl-[1,3,4] thiadiazoles-2-base sulfenyl)-N-thiazol-2-yl-benzamide,
80) 5-isopropoxy-3-(5-methyl-[1,3,4] thiadiazoles-2-base sulfenyl)-N-thiazol-2-yl-benzamide,
81) 5-(tetrahydrofuran (THF)-3-base-oxygen base)-N-thiazol-2-yl-3-(4H-[1,2,4] triazole-3-base sulfenyl)-benzamide,
82) 5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4] thiadiazoles-2-base sulfenyl)-benzamide,
83) 5-(3-hydroxyl-1-methyl-propoxy-)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4] thiadiazoles-2-base sulfenyl)-benzamide,
84) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-([1,3,4] thiadiazoles-2-base sulfenyl)-N-thiazol-2-yl-benzamide,
85) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenyl sulfenyl)-N-thiazol-2-yl-benzamide,
86) 3-(3-fluoro-thiophenyl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-thiazol-2-yl-benzamide,
87) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(pyridin-4-yl sulfenyl)-N-thiazol-2-yl-benzamide,
88) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(6-methyl-pyridin-3-yl sulfenyl)-N-thiazol-2-yl-benzamide,
89) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-benzamide,
90) N-[3-hydroxymethyl-1,2,4-thiadiazoles-5-yl]-3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-1-methyl-oxyethyl group) benzamide,
91) 5-(3-hydroxyl-1-methyl ethoxy)-3-(4-methylsulfonyl phenoxy group)-N-[5-methyl isophthalic acid, 2,4-thiadiazoles-3-yl] benzamide,
92) 5-(hydroxyl-1-methyl ethoxy)-3-(4-methylsulfonyl phenoxy group)-N-(3-methoxyl group-1,2,4-thiadiazoles-5-yl) benzamide,
93) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(1,2,5-thiadiazoles-3-yl) benzamide,
94) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(4-trifluoromethyl-thiazol-2-yl) benzamide,
95) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(4,5,6,7-tetrahydro benzothiazol-2-yl) benzamide,
96) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(pyridazine-3-yl)-benzamide,
97) 5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(3-sec.-propyl-[1,2,4]-triazole-5-yl)-3-(4-methylsulfonyl phenoxy group) benzamide,
98) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(3-methyl-[1,2,4]-oxadiazoles-5-yl) benzamide,
99) 5-(2-hydroxyl-1-methyl-oxyethyl group)-N-[4-(1-hydroxyl-1-methyl-ethyl)-thiazol-2-yl]-3-(4-methylsulfonyl phenoxy group) benzamide,
100) N-(4-cyano group-thiazol-2-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group) benzamide,
101) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
102) 5-(1-hydroxymethyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-(pyridine-2-yl) benzamide,
103) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(5-methyl-isothiazole-3-yl) benzamide,
104) 5-(3-hydroxyl-cyclopentyloxy)-3-(4-methylsulfonyl phenoxy group)-N-(thiazol-2-yl) benzamide,
105) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(5-methoxyl group-thiazol-2-yl) benzamide,
106) 5-(1-hydroxymethyl-2-methyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-(thiazol-2-yl) benzamide,
107) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(1H-[1,2,3] triazole-4-yl) benzamide,
108) N-(1-ethanoyl-1H-pyrazole-3-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group) benzamide,
109) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(pyrazole-3-yl) benzamide,
110) N-(5,6-dihydro-4H-cyclopenta thiazol-2-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group) benzamide,
111) 5-(1-hydroxymethyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
112) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(thieno-[3,2-d] thiazol-2-yl) benzamide,
113) 3-(3-fluoro-4-methylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
114) 3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-1-methyl-oxyethyl group)-N-(pyrazole-3-yl) benzamide,
115) 3-(4-cyano group-phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
116) 3-(4-ethylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
117) 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
118) 5-(3-hydroxyl-1-methyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
119) 3-(4-ethylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(isoxazole-3-base) benzamide,
120) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-sec.-propyl alkylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
121) 5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(4-hydroxy-4-methyl-4,5,6,6a-tetrahydrochysene-3aH-cyclopenta thiazol-2-yl)-3-(4-methylsulfonyl phenoxy group) benzamide,
122) 3-(4-formyl-dimethylamino-phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
123) 3-(4-ethanoyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
124) 5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-3-(1,3,4-thiadiazoles-2-base sulfenyl) benzamide,
125) N-(1-ethyl-1H-pyrazole-3-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group) benzamide,
126) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
127) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methoxycarbonyl amino methyl-phenoxy group)-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide,
128) 5-(1-hydroxymethyl-propoxy-)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
129) 3-(6-methylsulfonyl pyridin-3-yl oxygen base)-5-(1-methoxymethyl-propoxy-)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
130) 5-isopropoxy-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
131) 5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
132) 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(isoxazole-3-base) benzamide,
133) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenyl sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
134) 5-ring propoxy--3-(4-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
135) 3-(6-methylsulfonyl pyridin-3-yl oxygen base)-5-(1-methoxymethyl-propoxy-)-N-(pyrazole-3-yl) benzamide,
136) 5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
137) 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(1-hydroxymethyl-propoxy-)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
138) 5-(6-b sulfonyl pyridine-3-base oxygen base)-3-(2-methoxyl group-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
139) 2-[3-(4-methylsulfonyl phenoxy group)-5-(1-methyl isophthalic acid H-pyrazole-3-yl formamyl)-phenoxy group] the propionic acid tert-butyl ester,
140) 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-methoxyl group-1-methyl-oxyethyl group)-N-(pyrazole-3-yl)-benzamide,
141) 3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-(tetrahydrofuran (THF)-3-yl) benzamide,
142) N-(1-ethyl-1H-pyrazole-3-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base) benzamide,
143) 5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(pyrazole-3-yl) benzamide,
144) 3-(6-methylsulfonyl pyridin-3-yl oxygen base)-5-(2-methoxyl group-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
145) 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-fluoro-1-methyl fluoride-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
146) 2-[3-(4-methylsulfonyl phenoxy group)-5-(1-methyl isophthalic acid H-pyrazole-3-yl formamyl)-phenoxy group] propionic acid,
147) 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-isopropoxy-N-(pyrazole-3-yl) benzamide,
148) 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-isopropoxy-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
149) 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(pyrazole-3-yl) benzamide,
150) 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(pyridine-2-yl) benzamide,
151) 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-thiazol-2-yl-benzamide,
152) 5-(2-fluoro-1-methyl-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
153) 5-(2-chloro-1-methyl-oxyethyl group)-3-(6-b sulfonyl pyridine-3-base oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
154) 5-(2-fluoro-1-methyl fluoride-oxyethyl group)-N-(isoxazole-3-base)-3-(6-methylsulfonyl pyridin-3-yl oxygen base) benzamide,
155) 5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(pyridine-2-yl) benzamide,
156) 5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl) benzamide,
157) 3-(4-dimethylamino alkylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
158) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(3-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
159) 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(6-sec.-propyl sulfonyl pyridine-3-base oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
160) 3-(3-chloro-4-methylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
161) 5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-3-(pyridin-3-yl oxygen base) benzamide,
162) 5-(2-fluoro-1-methyl fluoride-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-3-(pyridin-3-yl oxygen base) benzamide,
163) 5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-3-(pyridin-4-yl oxygen base) benzamide,
164) 5-(2-fluoro-1-methyl fluoride-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-3-(pyridin-4-yl oxygen base) benzamide,
165) 2-[3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(1-methyl isophthalic acid H-pyrazole-3-yl formamyl)-phenoxy group] propionic acid,
166) 5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(3-fluoro-4-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;
(16) compound 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl-phenoxy group)-N-thiazol-2-yl-benzamide or its pharmacy acceptable salt;
(17) compound N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methylsulfonyl phenoxy group)-5-(1-methoxymethyl-propoxy-)-benzamide or its pharmacy acceptable salt;
(18) compound 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl-phenoxy group)-N-pyridine-2-base-benzamide or its pharmacy acceptable salt;
(19) compound 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl-phenoxy group)-N-(2-methylthiazol-4-yl)-benzamide or its pharmacy acceptable salt;
(20) compound 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-([1,3,4] thiadiazoles-2-base sulfenyl)-N-thiazol-2-yl-benzamide or its pharmacy acceptable salt;
(21) compound 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl-phenoxy group)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-benzamide or its pharmacy acceptable salt;
(22) compound 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl-phenoxy group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide or its pharmacy acceptable salt;
(23) compound 3-(3-fluoro-4-methylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide or its pharmacy acceptable salt;
(24) compound 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide or its pharmacy acceptable salt;
(25) compound 3-(6-ethylsulfonyl-pyridin-3-yl oxygen base)-5-isopropoxy-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide or its pharmacy acceptable salt;
(26) compound 5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(6-methylsulfonyl-pyridin-3-yl oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide or its pharmacy acceptable salt;
(27) compound 3-(6-ethylsulfonyl-pyridin-3-yl oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(isoxazole-3-base) benzamide or its pharmacy acceptable salt;
(28) compound 5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(6-methylsulfonyl-pyridin-3-yl oxygen base)-N-(pyrazole-3-yl) benzamide or its pharmacy acceptable salt;
(29) be used for type ii diabetes treatment, prevention and/or delayed onset contain following
(1)-(3) pharmaceutical composition:
(1) (I) shown in compound,
(2) be selected from 1 or the compound more than 2 kind of following (a)-(g),
(a) other activators of glucokinase,
(b) biguanides (bis-guanide),
(c) the PPAR agonist,
(d) Regular Insulin,
(e) somatostatin,
(f) alpha-glucosidase inhibitor and
(g) insulin secretion stimulators,
(3) pharmaceutically acceptable carrier;
(30) activators of glucokinase, this activator is an effective constituent with each compound in aforementioned (1)-(28);
(31) treatment of diabetes and/or preventive, this treats and/or prevents agent is effective constituent with each compound in aforementioned (1)-(28);
(32) fatly treat and/or prevent agent, this treats and/or prevents agent is effective constituent with each compound in aforementioned (1)-(28).
Connotation to used term in this specification sheets describes below, and further compound involved in the present invention is elaborated.
" aryl " for example has carbonatomss such as phenyl, naphthyl, xenyl, anthryl is hydrocarbon cyclophane base of 6-14 etc.
" low alkyl group " is meant preferably have the alkyl that carbonatoms is the straight or branched of 1-6, methyl for example, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, isopentyl, 1, the 1-dimethyl propyl, the 1-methyl butyl, the 2-methyl butyl, 1, the 2-dimethyl propyl, hexyl, isohexyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,2,2-trimethylammonium propyl group, 1-ethyl-2-methyl-propyl etc.
" low-grade alkenyl " is meant that carbonatoms is the straight or branched low-grade alkenyl of 1-6, for example vinyl, allyl group, 1-butylene base, crotyl, 1-pentenyl etc.
" alkoxyl group " is meant the group after the hydrogen atom of hydroxyl is replaced by above-mentioned low alkyl group, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, hexyloxy, different hexyloxy etc.
" heteroaryl " is meant that having 1-3 in the heteroaryl is selected from Sauerstoffatom, the first monocycle of the heteroatomic 5-7 of sulphur atom and nitrogen-atoms, be meant that perhaps this monocyclic heteroaryl and phenyl ring or pyridine ring condense the bicyclic heteroaryl that forms, furyl for example, thienyl, pyrryl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl group, isothiazolyl oxazolyl isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, pyrazinyl, quinolyl, isoquinolyl, quinazolyl, quinolizinyl, quinoxalinyl, the cinnolines base, benzimidazolyl-, imidazopyridyl, benzofuryl, naphthyridinyl, 1,2-benzoisoxazole base benzoxazolyl, benzothiazolyl oxazole and pyridyl, the pyrido thiazolyl, isothiazole and pyridyl, benzothienyl etc.
" halogen atom " is meant for example fluorine atom, chlorine atom, bromine atoms, iodine atom etc.
" hydroxyalkyl " is meant that 1 hydrogen atom in the above-mentioned low alkyl group is replaced the group that forms, for example hydroxymethyl, hydroxyethyl, 1-hydroxypropyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxyl-1-methyl-ethyl etc. by hydroxyl.
" alkyl-carbamoyl " is meant by the formamyl after above-mentioned low alkyl group one replacement, for example methylamino formyl radical, ethylamino formyl radical, propyl group formamyl, sec.-propyl formamyl, butyl formamyl, sec-butyl formamyl, tertiary butyl formamyl etc.
" dialkyl amido formyl radical " is meant that the example of " dialkyl amido formyl radical " has formyl-dimethylamino, diethylamino formyl radical, ethylmethylamino formyl radical, dipropyl formamyl, methyl-propyl formamyl, diisopropylaminoethyl formyl radical etc. by the formamyl after two replacements of identical or different above-mentioned low alkyl group.
" alkylamino " is meant by the monobasic amino of above-mentioned low alkyl group, methylamino, ethylamino, propyl group amino, sec.-propyl amino, butyl amino, sec-butyl amino or tertiary butyl amino etc. for example arranged.
" dialkyl amido " is meant by the identical or different dibasic amino of above-mentioned low alkyl group, for example dimethylamino, diethylamino, dipropyl amino, methyl-propyl amino or diisopropylaminoethyl etc.
" aminoalkyl group " is meant that 1 hydrogen atom that constitutes abovementioned alkyl is replaced the group that forms, for example amino methyl, amino-ethyl, aminopropyl etc. by amino.
" alkyloyl " is meant the group that abovementioned alkyl and carbonyl are formed by connecting, for example methyl carbonyl, ethyl carbonyl, propyl group carbonyl, sec.-propyl carbonyl etc.
" alkanoylamino " is meant aforementioned alkyloyl and the amino group that is formed by connecting, for example methyl carbonylamino, ethyl carbonylamino, sec.-propyl carbonylamino etc.
" alkanoylamino alkyl " is meant that 1 hydrogen atom of abovementioned alkyl is replaced the group that forms, for example acetylamino methyl, ethyl carbonylamino methyl, methyl carbonylamino ethyl, sec.-propyl carbonylamino methyl etc. by above-mentioned alkanoylamino.
" alkylthio " is meant the group that abovementioned alkyl and sulphur atom are formed by connecting, for example methylthio group, ethylmercapto group, rosickyite base, iprotiazem base etc.
" alkyl sulphonyl " is meant the group that abovementioned alkyl and alkylsulfonyl are formed by connecting, for example methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, sec.-propyl alkylsulfonyl etc.
" alkyl sulfonyl-amino " is meant amino hydrogen atom by the monobasic group of abovementioned alkyl alkylsulfonyl, for example methyl sulphonyl amino, ethylsulfonyl amino, sulfonyl propyl base amino or sec.-propyl sulfuryl amino etc.
" alkoxy carbonyl " is meant the group that the hydrogen atom of carboxyl is replaced by abovementioned alkyl, for example methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl etc.
" alkoxycarbonyl amino " is meant that 1 amino hydrogen atom is replaced the group that forms, for example methoxycarbonyl amino, ethoxy carbonyl amino, propyl group carbonylamino, sec.-propyl carbonylamino etc. by above-mentioned alkoxy carbonyl.
" alkoxycarbonyl amino alkyl " is meant that 1 hydrogen atom of abovementioned alkyl is replaced the group that forms, for example methoxycarbonyl amino methyl, ethoxy carbonyl amino methyl, sec.-propyl carbonylamino ethyl etc. by above-mentioned alkoxycarbonyl amino.
" alkylsulfamoyl group " is meant NH in the sulfamyl
21 hydrogen atom replaced the group that forms, for example methyl sulfamyl, ethyl sulfamyl, sec.-propyl sulfamyl etc. by above-mentioned low alkyl group.
" dialkyl sulfamine " is meant NH in the sulfamyl
22 hydrogen atoms replaced the group that forms, for example dimethylamino alkylsulfonyl, diethyl amino alkylsulfonyl, ethyl-methyl sulfamyl, di-isopropyl sulfamyl etc. by identical or different above-mentioned low alkyl group.
In order more specifically to disclose the related compound of above-mentioned formula of the present invention (I), various marks used in the formula (I) are specifically illustrated.
Formula (II)
Can have 1 or 2 above-mentioned R on the representative ring
1In the substituent 6-10 unit's aryl or the 5-7 unit heteroaryl that are exemplified.
The example of " 6-10 unit aryl " has phenyl, naphthyl shown in the A ring, wherein preferred phenyl.
The example of " 5-7 unit heteroaryl " shown in the A ring has in " heteroaryl " of above-mentioned definition the group with " 5-7 unit heteroaryl " synonymous, the wherein heteroaryl of preferred 5-6 unit.
" 5-7 unit heteroaryl " preference such as furyl, thienyl, pyrryl, imidazolyl, triazolyl, pyrazolyl, thiazolyl, thiadiazolyl group, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl shown in the A ring, wherein more preferably triazolyl, thiazolyl, thiadiazolyl group, pyridyl and pyrazinyl, further preferred triazolyl, thiadiazolyl group, pyridyl.
The A ring is preferably thiadiazolyl group, phenyl and pyridyl, more preferably phenyl or pyridyl.
Can have 1 or 2 R on the ring of A ring
1In the substituting group that provides.Here, R
1Expression is selected from the group of alkyl sulphonyl, alkyloyl, alkyl, hydroxyalkyl, hydroxyl, alkyl-carbamoyl, alkylsulfamoyl group, dialkyl sulfamine, alkylthio, alkoxyl group, dialkyl amido formyl radical, alkoxycarbonyl amino, halogen atom, cyano group, alkoxy carbonyl, alkanoylamino alkyl, alkyl sulfonyl-amino alkyl, alkoxycarbonyl amino alkyl and trifluoromethyl; when having 2 described substituting groups on the A ring, these substituting groups can be identical or different.
R
1Be preferably alkyl sulphonyl; alkyloyl; hydroxyalkyl; alkyl-carbamoyl; alkylsulfamoyl group; dialkyl sulfamine; the dialkyl amido formyl radical; alkoxycarbonyl amino; halogen atom; the alkanoylamino alkyl; alkyl sulfonyl-amino alkyl or alkoxycarbonyl amino alkyl; alkyl sulphonyl more preferably; alkyloyl; hydroxyalkyl; halogen atom; the alkanoylamino alkyl; alkyl sulfonyl-amino alkyl or alkoxycarbonyl amino alkyl; alkyl sulphonyl more preferably; alkyloyl; halogen atom or hydroxyalkyl, special preferred alkyl alkylsulfonyl.
Has R in the ring of A ring
1The time, for R
1Link position on the A ring is not particularly limited, and can be any position that can connect.
When the A ring is phenyl, R
1Link position on phenyl is preferably X
1The contraposition that connects into this phenyl.
X
1Expression O, S or NH, wherein preferred O or S, more preferably O.
Therefore, as-X
1-A ring-R
1, work as X
1For O and A ring during for phenyl; its object lesson has 4-(1-hydroxyethyl)-phenoxy group; 4-(1-hydroxypropyl)-phenoxy group; 4-methylsulfonyl phenoxy group; 4-methyl carbonyl-phenoxy group; 4-methylamino formyl radical-phenoxy group; 4-ethyl carbonyl-phenoxy group; 4-formyl-dimethylamino-phenoxy group; 4-methyl carbonylamino methyl-phenoxy group; 4-methylsulfonyl amino methyl-phenoxy group; 4-methoxycarbonyl amino methyl-phenoxy group; 2-fluoro-phenoxy group; 4-methoxycarbonyl-phenoxy group; 4-hydroxymethyl-phenoxy group; 4-methylsulfonyl-2-fluoro-phenoxy group; 4-cyano group-phenoxy group; 4-methyl-phenoxy group; 4-trifluoromethyl-phenoxy group; 3-fluoro-4-methylsulfonyl phenoxy group; 4-dimethylamino alkylsulfonyl phenoxy group; 3-chloro-4-methylsulfonyl phenoxy group; 3-methylsulfonyl phenoxy group; wherein preferred 4-(1-hydroxyethyl)-phenoxy group; 4-(1-hydroxypropyl)-phenoxy group; 4-methylsulfonyl phenoxy group; 4-methyl carbonyl-phenoxy group; 4-methylamino formyl radical-phenoxy group; 4-ethyl carbonyl-phenoxy group; 4-formyl-dimethylamino-phenoxy group; 4-methyl carbonylamino methyl-phenoxy group; 4-methylsulfonyl amino methyl-phenoxy group; 4-methoxycarbonyl amino methyl-phenoxy group; 4-hydroxymethyl-phenoxy group; 4-methylsulfonyl-2-fluoro-phenoxy group; 3-fluoro-4-methylsulfonyl phenoxy group; 4-dimethylamino alkylsulfonyl phenoxy group; 3-chloro-4-methylsulfonyl phenoxy group; more preferably 4-(1-hydroxyethyl)-phenoxy group; 4-(1-hydroxypropyl)-phenoxy group; 4-methylsulfonyl phenoxy group; 4-methyl carbonyl-phenoxy group; 4-ethyl carbonyl-phenoxy group; 4-methyl carbonylamino methyl-phenoxy group; 4-methylsulfonyl amino methyl-phenoxy group; 4-methoxycarbonyl amino methyl-phenoxy group; 4-hydroxymethyl-phenoxy group; 3-fluoro-4-methylsulfonyl phenoxy group; 4-dimethylamino alkylsulfonyl phenoxy group; 3-chloro-4-methylsulfonyl phenoxy group; wherein further preferred 4-(1-hydroxyethyl)-phenoxy group; 4-(1-hydroxypropyl)-phenoxy group; 4-methylsulfonyl phenoxy group; 4-methyl carbonyl-phenoxy group; 4-ethyl carbonyl-phenoxy group or 4-hydroxymethyl-phenoxy group; 3-fluoro-4-methylsulfonyl phenoxy group, wherein preferred especially 4-methylsulfonyl phenoxy group.
Work as X
1For S and A ring during for phenyl ,-X
1-A ring-R
1Object lesson 4-fluoro-phenyl sulfenyl is arranged; 4-methyl-phenyl sulfenyl; 4-trifluoromethyl-phenyl sulfenyl; 4-(1-hydroxyethyl)-phenyl sulfenyl; 4-methylsulfonyl phenyl sulfenyl; 4-methyl carbonyl-phenyl sulfenyl; 4-ethyl carbonyl-phenyl sulfenyl; 4-methylamino formyl radical-phenyl sulfenyl; 4-formyl-dimethylamino-phenyl sulfenyl; 4-methyl carbonylamino methyl-phenyl sulfenyl; 4-methyl sulphonyl amino methyl-phenyl sulfenyl; 4-methoxycarbonyl-phenyl sulfenyl; 4-methoxycarbonyl-amino methyl-phenyl sulfenyl; 4-hydroxymethyl-phenyl sulfenyl; 4-cyano group-phenyl sulfenyl etc.; wherein preferred 4-fluoro-phenyl sulfenyl; 4-(1-hydroxyethyl)-phenyl sulfenyl; 4-methylsulfonyl phenyl sulfenyl; 4-methyl carbonyl-phenyl sulfenyl; 4-ethyl carbonyl-phenyl sulfenyl; 4-methylamino formyl radical-phenyl sulfenyl; 4-formyl-dimethylamino-phenyl sulfenyl; 4-methyl carbonylamino methyl-phenyl sulfenyl; 4-methyl sulphonyl amino methyl-phenyl sulfenyl; 4-methoxycarbonyl-amino methyl-phenyl sulfenyl or 4-hydroxymethyl-phenyl sulfenyl; more preferably 4-(1-hydroxyethyl)-phenyl sulfenyl; 4-methylsulfonyl phenyl sulfenyl; 4-methyl carbonyl-phenyl sulfenyl; 4-ethyl carbonyl-phenyl sulfenyl; 4-methyl carbonylamino methyl-phenyl sulfenyl; 4-methyl sulphonyl amino methyl-phenyl sulfenyl; 4-methoxycarbonyl-amino methyl-phenyl sulfenyl or 4-hydroxymethyl-phenyl sulfenyl; wherein further preferred 4-(1-hydroxyethyl)-phenyl sulfenyl; 4-methylsulfonyl phenyl sulfenyl; 4-methyl carbonyl-phenyl sulfenyl; 4-ethyl carbonyl-phenyl sulfenyl or 4-hydroxymethyl-phenyl sulfenyl, wherein preferred especially 4-methylsulfonyl phenyl sulfenyl.
Work as X
1For S and A ring during for 5-7 unit heteroaryl ,-X
1-A ring-R
1Object lesson 5-cyano group-pyridine-2-base sulfenyl is arranged; 5-bromo-pyridine-2-base sulfenyl; 5-methoxycarbonyl-pyridine-2-base sulfenyl; 5-hydroxymethyl-pyridine-2-base sulfenyl; 5-methylsulfonyl pyridine-2-base sulfenyl; 5-methyl-pyridine-2-base sulfenyl; 5-trifluoromethyl-pyridine-2-base sulfenyl; pyridine-2-base sulfenyl; the pyridin-4-yl sulfenyl; 6-methyl-pyridin-3-yl sulfenyl; [1; 3; 4] thiadiazoles-2-base sulfenyl; 5-methylthio group-[1; 3; 4] thiadiazoles-2-base sulfenyl; 5-methylsulfonyl [1; 3; 4] thiadiazoles-2-base sulfenyl; [1; 2; 4]-triazole-3-base sulfenyl; furans-3-base sulfenyl; the thiene-3-yl-sulfenyl; pyrroles-3-base sulfenyl; imidazoles-2-base sulfenyl; thiazol-2-yl sulfenyl oxazole-2-base sulfenyl isoxazole-3-base sulfenyl; pyrazine-2-base sulfenyl; the pyrimidine-2-base sulfenyl; pyridazine-3-base sulfenyl and 3H-pyrazole-3-yl sulfenyl etc.; wherein preferred 5-bromo-pyridine-2-base sulfenyl; 5-hydroxymethyl-pyridine-2-base sulfenyl; 5-methylsulfonyl pyridine-2-base sulfenyl; pyridine-2-base sulfenyl; the pyridin-4-yl sulfenyl; [1; 3; 4] thiadiazoles-2-base sulfenyl; 5-methylsulfonyl [1; 3; 4] thiadiazoles-2-base sulfenyl; [1; 2; 4]-triazole-3-base sulfenyl; furans-3-base sulfenyl; the thiene-3-yl-sulfenyl; pyrroles-3-base sulfenyl; imidazoles-2-base sulfenyl; thiazol-2-yl sulfenyl oxazole-2-base sulfenyl isoxazole-3-base sulfenyl; pyrazine-2-base sulfenyl; the pyrimidine-2-base sulfenyl; pyridazine-3-base sulfenyl; 3H-pyrazole-3-yl sulfenyl; more preferably 5-hydroxymethyl-pyridine-2-base sulfenyl wherein; 5-methylsulfonyl pyridine-2-base sulfenyl; pyridine-2-base sulfenyl; the pyridin-4-yl sulfenyl; [1; 3; 4] thiadiazoles-2-base sulfenyl; 5-methylsulfonyl [1; 3; 4] thiadiazoles-2-base sulfenyl; [1; 2; 4]-triazole-3-base sulfenyl; thiazol-2-yl sulfenyl and pyrazine-2-base sulfenyl; wherein further preferred 5-hydroxymethyl-pyridine-2-base sulfenyl; 5-methylsulfonyl pyridine-2-base sulfenyl; pyridine-2-base sulfenyl; the pyridin-4-yl sulfenyl; [1; 3; 4] thiadiazoles-2-base sulfenyl; 5-methylsulfonyl [1; 3; 4] thiadiazoles-2-base sulfenyl; [1; 2; 4]-triazole-3-base sulfenyl and thiazol-2-yl sulfenyl; wherein preferred especially pyridine-2-base sulfenyl; the pyridin-4-yl sulfenyl; [1; 3; 4] thiadiazoles-2-base sulfenyl; [1; 2,4]-triazole-3-base sulfenyl or thiazol-2-yl sulfenyl.
Work as X
1For O and A ring during for 5-7 unit heteroaryl ,-X
1-A ring-R
1Object lesson pyrimidine-4-base oxygen base is arranged; pyridazine-3-base oxygen base; pyrazine-2-base oxygen base; pyridine-2-base oxygen base; 2-hydroxyl-pyridin-3-yl oxygen base; 2-hydroxyl-pyridin-4-yl oxygen base; 5-hydroxymethyl-pyridine-2-base oxygen base; 5-methyl carbonyl-pyridine-2-base oxygen base; 5-(1-hydroxyethyl)-pyridine-2-base oxygen base; 5-methoxycarbonyl amino methyl-pyridine-2-base oxygen base; 5-methylsulfonyl pyridine-2-base oxygen base; 5-methoxycarbonyl-pyridine-2-base oxygen base; 5-cyano group-pyridine-2-base oxygen base; 5-bromo-pyridine-2-base oxygen base; 5-formyl-dimethylamino-pyridine-2-base oxygen base; 5-methoxycarbonyl-pyridine-2-base oxygen base; 5-methyl carbonylamino methyl-pyridine-2-base oxygen base; 5-trifluoromethyl-pyridine-2-base oxygen base; 5-methyl carbonyl-imidazoles-2-base oxygen base; 6-hydroxymethyl-pyrimidine-2-yloxy; 6-methyl carbonyl-pyrimidine-2-yloxy; 6-methanesulfonyl pyrimidine-2-base oxygen base; 6-hydroxymethyl-pyridazine-3-base oxygen base; 6-methyl carbonyl-pyridazine-3-base oxygen base; 6-methylsulfonyl pyridazine-3-base oxygen base; 5-hydroxymethyl-pyrazine-2-base oxygen base; 5-methyl carbonyl-pyrazine-2-base oxygen base; 5-methylsulfonyl pyrazine-2-base oxygen base; 6-b sulfonyl pyridine-3-base oxygen base; 6-methylsulfonyl pyridin-3-yl oxygen base; pyridin-3-yl oxygen base; pyridin-4-yl oxygen base and 6-sec.-propyl sulfonyl pyridine-3-base oxygen base etc.; wherein preferred pyrimidine-4-base oxygen base; pyridazine-3-base oxygen base; pyrazine-2-base oxygen base; pyridine-2-base oxygen base; 2-hydroxyl-pyridin-3-yl oxygen base; 2-hydroxyl-pyridin-4-yl oxygen base; 5-hydroxymethyl-pyridine-2-base oxygen base; 5-methyl carbonyl-pyridine-2-base oxygen base; 5-(1-hydroxyethyl)-pyridine-2-base oxygen base; 5-methoxycarbonyl amino methyl-pyridine-2-base oxygen base; 5-methylsulfonyl pyridine-2-base oxygen base; 5-bromo-pyridine-2-base oxygen base; 5-formyl-dimethylamino-pyridine-2-base oxygen base; 5-methyl carbonylamino methyl-pyridine-2-base oxygen base; 5-methyl carbonyl-imidazoles-2-base oxygen base; 6-hydroxymethyl-pyrimidine-2-yloxy; 6-methyl carbonyl-pyrimidine-2-yloxy; 6-methanesulfonyl pyrimidine-2-base oxygen base; 6-hydroxymethyl-pyridazine-3-base oxygen base; 6-methyl carbonyl-pyridazine-3-base oxygen base; 6-methylsulfonyl pyridazine-3-base oxygen base; 5-hydroxymethyl-pyrazine-2-base oxygen base; 5-methyl carbonyl-pyrazine-2-base oxygen base; 5-methylsulfonyl pyrazine-2-base oxygen base; 6-b sulfonyl pyridine-3-base oxygen base; 6-methylsulfonyl pyridin-3-yl oxygen base; pyridin-3-yl oxygen base; pyridin-4-yl oxygen base; more preferably pyrazine-2-base oxygen base wherein; pyridine-2-base oxygen base; 2-hydroxyl-pyridin-3-yl oxygen base; 2-hydroxyl-pyridin-4-yl oxygen base; 5-hydroxymethyl-pyridine-2-base oxygen base; 5-methyl carbonyl-pyridine-2-base oxygen base; 5-(1-hydroxyethyl)-pyridine-2-base oxygen base; 5-methoxycarbonyl amino methyl-pyridine-2-base oxygen base; 5-methylsulfonyl pyridine-2-base oxygen base; 5-methyl carbonylamino methyl-pyridine-2-base oxygen base; 5-hydroxymethyl-pyrazine-2-base oxygen base; 5-methyl carbonyl-pyrazine-2-base oxygen base; 5-methylsulfonyl pyrazine-2-base oxygen base; 6-b sulfonyl pyridine-3-base oxygen base; 6-methylsulfonyl pyridin-3-yl oxygen base, wherein preferred especially 2-hydroxyl-pyridin-3-yl oxygen base; 2-hydroxyl-pyridin-4-yl oxygen base; 5-hydroxymethyl-pyridine-2-base oxygen base; 5-methyl carbonyl-pyridine-2-base oxygen base; 5-(1-hydroxyethyl)-pyridine-2-base oxygen base; 5-methylsulfonyl pyridine-2-base oxygen base; 6-methylsulfonyl pyridin-3-yl oxygen base; 6-b sulfonyl pyridine-3-base oxygen base.
X
2Expression O, S or CH
2, wherein preferred O or CH
2, more preferably O.
R
2It is cyclic alkyl, straight or branched low alkyl group or the low-grade alkenyl of 3-7 that expression can have 1 or 2 substituent carbonatoms that is selected from halogen atom, carboxyl, alkoxy carbonyl, hydroxyl, amino (this amino can be further replaced by 1 or 2 alkyloyls or low alkyl group), alkoxyl group and N-alkyl-carbamoyl.
R
2Represented " halogen atom " is the same with group in the above-mentioned definition.Wherein preferred chlorine atom or fluorine atom.
R
2Represented " alkoxy carbonyl " is meant the carbonyl with the alkoxyl group in the above-mentioned definition, for example methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, tertiary butyl oxygen base carbonyl etc.
R
2Represented " carbonatoms is the cyclic alkyl of 3-7 " for example has cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc., wherein preferred cyclopentyl or cyclohexyl, more preferably cyclopentyl.
Work as R
2When constituting carbonatoms and being the cyclic alkyl of 3-7, constitute in the carbon atom of this ring and remove and X
2Outer any 1 carbon atom of the carbon atom that links to each other can be by Sauerstoffatom, NH, N-alkyloyl or CONH displacement.
For R
2It is represented that " 1 carbon atom of cyclic alkyl that constitutes carbonatoms 3-7 is (with X
2Except the carbon atom that links to each other) can be by Sauerstoffatom, NH, N-alkyloyl or CONH displacement " group, preferred described carbon atom is by Sauerstoffatom, NH or N-alkyloyl metathetical situation, more preferably by Sauerstoffatom or N-alkyloyl metathetical situation.This R
2Example more specifically be preferably tetrahydrofuran base, THP trtrahydropyranyl, pyrrolidyl, piperidyl, N-ethanoyl piperidyl, more preferably tetrahydrofuran base, THP trtrahydropyranyl or N-ethanoyl piperidyl.
R
2Represented " straight or branched low alkyl group " expression and the low alkyl group of above-mentioned definition synonymous.This low alkyl group is preferably ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, more preferably propyl group, sec.-propyl, isobutyl-, sec-butyl.
R
2The example of represented " low-grade alkenyl " have with above-mentioned definition in the identical group of group, wherein preferred propenyl, pseudoallyl, isobutenyl, more preferably pseudoallyl.
Preferred R
2For 1 carbon atom of the cyclic alkyl of the cyclic alkyl, straight or branched low alkyl group or the carbonatoms 3-7 that constitute carbonatoms 3-7 (constitutes in the carbon atom of this ring and X
2Except the carbon atom that links to each other) by Sauerstoffatom, NH, N-alkyloyl or CONH metathetical group, 1 carbon atom that more preferably constitutes the cyclic alkyl of straight or branched low alkyl group or carbonatoms 3-7 (constitutes in the carbon atom of this ring and X
2Except the carbon atom that links to each other) by Sauerstoffatom, NH, N-alkyloyl or CONH metathetical group.
Therefore ,-X
2-R
2Example has propyl group; isobutyl-; sec-butyl; 3-methoxyl group-2-methyl-propyl group; 2-methoxymethyl-butyl; 4-hydroxy-2-methyl-butyl; 2-hydroxymethyl-butyl; 3-hydroxyl-butyl; 3-methoxyl group butyl; 3-hydroxy-2-methyl-propyl group; 3-hydroxyl-butyl; 3-methylamino formyl radical-propyl group; 3-acetylamino-2-methyl-propyl group; 2-hydroxymethyl-3-propenyl; 2-methyl-2-propenyl; oxyethyl group; isopropoxy; 2-methoxyl group-1-methyl-oxyethyl group; 1-methoxymethyl-propoxy-; 3-hydroxyl-1-methyl-propoxy-; 1-hydroxymethyl-propoxy-; 2-amino-1-oxyethyl group; 2-hydroxyl-propoxy-; the 2-methoxy propoxy; 2-hydroxyl-1-methyl-oxyethyl group; 2-hydroxyl-oxyethyl group; 2-dimethylamino-1-methyl-oxyethyl group; 1-carboxyl-oxyethyl group; 2-methylamino formyl radical-oxyethyl group; 2-acetylamino-1-methyl-oxyethyl group; cyclopentyloxy; cyclohexyloxy; ring oxygen base in heptan; 2-hydroxyl-cyclopentyloxy; tetrahydrofuran (THF)-3-base oxygen base; tetrahydrofuran (THF)-2-base oxygen base; tetrahydrofuran (THF)-4-base oxygen base; piperidin-4-yl oxygen base; piperidines-3-base oxygen base; tetramethyleneimine-3-base oxygen base; tetramethyleneimine-2-base oxygen base; 1-ethanoyl-piperidin-4-yl oxygen base; 1-ethanoyl-piperidines-3-base oxygen base; the 3-allyloxy; the different propenyloxy group of 3-; 1-methyl-allyloxy; 2-fluoro-1-methyl fluoride-oxyethyl group; 2-fluoro-1-methyl-oxyethyl group; 2-chloro-1-methyl-oxyethyl group etc.; be preferably oxyethyl group; isopropoxy; 2-methoxyl group-1-methyl-oxyethyl group; 1-methoxymethyl-propoxy-; 3-hydroxyl-1-methyl-propoxy-; 1-hydroxymethyl-propoxy-; 2-hydroxyl-propoxy-; the 2-methoxy propoxy; 2-hydroxyl-1-methyl-oxyethyl group; 2-hydroxyl-oxyethyl group; 2-methylamino formyl radical-oxyethyl group; 2-acetylamino-1-methyl-oxyethyl group; cyclopentyloxy; cyclohexyloxy; 2-hydroxyl-cyclopentyloxy; tetrahydrofuran (THF)-3-base oxygen base; tetrahydrofuran (THF)-2-base oxygen base; tetrahydropyran-3-base oxygen base; tetrahydrofuran (THF)-4-base oxygen base; piperidin-4-yl oxygen base; piperidines-3-base oxygen base; tetramethyleneimine-3-base oxygen base; tetramethyleneimine-2-base oxygen base; 1-ethanoyl-piperidin-4-yl oxygen base; 1-ethanoyl-piperidines-3-base oxygen base; the different propenyloxy group of 3-; 1-methyl-allyloxy; butyl; isobutyl-; sec-butyl; 3-methoxyl group-2-methyl-propyl group; 2-methoxymethyl-butyl; 4-hydroxy-2-methyl-butyl; 2-hydroxymethyl-butyl; 3-hydroxyl-butyl; 3-methoxyl group butyl; 3-hydroxy-2-methyl-propyl group; 3-hydroxyl-butyl; 3-methylamino formyl radical-propyl group; 3-acetylamino-2-methyl-propyl group; 2-hydroxymethyl-3-propenyl; 2-methyl-2-propenyl; 2-fluoro-1-methyl fluoride-oxyethyl group; 2-fluoro-1-methyl-oxyethyl group; 2-chloro-1-methyl-oxyethyl group; more preferably 2-methoxyl group-1-methyl-oxyethyl group wherein; 1-methoxymethyl-propoxy-; 3-hydroxyl-1-methyl-propoxy-; 1-hydroxymethyl-propoxy-; 2-hydroxyl-propoxy-; the 2-methoxy propoxy; 2-hydroxyl-1-methyl-oxyethyl group; 2-hydroxyl-oxyethyl group; 2-methylamino formyl radical-oxyethyl group; 2-acetylamino-1-methyl-oxyethyl group; cyclopentyloxy; cyclohexyloxy; 2-hydroxyl-cyclopentyloxy; tetrahydrofuran (THF)-3-base oxygen base; tetrahydropyran-3-base oxygen base; 1-ethanoyl-piperidin-4-yl oxygen base; 1-ethanoyl-piperidines-3-base oxygen base; the different propenyloxy group of 3-; 3-methoxyl group-2-methyl-propyl group; 2-methoxymethyl-butyl; 4-hydroxy-2-methyl-butyl; 2-hydroxymethyl-butyl; 3-hydroxyl-butyl; 3-methoxyl group butyl; 3-hydroxy-2-methyl-propyl group; 3-hydroxyl-butyl; 3-methylamino formyl radical-propyl group; 3-acetylamino-2-methyl-propyl group; 2-hydroxymethyl-3-propenyl; 2-methyl-2-propenyl; 2-fluoro-1-methyl fluoride-oxyethyl group; 2-fluoro-1-methyl-oxyethyl group, wherein preferred especially 2-methoxyl group-1-methyl-oxyethyl group; 1-methoxymethyl-propoxy-; 3-hydroxyl-1-methyl-propoxy-; 1-hydroxymethyl-propoxy-; 2-hydroxyl-1-methyl-oxyethyl group; 2-acetylamino-1-methyl-oxyethyl group; 2-hydroxyl-cyclopentyloxy; tetrahydrofuran (THF)-3-base oxygen base; 1-ethanoyl-piperidin-4-yl oxygen base; 3-methoxyl group-2-methyl-propyl group; 2-methoxymethyl-butyl; 4-hydroxy-2-methyl-butyl; 2-hydroxymethyl-butyl; 3-hydroxy-2-methyl-propyl group; 3-acetylamino-2-methyl-propyl group; 2-hydroxymethyl-3-propenyl; 2-fluoro-1-methyl fluoride-oxyethyl group.
The B ring is above-mentioned formula (III)
Shown in group, represent in this B ring that carbon atom that the nitrogen-atoms with the amido of following formula (I) links to each other and this ring nitrogen form monocycle or the bicyclic heteroaryl of C=N.
Here, represented " heteroaryl " of B ring is meant that the carbon atom that links to each other with amido bond shown in the following formula (I) in the B ring and nitrogen-atoms form " heteroaryl " of above-mentioned definition shown in the formula (III) of C=N.The expression of the two keys of C=N is pro forma expression in the B ring, and B encircles so long as heteroaryl gets final product.
Encircle as B, the heteroaryl of preferred this ring does not contain the situation of 5-alkoxy carbonyl-pyridine-2-base or 5-carboxyl-pyridine-2-base, more preferably form the nitrogen-atoms of C=N, also have at least one the heteroatomic monocycle that is selected from nitrogen-atoms, sulphur atom and Sauerstoffatom or the situation of bicyclic heteroaryl in the B ring except the continuous carbon atom of the nitrogen-atoms of the amido of same following formula (I) in this ring.
And then, preferred especially B ring is that the carbon atom that the nitrogen-atoms except the amido of same following formula (I) in this B ring links to each other forms the nitrogen-atoms of C=N, also have heteroatomic monocycle or the bicyclic heteroaryl that at least one is selected from nitrogen-atoms, sulphur atom and Sauerstoffatom in the B ring, and at the B ring is that 5 bit substituents of this thiazolyl do not contain the situation of sec.-propyl under the situation of thiazolyl.
When B ring during for monocycle, preferred to constitute this monocyclic atomicity be 5 or 6, more preferably 5.When B ring during for dicyclo, be preferably the dicyclo that 5 or 6 yuan monocycle and phenyl ring or pyridine ring condense the 9-10 unit that forms, more preferably 5 yuan of monocycles and pyridine ring condense 9 yuan of dicyclos that form.
The object lesson of B ring has thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl group, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl, pyrimidyl, pyrido thiazolyl and benzothiazolyl etc., wherein preferred thiazolyl, thiadiazolyl group, isoxazolyl, pyrazinyl, pyridyl, pyrido thiazolyl and pyrazolyl, more preferably thiazolyl, thiadiazolyl group, isoxazolyl, pyrido thiazolyl and pyrazolyl.
Can have 1 or 2 R in the ring of B ring
3Represented substituting group.
Here, R
3Expression is selected from the group of low alkyl group, alkoxyl group, alkylamino, lower dialkyl amino, halogen atom, trifluoromethyl, hydroxyalkyl (hydrogen atom of hydroxyl can be replaced by low alkyl group in this hydroxyalkyl), aminoalkyl group, alkyloyl, carboxyl, alkoxy carbonyl and cyano group.
In the ring of B ring, have 2 above-mentioned R
3The time, they can be identical or different.
For R
3Link position on the B ring, no matter B ring is the bicyclic heteroaryl of 5-7 unit or the bicyclic heteroaryl of 9-11 unit, so long as the position that can connect on the B ring, then can, be not particularly limited.
Wherein, preferred R
3Be low alkyl group, alkoxyl group, halogen atom, hydroxyalkyl (hydrogen atom of the hydroxyl in this hydroxyalkyl can be replaced by low alkyl group), aminoalkyl group or alkyloyl, more preferably low alkyl group, hydroxyalkyl (hydrogen atom of hydroxyl can be replaced by low alkyl group in this hydroxyalkyl) or alkyloyl.
R
3Example more specifically methyl is arranged, ethyl, propyl group, sec.-propyl, butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, chlorine, fluorine, bromine, hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxyethyl group, methoxy ethyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, amino methyl, amino-ethyl, aminopropyl, the methyl carbonyl, the ethyl carbonyl, propyl group carbonyl etc., preferable methyl wherein, ethyl, chlorine, fluorine, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxy ethyl, methoxycarbonyl, ethoxy carbonyl, amino methyl, amino-ethyl, the methyl carbonyl, ethyl carbonyl, more preferably methyl, hydroxymethyl, methoxymethyl, the methyl carbonyl.
Therefore, following formula (VII)
Group specifically is preferably thiazol-2-yl shown in [each mark is identical with above-mentioned definition in the formula]; 4-methyl-thiazol-2-yl; 4-hydroxymethyl-thiazol-2-yl; 4-methoxycarbonyl-thiazol-2-yl; 4-methoxymethyl-thiazol-2-yl; 4-amino methyl-thiazol-2-yl; 4-cyano group-thiazol-2-yl; 4-cyano group-thiazol-2-yl; 4-fluoro-thiazol-2-yl; imidazoles-2-base; 4-methyl-imidazoles-2-base; 4-methoxycarbonyl-imidazoles-2-base; isothiazole-3-base; 4-hydroxymethyl-isothiazole-3-base; [1; 3; 4] thiadiazoles-2-base; 5-ethanoyl-[1; 3; 4] thiadiazoles-2-base; [1; 2; 4] triazole-2-base; 5-hydroxymethyl-[1; 2; 4] triazole-3-base; pyrazine-2-base; pyridine-2-base; 4-methyl-pyridine-2-base; 4-methoxymethyl-imidazoles-2-base; 4-ethanoyl-imidazoles-2-base; 5-hydroxymethyl-imidazoles-2-base; 5-methyl-[1; 3; 4] thiadiazoles-2-base; 5-fluoro-[1; 3; 4] thiadiazoles-2-base; 5-methyl-[1; 2; 4] triazole-2-base; 5-ethanoyl-[1; 2; 4] triazole-3-base isoxazole-3-base; 4-methoxymethyl-isoxazoles-2-base; 5-methyl-isoxazole-3-bases; 5-hydroxymethyl-isoxazole-3-bases; 5-methoxymethyl-isoxazole-3-bases; 5-methyl carbonyl-isoxazole-3-bases; 5-chlorine-isoxazole-3-bases; 5-amino methyl-isoxazole-3-bases; pyrazole-3-yl; 4-methyl isophthalic acid H-pyrazole-3-yl; 6-methyl-pyridazine-3-base; thiazole-4-base; 2-methyl-thiazole-4-base isoxazole-3-base; thiazole also [5; 4-b] pyridine-2-base; 3-methyl-[1; 2,4] thiadiazolyl group-5-base and 1-methyl isophthalic acid H-pyrazole-3-yl.
From the above, formula (I) involved in the present invention
Heteroarylcarbamoylbderivative derivative involved in the present invention can exist with the form of pharmacy acceptable salt.This salt can be acid salt or base addition salt.
Compound involved in the present invention exists steric isomer or tautomers such as optically active isomer, diastereomer, geometrical isomer sometimes according to its substituent form.Much less, these isomer all are included in the compound scope involved in the present invention.And any mixture of these isomer is also included within the compound scope involved in the present invention certainly.
Compound of the present invention has the glucokinase activation, therefore can be used as treatment of diabetes medicine and/or prophylactic agent, also can be used as the medicine and/or the prophylactic agent of diabetic complication.
Here, diabetic complication is because of the concurrent disease of onset diabetes, and described diabetic complication for example has diabetic nephropathy, diabetic retinopathy, diabetic neurosis, diabetic arteriosclerosis etc.
Compound involved in the present invention is all applicable to insulin-dependent diabetes (IDDM) and two kinds of diabetes of non-insulin-dependent diabetes mellitus (NIDDM) (NIDDM).
It is generally acknowledged that insulin-dependent diabetes (IDDM) is because the heredity insulin secretion is low and the factors such as insulin resistance of skeletal muscle, add the insulin resistance that obesity causes and cause morbidity, being mainly seen in adult's morbidity.Someone proposes described insulin-dependent diabetes according to different I type and the II types of being divided into of its inducement.
Compound involved in the present invention is not only effective to I type insulin-dependent diabetes, but also can think that it is also effective to type ii diabetes, and existing diabetes medicament is for the abundant lowering blood glucose value of type ii diabetes.
The type ii diabetes degree of back hyperglycemia on the feed obviously continues to be higher than healthy people for a long time, and compound of the present invention also is effective to this type ii diabetes.
The working of an invention mode
Preparation method to The compounds of this invention describes below.
Compound of the present invention (I) can adopt known reaction method or easily prepare according to itself known method.Compound of the present invention (I) not only can also for example make up the method preparation that synthesis method or parallel synthesis method etc. adopt solid phase by developed recently rapidly by common liquid phase synthesizing method preparation.
The compounds of this invention preferably is prepared by for example following method.
[in the formula, R represents low alkyl group, and X represents halogen atom, and other mark is identical with above-mentioned definition.]
(step 1-1) this step is by to 3, imports protecting group on the carboxyl that 5-dihydrobenzene formic acid (1a) is had and prepares the method for compound (1).The protecting group R of the carboxyl that compound (1) is had, so long as can in step 1-3, play the effect of the protecting group of carboxyl, and can easily remove in step 4, then can be any group, for example straight chain such as methyl, ethyl and tertiary butyl or have the low alkyl group of side chain; 2-iodine ethyl, 2,2, junior alkyl halides such as 2-three chloroethyls; Allyl group, 2-propenyl, 2-methyl-low-grade alkenyls such as 2-propenyl; Benzyl; Aralkyl such as PMB base etc.
About the method that imports and remove such carboxyl-protecting group R, can adopt method (Protective Groups in Organic Synthesis for example, T.W.Green work, the 2nd edition, the John Wiley ﹠amp of document record; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
Can for example concentrate with the compound (1) that obtains thus by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification, perhaps can be directly used in step subsequently without separation and purification.
(this step of step 1) is in the presence of venus crystals and alkali, makes compound (1) and methylthio phenyl ylboronic acid (2) is reacted, and prepares the method for 5-hydroxyl-3-(4-methylthio group phenoxy group) benzoic ether (3) thus.
With respect to 1 equivalent compound (1), the consumption of methylthio phenyl ylboronic acid (2) is generally the 1-10 equivalent, preferred 1-2.5 equivalent.
Except that venus crystals, can also use cupric nitrate, but more preferably venus crystals.
The consumption of venus crystals or cupric nitrate is generally the 0.1-5 equivalent, preferred 1-1.5 equivalent.
The example of used alkali has triethylamine, diisopropyl ethyl amine etc., wherein preferred triethylamine.
The consumption of alkali is generally the 0-10 equivalent, preferred 4-6 equivalent.
Temperature of reaction is generally 0 reflux temperature of spending to reaction solvent, preferred 15-30 degree.
Reaction times in this step is generally 2-48 hour, is preferably 12 hours.
As long as used reaction solvent in this step then can use any solvent, but preferably use for example methylene dichloride, acetonitrile, toluene etc. to reacting without hindrance, wherein preferred methylene dichloride.
Can for example concentrate with the compound (3) that obtains thus by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatography etc. carry out separation and purification, perhaps can be directly used in step subsequently without separation and purification.
(step 2) this step is in the presence of alkali, makes above-mentioned steps 1 gained compound (3) and halogenated alkyl compounds (4) reaction, prepares the method for compound (5) thus.
Compound used therefor (4) is as long as can make the reaction in this step unhinderedly carry out, make compound (5), it then can be any halogenated alkyl compounds, for example iodoethane, 2-N-PROPYLE BROMIDE, bromocyclopentane, ethylene bromohyrin etc., wherein preference such as 2-N-PROPYLE BROMIDE, bromocyclopentane etc., more preferably 2-N-PROPYLE BROMIDE.
With respect to 1 equivalent compound (3), the consumption of compound (4) is generally the 0.5-10 equivalent, preferred 1-3 equivalent.
Used alkali for example can be salt of wormwood, Diisopropylamine etc., wherein preferred salt of wormwood.
The consumption of alkali is generally the 1-10 equivalent, preferred 1.5-3 equivalent.
Temperature of reaction is generally 0 reflux temperature of spending to reaction solvent, preferred 25-40 degree.
Reaction times is generally 1-12 hour, preferred 4-8 hour.
As long as used reaction solvent in this step then can use any solvent to reacting without hindrance, but preferred N, dinethylformamide.Can for example concentrate with the compound (5) that obtains thus by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification, perhaps can be directly used in step subsequently without separation and purification.
(this step of step 3) is by making above-mentioned steps 2 gained compounds (5) and mCPBA reaction, preparing the method for compound (6) thus.The oxidizing reaction that is adopted in this step can adopt the method (work such as Brown.D. for example of document record, Simple pyrimidines.X.The formation and reactivity of 2-, 4-, and 5-pyrimidinyl sulfones andsulfoxides, Journal of the Chemical Society[Section] C:Organic, the 7th volume, 1967, p568-572), make up based on its method or with these methods and ordinary method and to carry out.
With respect to 1 equivalent compound (5), the consumption of mCPBA is generally the 2-10 equivalent, preferred 3-4 equivalent.
Reaction times is generally 10 minutes to 12 hours, preferred 30 minutes to 1 hour.
Temperature of reaction is generally-78 degree to 15 degree, preferred 0-10 degree.
As long as used reaction solvent in this step then can use any solvent to reacting without hindrance, and methylene dichloride, chloroform etc. are for example arranged, wherein preferred chloroform.
Can for example concentrate with the compound (6) that obtains thus by known separation purification method, concentrating under reduced pressure, crystallization, redeposition, solvent extraction, chromatography etc. carry out separation and purification, perhaps can be directly used in step subsequently without separation and purification.
(this step of step 4) is to remove the carboxyl-protecting group R that above-mentioned steps 3 gained compounds (6) are had, and prepares the method for compound (7) thus.
The method of removing carboxyl-protecting group R can adopt method (Protective Groups in Organic Synthesis, T.W.Green work for example, the 2nd edition, the JohnWiley ﹠amp of document record; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
Can for example concentrate with the compound (7) that obtains thus by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification, perhaps can be directly used in step subsequently without separation and purification.
(this step of step 5) is to make above-mentioned steps 4 gained compounds (7) and following formula (8)
Aminocompound shown in [each mark is identical with above-mentioned definition in the formula] reacts, and prepares the method for The compounds of this invention (I-1) thus.
This reaction can be by document record method (for example, peptide synthetic basis and experiment, spring room letter husband etc., ball is kind, nineteen eighty-three, Comprehensive Organic Synthesis, the 6th volume, Pergamon Press society, 1991, etc.), combine with ordinary method based on its method or with these methods, carrying out common one-tenth acid amides reaction gets final product, that is to say that can use the known condensing agent of those skilled in the art to carry out, perhaps the ester activation method that can utilize by those skilled in the art, mixed anhydride method, chloride method, carbodlimide method etc. carry out.Such one-tenth amide reagent for example has thionyl chloride, oxalyl chloride, N, N-dicyclohexylcarbodiimide, iodate 1-methyl-2-bromopyridine, N, N '-carbonyl dimidazoles, diphenyl phosphoryl chloride, two phenoxy group phosphoryl azides, carbonic acid N, N '-two succinimide ester, oxalic acid N, N '-two succinimide ester, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, Vinyl chloroformate, isobutyl chlorocarbonate or phosphofluoric acid benzotriazole-1-base-oxygen base-three (dimethylamino) Phosphonium etc.Wherein preference such as thionyl chloride, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, N, N-dicyclohexylcarbodiimide or phosphofluoric acid benzotriazole-1-base-oxygen base-three (dimethylamino) Phosphonium etc.Become in the acid amides reaction, can use alkali, condensation auxiliary agent with above-mentioned one-tenth amide reagent.
Available alkali for example has Trimethylamine 99, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-crassitude, N-methyl piperidine, N, accelerine, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), 1,5-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene aliphatic tertiary amines such as (DBN); Arylamine such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline 99.9 etc. for example, wherein preference such as aliphatic tertiary amine etc., particularly preferred example such as triethylamine or N, N-diisopropylethylamine etc.
Available condensation auxiliary agent for example has N-hydroxy benzotriazole hydrate, N-hydroxy-succinamide, N-hydroxyl-5-norbornylene-2,3-dicarboximide or 3-hydroxyl-3,4-dihydro-4-oxo-1,2,3-benzotriazole etc., wherein preference such as N-hydroxybenzotriazole etc.
The amount of compound used therefor (8) is different and different with compound used therefor and solvent types, other reaction conditions, with respect to 1 equivalent carboxylic acid derivative (7) or its reactive derivatives, is generally the 0.1-10 equivalent, is preferably the 0.5-3 equivalent.
The amount of used one-tenth amide reagent is different and different with compound used therefor and solvent types, other reaction conditions, with respect to 1 equivalent carboxylic acid cpd (7) or its reactive derivatives, is generally the 1-10 equivalent, is preferably the 1-3 equivalent.
The amount of used condensation auxiliary agent is different and different with compound used therefor and solvent types, other reaction conditions, with respect to 1 equivalent carboxylic acid cpd (7) or its reactive derivatives, is generally the 1-10 equivalent, is preferably the 1-3 equivalent.
The amount of used alkali is different and different with compound used therefor and solvent types, other reaction conditions, is generally the 1-10 equivalent, is preferably the 1-5 equivalent.
Used reaction solvent can be an inert solvent for example in this step, only otherwise hinder reaction, then there is no particular limitation as to it, specifically, methylene dichloride, chloroform, 1 are for example arranged, 2-ethylene dichloride, N, dinethylformamide, ethyl acetate, methyl acetate, acetonitrile, benzene, dimethylbenzene, toluene, 1,4-diox, tetrahydrofuran (THF), glycol dimethyl ether or their mixed solvent, from guaranteeing preferred temperature of reaction, preference such as methylene dichloride, chloroform, 1,2-ethylene dichloride, acetonitrile or N, dinethylformamide etc.
The temperature of reaction of this step is generally-78 boiling temperatures of spending to solvent, is preferably the 0-30 degree.
The reaction times of this step is generally 0.5-96 hour, is preferably 3-24 hour.
Alkali, one-tenth amide reagent, condensation auxiliary agent used in this step can use a kind, or be used in combination.
B substitution in ring base R when the compound (I-1) of this step preparation
3When having protecting group, can remove this protecting group as required.Removing of this protecting group can be by method (Protective Groups in Organic Synthesis, T.W.Green work, the 2nd edition, the John Wiley ﹠amp of document record; Sons society, 1991, etc.), make up based on its method or with these methods and ordinary method and to carry out.
The compound of the present invention (I-1) that makes thus can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatography etc. carry out separation and purification.
The compound (5) of preparation also can be by following method preparation in the above-mentioned steps 3.
[in the formula, each mark is identical with above-mentioned definition.]
(this step of step 6) is to make the compound (3) and alkylol cpd (9) reaction that makes in the above-mentioned steps 1, prepares the method for compound (5) thus.
This reaction is that so-called light prolongs reaction, can be in the presence of phosphine compound and azo-compound, method by document record (Mitsunobu, O work for example, The use of diethylazodicarboxylate and triphenylphosphine in synthesis and transformationof natural products, Synthesis, the 1st volume, 1981, p1-28), make up based on its method or with these methods and ordinary method and to carry out.
With respect to 1 equivalent compound (3), the amount of used alkylol cpd (9) is generally the 0.5-10 equivalent in this step, preferred 1-3 equivalent.
Used phosphine compound is generally for example triphenyl phosphine, triethylphosphine etc. in this step.
With respect to 1 equivalent compound (3), the amount of used phosphine compound is generally the 0.5-10 equivalent, preferred 1-3 equivalent.
Used azo-compound can be for example diethyl azodiformate, diisopropyl azodiformate etc.
With respect to 1 equivalent compound (3), the amount of used azo-compound is generally the 0.5-10 equivalent, preferred 1-3 equivalent.
Reaction times of the present invention is generally 1-48 hour, preferred 4-12 hour.
Temperature of reaction in this step is generally 0 return time of spending to reaction solvent, preferred 15-30 degree.
In this step used reaction solvent only otherwise hinder reaction, then there is no particular limitation as to it, specifically can exemplify tetrahydrofuran (THF), toluene etc.
The compound that makes thus (I-1) can for example concentrate by known separation purification method, concentrating under reduced pressure, redeposition, solvent extraction, crystallization, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
The compounds of this invention (I-2) can be by following method preparation.
[in the formula, each mark is identical with above-mentioned definition.]
(this step of step 7) is to make the compound (1) and compound (4) reaction that makes in the above-mentioned steps, prepares the method for compound (10) thus.
This reaction can be undertaken by the method the same with above-mentioned steps 2.
Halogenated alkyl compounds (4) is with respect to reaction conditionss such as the equivalents of compound (1), temperature of reaction, reaction times, can be the method for benchmark or these methods and ordinary method be made up carry out by the method the same with above-mentioned 2 or with it.
(this step of step 8) is to make above-mentioned steps 7 gained compounds (10) and following formula (11)
The reaction of boric acid derivatives shown in [in the formula, each mark is identical with above-mentioned definition] prepares the method for compound (12) thus.
At R
1Under the basic situation that needs protection, can be according to R
1Kind import necessary protecting group.This R
1Protecting group so long as can be as R in step 8-10
1Protecting group work, and remove easily afterwards, and can make The compounds of this invention (I-2), then can be any group.
Import and remove this R
1The method of protecting group, can adopt method (Protective Groups in Organic Synthesis for example, T.W.Green work, the 2nd edition, the JohnWiley﹠amp of document record; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
Can pass through the substituent R on the A ring
11Change, it is become R
1,
With the substituent R on the A ring
11Convert R to
1Reaction, method that can be by document record (Comprehensive Organic Synthesis for example, the 6th volume, Pergamon Press company, 1991; Comprehensive Organic Transformations, Richard L etc., VCH Publishers company, 1988; Deng), carry out based on its method or with the combination of these methods and ordinary method.
R
11Example formyl radical, halogen atom, alkoxy carbonyl etc. are arranged.
R
11When for example being formyl radical, can convert thereof into hydroxymethyl by the reduction formyl radical.Convert the conversion reaction of hydroxymethyl to from formyl radical, can have hydroxymethyl as R by making compound and sodium borohydride reaction, making with formyl radical
1Compound.
And then, by having hydroxymethyl as R
1Compound carry out azide, and carry out reduction reaction subsequently, can convert thereof into amino methyl.
From the conversion reaction of alkoxy carbonyl to alkyl-carbamoyl, can be by having the compound hydrolysis of alkoxy carbonyl, make itself and alkylamine be carried out to the acid amides reaction then, make and have alkyl-carbamoyl as R
1Compound.
Boric acid derivatives shown in above-mentioned (11) for example can be 4-bromo-phenyl-boron dihydroxide, 4-fluoro-phenyl-boron dihydroxide, 4-methyl-phenyl-boron dihydroxide, 4-methoxyl group-phenyl-boron dihydroxide, 4-trifluoromethyl-phenyl-boron dihydroxide, 4-hydroxymethyl-phenyl-boron dihydroxide, 4-ethanoyl-phenyl-boron dihydroxide, 4-cyano group-phenyl-boron dihydroxide, 4-methoxycarbonyl-phenyl-boron dihydroxide, 4-carboxyl-phenyl-boron dihydroxide, 4-formyl radical-phenyl-boron dihydroxide, 4-amino methyl-phenyl-boron dihydroxide and 4-formamyl-phenyl-boron dihydroxide etc.
When phenyl-boron dihydroxide derivative shown in the following formula (11) has substituent R on the A ring
11The time, R
11Can have protecting group.
Import the method for this protecting group, can adopt method (ProtectiveGroups in Organic Synthesis for example, T.W.Green work, the 2nd edition, the John Wiley ﹠amp of document record; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
The compound that makes thus can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(this step of step 9) is the method for removing the carboxyl-protecting group R that gained compound (12) is had in the above-mentioned steps 8.This step can be undertaken by the reaction conditions the same with above-mentioned steps 4, method that can be by the document record (Protective Groups in OrganicSynthesis for example, T.W.Green work, the 2nd edition, John Wiley ﹠amp; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
The compound that makes thus (13) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(this step of step 10) is by making above-mentioned steps 9 gained compounds (13) and aminocompound (8) reaction, preparing the method for The compounds of this invention (I-2).This reaction can be undertaken by the reaction conditions the same with above-mentioned steps 5.
The compound that makes thus (I-2) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification.
The compounds of this invention (I-3) can be by following method preparation.
[Y represents halogen atom in the formula, and other mark is identical with above-mentioned definition]
(this step of step 11) is to make compound (14) and above-claimed cpd (4) reaction, prepares the method for compound (14-1) thus.In this step, compound used therefor (4) is the same with above-mentioned steps 7 etc. with respect to reaction conditionss such as the equivalents of 1 equivalent phenol derivatives (14), temperature of reaction, reaction solvents.
The compound that makes thus (14-1) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, redeposition, crystallization, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(this step of step 12) is to make gained compound (14-1) and compound (15) reaction in the above-mentioned steps 11, prepares the method for compound.
This reaction is in the presence of alkali, quinhydrones and cupric bromide, is undertaken by making compound (14-1) and mercapto derivatives (15) reaction.
Used alkali for example can be salt of wormwood, cesium carbonate, sodium hydride etc. in this reaction, wherein preferred salt of wormwood, sodium hydride.
With respect to 1 equivalent compound (14-1), the consumption of alkali is generally the 0.5-20 equivalent in this step, preferred 3-10 equivalent.
With respect to 1 equivalent compound (14-1), the consumption of quinhydrones is generally the 0.1-10 equivalent in this step, preferred 0.2-1.5 equivalent.
With respect to 1 equivalent compound (14-1), the consumption of cupric bromide is generally the 0.1-10 equivalent in this step, preferred 0.2-2 equivalent.
Temperature of reaction is generally 25 reflux temperatures of spending to reaction solvent, and preferred 50 spend the reflux temperature to reaction solvent.
Reaction times is generally 10 minutes to 24 hours, preferred 15 minutes to 3 hours.
Used reaction solvent only otherwise hinder reaction does not then have particular determination to it in this step, specifically can use for example N, dinethylformamide.
The compound that makes thus (16) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(this step of step 13) is to remove the carboxyl-protecting group that gained compound (16) is had in the above-mentioned steps 12, prepares the method for compound (17).
This step can be undertaken by the method the same with above-mentioned steps 4 or 9, the method by document record (Protective Groups in Organic Synthesis for example, T.W.Green work, the 2nd edition, John Wiley ﹠amp; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
The compound that makes thus (17) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(this step of step 14) is to make gained compound (17) and compound (8) reaction in the above-mentioned steps 13, prepares the method for The compounds of this invention (I-3).
This reaction is into amido linkage reaction, reaction conditionss such as temperature of reaction, reaction solvent and above-mentioned steps 5 or 10 the same getting final product.
The The compounds of this invention that makes thus (I-3) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification.
The compounds of this invention (I-4) can be by following method preparation.
[in the formula, each mark is identical with above-mentioned definition.]
(this step of step 15) is the method for removing the carboxyl-protecting group that gained compound (10) is had in the above-mentioned steps 7.This step can be undertaken by the reaction conditions the same with above-mentioned steps 4, the method by the document record (Protective Groups in OrganicSynthesis for example, T.W.Green work, the 2nd edition, John Wiley﹠amp; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
The compound that makes thus (18) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(step 16) this step is to make gained compound (18) and compound (8) reaction in the above-mentioned steps 15, prepares the method for compound (19).This reaction is into amido linkage reaction, reaction conditionss such as temperature of reaction, reaction solvent and above-mentioned steps 5 or 10 the same getting final product.
The The compounds of this invention that makes thus (19) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(step 17) this step is in the presence of alkali, makes gained compound (19) and following formula (20) in the above-mentioned steps 16
Halide reaction shown in [in the formula, A ring expression pyridine ring, pyrazine ring, pyrimidine ring or pyridazine ring, each mark is identical with above-mentioned definition] prepares the method for The compounds of this invention (I-4) thus.
With respect to 1 equivalent compound (19), the consumption of halogenide in this step (20) is generally the 0.5-20 equivalent, preferred 1-3 equivalent.
Used alkali for example can be salt of wormwood, cesium carbonate, sodium hydride etc. in this reaction, wherein preferred salt of wormwood.
With respect to 1 equivalent compound (19), the consumption of alkali is generally the 0.5-20 equivalent in this step, preferred 1-10 equivalent.
Temperature of reaction is generally 25 reflux temperatures of spending to reaction solvent, and preferred 50 spend the reflux temperature to reaction solvent.
Reaction times is generally 1-48 hour, preferred 1-24 hour.
Used reaction solvent only otherwise hinder reaction does not then have particular determination to it in this step, specifically preferably uses for example N, dinethylformamide.
At R
1Under the basic situation that needs protection, can be according to R
1Kind import necessary protecting group.This R
1Protecting group so long as can in step 17, bring into play R
1The effect of protecting group, and remove easily afterwards, then can be any group.
Import and remove R
1The method of protecting group, can adopt method (Protective Groups in Organic Synthesis for example, T.W.Green work, the 2nd edition, the JohnWiley ﹠amp of document record; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
Can pass through the substituent R on the A ring
11Change, it is become R
' 1,
With the substituent R on the A ring
11Convert R to
1Reaction, method that can be by document record (Comprehensive Organic Synthesis for example, the 6th volume, Pergamon Press company, 1991; Comprehensive Organic Transformations, Richard L etc., VCH Publishers company, 1988; Deng), carry out based on its method or with the combination of these methods and ordinary method.
R
11Example halogen atom, alkoxy carbonyl etc. are arranged.
R
11During for alkoxy carbonyl, can convert thereof into hydroxymethyl by the reduction alkoxy carbonyl.
Convert the conversion reaction of hydroxymethyl to from alkoxy carbonyl, can have hydroxymethyl as R by making compound and lithium aluminum hydride reaction, making with alkoxy carbonyl
1Compound.
And then, by having hydroxymethyl as R
1Compound carry out azide, and carry out reduction reaction subsequently, can convert thereof into amino methyl.
When halogenide shown in the following formula (20) has substituent R on the A ring
11The time, R
11Can have protecting group.
Import the method for this protecting group, can adopt method (ProtectiveGroups in Organic Synthesis for example, T.W.Green work, the 2nd edition, the John Wiley ﹠amp of document record; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
The compound that makes thus (I-4) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification.
The compounds of this invention (I-5) can be by following method preparation.
[in the formula, R
22Expression can have the R of protecting group
2, each mark is identical with above-mentioned definition.]
(step 18) this step is in the presence of alkali, makes compound (21) and following formula (20)
[in the formula, R
4The expression hydroxyl protecting group, each mark is identical with above-mentioned definition] shown in halide reaction, prepare the method for compound (23) thus.
The hydroxyl protecting group R that compound used therefor in this step (21) is had
4Importing, method that can be by the record of above-mentioned document (Protective Groups in Organic Synthesis for example, T.W.Green work, the 2nd edition, John Wiley ﹠amp; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
This step can be that the method for benchmark or these methods and ordinary method make up and carry out by the method the same with above-mentioned steps 17, with it.
R
4More specifically example methoxymethyl, benzyl, 4-methoxyl group-benzyl, 2-(trimethyl silyl) ethoxyl methyl, t-butyldimethylsilyl and tertiary butyl carbonyl etc. are arranged.
The consumption of compound (20) with respect to 1 equivalent compound (21), is generally the 0.1-20 equivalent, preferred 0.5-5 equivalent with compound used therefor and solvent types, other reaction conditions and different.
The amount of used alkali is generally the 0.1-20 equivalent, preferred 0.5-5 equivalent with compound used therefor and solvent types, other reaction conditions and different.
Used alkali then can use any alkali, for example cesium carbonate, yellow soda ash, salt of wormwood, potassiumphosphate, potassium acetate, potassium tert.-butoxide, triethylamine etc. so long as can pass through the alkali of the prepared in reaction compound (23) of compound (20) and compound (21) in this step.
Used reaction solvent can be an inert solvent, only otherwise hinder reaction, then is not particularly limited, specifically can be for example pyridine, toluene, 1,4-diox, N, dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), 1-Methyl-2-Pyrrolidone etc.
In this step, can be that cupric oxide (I), cupric oxide (II) or cupric chloride (I) are present in the reaction system jointly.
In this step, acid chloride (II) or Palladous chloride salt such as (II) palladium and parts such as 2-(di-t-butyl phosphino-) biphenyl or triphenyl phosphine are present in the reaction system jointly.
In this step, silver carbonate, silver acetate, silver suboxide or trifluoroacetic acid silver etc. are present in the reaction system jointly.
Temperature of reaction in this step is generally 0 reflux temperature of spending to reaction solvent, is preferably room temperature to 150 degree.
Reaction times in this step is generally 0.1-72 hour, preferred 0.5-5 hour.
The compound that makes thus (23) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(step 19) this step is to remove the carboxyl-protecting group that gained compound (23) is had in the above-mentioned steps 18, prepares the method for compound (24).
This step protecting group remove can be by document record method (ProtectiveGroups in Organic Synthesis for example, T.W.Green work, the 2nd edition, John Wiley ﹠amp; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method, work as R
4During for methoxymethyl, for example removing of this protecting group can wait and carry out by using trifluoroacetic acid (TFA), hydrochloric acid.
Use TFA to remove R
4The time, the amount of TFA is generally the 0.5-1000 equivalent, preferred 1-100 equivalent.
Remove R with hydrochloric acid
4The time, the amount of hydrochloric acid is generally the 0.5-1000 equivalent, preferred 1-100 equivalent.
In this step used reaction solvent only otherwise hinder reaction, then there is no particular limitation as to it, can be for example methylene dichloride, chloroform, methyl alcohol, 1,4-diox etc.
Temperature of reaction is generally 0 reflux temperature of spending to reaction solvent, and preferred room temperature is to the reflux temperature of reaction solvent.
Reaction times is generally 0.1-72 hour, preferred 0.5-12 hour.
The compound that makes thus (24) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(step 20) this step is to make above-mentioned steps gained compound (24) and compound (25-1) or (25-2) reaction, prepares the method for compound (26) thus.
Compound (24) is that so-called light prolongs reaction with the reaction of compound (25-1), can be in the presence of phosphine compound and azo-compound, method by document record (Mitsunobu, O work for example, The use of diethyl azodicarboxylate and triphenylphosphine insynthesis and transformation of natural products, Synthesis, the 1st volume, 1981, p1-28), make up based on its method or with these methods and ordinary method and to carry out.
With respect to 1 equivalent compound (24), the amount of used alkylol cpd (25-1) is generally the 0.5-10 equivalent in this step, preferred 1-3 equivalent.
Used phosphine compound is generally for example triphenyl phosphine, triethylphosphine etc. in this step.
With respect to 1 equivalent compound (24), the amount of used phosphine compound is generally the 0.5-10 equivalent, preferred 1-3 equivalent.
Used azo-compound can be for example diethyl azodiformate, diisopropyl azodiformate etc.
With respect to 1 equivalent compound (24), the amount of used azo-compound is generally the 0.5-10 equivalent, preferred 1-3 equivalent.
Reaction times of the present invention is generally 1-48 hour, preferred 4-12 hour.
Temperature of reaction in this step is generally 0 reflux temperature of spending to reaction solvent, preferred 15-30 degree.
In this step used reaction solvent only otherwise hinder reaction, then there is no particular limitation as to it, specifically can exemplify tetrahydrofuran (THF), toluene etc.
The reaction of compound (24) and compound (25-2) can be undertaken by the method the same with above-mentioned steps 2.
Reaction conditionss such as the equivalents of halogenide (25-2) and compound (24), temperature of reaction, reaction times can be by being the method for benchmark or these methods and ordinary method being made up carry out with above-mentioned 2 the same methods or with it.
And then compound (26) can pass through compound (24) and formula (25-3)
R
22-X
3 (25-3)
[in the formula, R
22Expression can have the R of protecting group
2, X
3Leavings groups such as expression methanesulfonate or tosylate] shown in compound react and prepare.
Reaction conditionss such as the equivalents of compound (25-3) and compound (24), temperature of reaction, reaction times can be by being the method for benchmark or these methods and ordinary method being made up carry out with above-mentioned 2 the same methods or with it.
The compound that makes thus (26) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, redeposition, solvent extraction, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(step 21) this step is by removing the carboxyl-protecting group R that above-mentioned steps gained compound (26) is had, preparing the method for compound (27).
This step can be undertaken by the reaction conditions the same with above-mentioned steps 4, the method by above-mentioned document record (Protective Groups in Organic Synthesis for example, T.W.Green work, the 2nd edition, John Wiley ﹠amp; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
The compound that makes thus (27) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(step 22) this step is to make above-mentioned steps gained compound (27) and aminocompound (III) reaction, prepares the method for compound (28).
This reaction is into amido linkage reaction, the same getting final product such as reaction conditionss such as temperature of reaction, reaction solvent and above-mentioned steps 5,10.
The The compounds of this invention that makes thus (28) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification.
R when compound (28)
22When not having protecting group, compound (28) is equivalent to compound of the present invention.
R when compound (28)
22And/or R
3When having protecting group, remove its protecting group, can prepare The compounds of this invention (I-5).Protecting group remove can be by document record method (Protective Groups in Organic Synthesis for example, T.W.Green work, the 2nd edition, JohnWiley ﹠amp; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
For example, under the situation of base that needs protection, R
2On when having hydroxyl as substituting group, the protecting group of hydroxyl for example can be a t-butyldimethylsilyl etc., removing of this protecting group can be used for example hydrochloric acid, trifluoroacetic acid, sodium hydroxide, tetrabutylammonium fluoride etc.
An example of compound used therefor in the step 18 (20) is following formula (22)
Compound shown in [in the formula, each mark is represented definition same as described above], this compound can be by following method preparation.
[each mark is identical with above-mentioned definition.]
(step 18-1) this step is by dihalo pyridine compounds (22-1) and the reaction of thio alkoxy sodium, prepares the method for alkylthio pyridine derivate (22-2).
Used dihalo pyridine for example specifically has 2 in this step, 5-dibromo pyridine, 2,5-dichloropyridine, 2,5-diiodopyridine, 5-bromo-2-chloropyridine, 2-chloro-5-iodine pyridine and 5-bromo-2-fluorine pyridine etc.
With respect to 1 equivalent compound (22-1), the amount of used thio alkoxy sodium is generally the 0.1-3 equivalent in this step, preferred 1-2 equivalent.
The object lesson of used thio alkoxy sodium has sulfo-sodium methoxide, thio ethoxy sodium etc.
Used reaction solvent can be an inert solvent for example in this step, only otherwise hinder reaction, then is not particularly limited, and specifically can be N for example, dinethylformamide, tetrahydrofuran (THF), 1-Methyl-2-Pyrrolidone, water etc.
Reaction times in this step is generally 0.5-72 hour, preferred 1-12 hour.
The compound that makes thus (22-2) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(step 18-2) this step is by making above-mentioned steps 18-1 gained compound (22-2) and mCPBA reaction, preparing the method for compound (22) thus.
The oxidizing reaction that is adopted in this step can be by the method the same with above-mentioned steps 3, carry out based on its method or with these methods and ordinary method combination.
The amount of used mCPBA, temperature of reaction, reaction times, reaction solvent all can be by the same with step 3 or be that the method for benchmark is carried out with it in this step.
Used oxygenant can be aqueous hydrogen peroxide solution, sodium wolframate, clorox etc. in this step.
With respect to 1 equivalent compound (22-2), the amount of used oxygenant is generally the 0.1-10 equivalent among the present invention, preferred 1-5 equivalent.
As long as used reaction solvent in this step then can use any solvent to reacting without hindrance, and concrete example is if any acetonitrile, ethanol, methyl alcohol etc.
Can for example concentrate with the compound (22) that obtains thus by known separation purification method, concentrating under reduced pressure, crystallization, redeposition, solvent extraction, chromatography etc. carry out separation and purification.
The compounds of this invention (I-6) can be by following method preparation.
[in the formula, each mark is identical with above-mentioned definition.]
(step 24) this step is in the presence of alkali, makes compound (21) and compound (29) reaction, prepares the method for compound (30) thus.
The X that compound used therefor in this step (29) is had represents the halogen atom in the above-mentioned definition, wherein specifically more preferably bromine atoms, iodine atom.
This step compound used therefor (29) R that is had represents the low alkyl group of above-mentioned definition, wherein specifically more preferably methyl, ethyl, propyl group, sec.-propyl etc.
Used alkali can be for example potassiumphosphate, potassium acetate, potassium tert.-butoxide, triethylamine etc. in this step.
With respect to 1 equivalent compound (21), the amount of used alkali is generally the 0.01-10 equivalent in this step, preferred 0.1-2 equivalent.
In this step, acid chloride (II) or Palladous chloride salt such as (II) palladium and parts such as 2-(di-t-butyl phosphino-) biphenyl or triphenyl phosphine are present in the reaction system jointly.
With respect to 1 equivalent compound (21), the amount of used palladium salt is generally the 0.01-10 equivalent in this step, preferred 0.1-2 equivalent.
With respect to compound (21), the amount of used part is generally the 0.1-10 equivalent in this step, preferred 0.5-2 equivalent.
Temperature of reaction is generally the reflux temperature of room temperature to reaction solvent, and preferred 50 spend the reflux temperature to reaction solvent.
Reaction solvent only otherwise hinder reaction can use any solvent, toluene, 1 for example, 4-diox, N, dinethylformamide, tetrahydrofuran (THF), 1-Methyl-2-Pyrrolidone etc.
Reaction times is generally 0.5-72 hour, preferred 1-12 hour.
The compound that makes thus (30) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(step 25) this step is to remove the hydroxyl protecting group R of gained compound (30) in the above-mentioned steps 24
4, prepare the method for compound (31).Remove the method that the reaction of the hydroxyl protecting group that (30) had can be by above-mentioned document record (Protective Groups inOrganic Synthesis for example, T.W.Green work, the 2nd edition, John Wiley﹠amp; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method, can make up by the method the same, based on its method or with these methods and ordinary method and prepare with above-mentioned steps 19.
The compound that makes thus (31) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(step 26) this step is to make above-mentioned steps 25 gained compound (31) and R
22The OH reaction prepares the method for compound (32) thus.
The reaction that this step adopted is that so-called light prolongs reaction, can be in the presence of phosphine compound and azo-compound, method by document record (Mitsunobu, O work for example, The useof diethyl azodicarboxylate and triphenylphosphine in synthesis andtransformation of natural products, Synthesis, the 1st volume, 1981, p1-28), make up based on its method or with these methods and ordinary method and to carry out.
With respect to 1 equivalent compound (31), the amount of used alkylol cpd (25) is generally the 0.5-10 equivalent in this step, preferred 1-3 equivalent.
Used phosphine compound is generally for example triphenyl phosphine, triethylphosphine etc. in this step.
With respect to 1 equivalent compound (31), the amount of used phosphine compound is generally the 0.5-10 equivalent, preferred 1-3 equivalent.
Used azo-compound can be for example diethyl azodiformate, diisopropyl azodiformate etc.
With respect to 1 equivalent compound (31), the amount of used azo-compound is generally the 0.5-10 equivalent, preferred 1-3 equivalent.
Reaction times of the present invention is generally 1-48 hour, preferred 4-12 hour.
Temperature of reaction in this step is generally 0 reflux temperature of spending to reaction solvent, preferred 15-30 degree.
In this step used reaction solvent only otherwise hinder reaction, then there is no particular limitation as to it, specifically can exemplify tetrahydrofuran (THF), toluene etc.
The compound that makes thus (32) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(step 27) this step is to remove the carboxyl-protecting group that above-claimed cpd (32) is had, and prepares the method for compound (33).This step can make up by the method the same with above-mentioned steps 21 grades, based on its method or with these methods and ordinary method and prepare.
The compound that makes thus (33) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.
(step 28) this step is to make above-mentioned steps 27 gained compounds (33) and the reaction of compound shown in the formula (III), prepares the method for compound (34).
Reaction in this step is the reaction of so-called one-tenth amido linkage, can make up by the method the same with above-mentioned steps 22, based on its method or with these methods and ordinary method to prepare.
The The compounds of this invention that makes thus (34) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification or be used for subsequently step without separation and purification.R in compound (34)
3And/or R
22When not having protecting group, compound (34) is The compounds of this invention.
(step 29) this step is the R in the compound (34) that obtains in above-mentioned steps 28
3And/or R
22When having protecting group, suitably remove its protecting group, prepare the method for The compounds of this invention (I-5).
Reaction in this step can be by document record method (Protective Groups inOrganic Synthesis for example, T.W.Green work, the 2nd edition, John Wiley﹠amp; Sons company, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
The The compounds of this invention that makes thus (I-5) can for example concentrate by known separation purification method, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification.
Can exist with the form of pharmacy acceptable salt by Heteroarylcarbamoylbderivative derivative provided by the invention; described salt can use following formula (I-1) that The compounds of this invention (I) comprised, (I-2), (I-3), (I-4), (I-5) and (I-6), prepares according to ordinary method.
Specifically, when having the basic group that for example is derived from amino, pyridyl etc. in above-mentioned (I-1), (I-2), (I-3), (I-4), (I-5) or the compound molecule (I-6), can use these compounds of acid treatment, make it be transformed into corresponding pharmacy acceptable salt.
Shown in acid salt halogen acid salts such as hydrochloride, hydrofluoride, hydrobromate, hydriodate are for example arranged; Inorganic acid salts such as nitrate, perchlorate, vitriol, phosphoric acid salt, carbonate; Low-grade alkane sulfonates such as mesylate, fluoroform sulphonate, esilate; Arylsulphonate such as benzene sulfonate, tosilate; Organic acid salts such as fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate; And organic acid acid salt such as amino acid such as glutaminate, aspartate.When The compounds of this invention has acidic groups in its group, when for example having carboxyl etc., can make it be transformed into corresponding pharmacy acceptable salt by these compounds being handled with alkali.The example of described base addition salt has an alkali metal salts such as sodium, potassium, alkaline earth salts such as calcium, magnesium, the salt that ammonium salt, guanidine, triethylamine, dicyclohexyl amine etc. are formed by organic bases.And compound of the present invention can also exist with any hydrate of free cpds or its salt or the form of solvate.
When manufacturing was used to prevent or treat the medicine of type ii diabetes or its relevant disease or symptom, formula of the present invention (I) compound can be used in combination formula (I) compound and carrier substance.
The dosage of formula of the present invention (I) compound changes with the character of treatment symptom, selected specific compound and route of administration certainly when being used for prevention or treatment.
Also the susceptibility with age, body weight and each patient changes.Usually the dosage of every day is the about 100mg of the about 0.001mg-of every 1kg body weight, the about 50mg of the preferred about 0.01mg-of every 1kg body weight, and 0.1mg-10mg more preferably from about, this is the amount of single administration or administration several times.Sometimes also need use with the dosage that exceeds this limited field.
As the example of suitable oral administration amount, the dosage of single administration or 2-4 administration of 1 natural gift is at least about 0.01mg to maximum 2.0g.The scope of preferred dosage is 1 day 1 time or divides the about 200mg of about 1.0mg-2 times.More preferably the scope of dosage is 1 day 1 time about 10mg-100mg.
When adopting intravenously administrable or oral administration, representative administration scope is formula (I) compound of per 1 day, the about 100mg of the about 0.001mg-of every 1kg body weight (the preferred about 10mg of 0.01mg-), more preferably per 1 day, formula (I) compound of the about 0.1mg-10mg of every 1kg body weight.
As mentioned above, pharmaceutical composition contains formula (I) compound and pharmaceutically acceptable carrier." composition " this term not only comprises directly or indirectly two or more any compositions combinations, compound or material that cohesion forms, the material that one or more compositions are dissociated and form, perhaps the material that effect or the interaction by other type forms between composition also comprises the activity and the inert fraction (pharmaceutically acceptable vehicle) that constitute carrier.
Preferably, contain formula (I) compound compositions of the significant quantity of treatment, prevention or the morbidity of delay type ii diabetes with pharmaceutically acceptable carrier combinations.
Can adopt any suitable route of administration, give Mammals with the The compounds of this invention of significant quantity, particularly the people.For example, can adopt oral administration, rectal administration, topical, intravenously administrable, administration through eye, through modes such as lung administration, nose administrations.Formulation can be for example tablet, buccal tablet, powder, suspensoid, solution, capsule, ointment, aerosol etc., the tablet that preferred per os uses.
When the preparation per os is used composition, so long as common medicinal medium, then can adopt, its example has water, glycol, oil, alcohol, spice additive, sanitas, tinting material etc., the preparation per os use liquid composition the time, suspensoid, elixir and solution etc. are for example arranged, carrier for example has starch, sugar, Microcrystalline Cellulose, thinner, granulation agent, lubricant, tackiness agent, disintegrating agent etc., the preparation per os use solids composition the time, powder, capsule, tablet etc. are for example arranged, the solids composition that wherein preferred per os is used.
Consider that from the easy degree of administration tablet and capsule are the most favourable per os formulations.If desired, can carry out dressing to tablet by the water-based or the non-aqueous technology of standard.
Except that above-mentioned common formulation, can also be by the controlled release equipment and/or doser giving construction (I) compound of record in the United States Patent (USP) 3,845,770,3,916,899,3,536,809,3,598,123,3,630,200 and 4,008,719 for example.
Be suitable for peroral administration pharmaceutical composition of the present invention as powder or particle,, capsule, cachet or the tablet of the activeconstituents that contains predetermined amount arranged respectively perhaps as water soluble liq, non-water-soluble liquid, oil-in-water emulsion or water-in-oil emulsion.Such composition can adopt any method on the pharmaceutics to prepare, and all methods all comprise the method that activeconstituents and the carrier of being made up of one or more neccessary compositions are combined.
Usually, the solid carrier after activeconstituents and liquid vehicle or the good separation or both evenly and are fully mixed, then if desired, product is made suitable shape, make composition thus.For example, tablet can pass through compression and moulding, and is prepared from one or more minor components as required.Available suitable machinery as required, with binding agent, lubricant, inert excipient, tensio-active agent or dispersant, freely is compressed into powder or particle shape with activeconstituents, thereby makes compressed tablets.
The moulding tablet can be by pulverous humidifying compound and inert liquid diluent mixture with suitable mechanical-moulded the preparation.
Preferred each tablet contains the activeconstituents of the 1mg to 1g that has an appointment, and each cachet or capsule contain the activeconstituents of the 1mg to 500mg that has an appointment.
The formulation of the medical aspect of formula (I) compound is for example described down.
(table 1)
Suspension for injection (I.M.)
| mg/ml | |
| Formula (I) compound | 10 |
| Methylcellulose gum | 5.0 |
| Tween 80 | 0.5 |
| Benzylalcohol | 9.0 |
| Benzalkonium chloride | 1.0 |
Add water for injection, make it reach 1.0ml.
(table 2)
Tablet
| The mg/ sheet | |
| Formula (I) compound | 25 |
| Methylcellulose gum | 415 |
| Tween 80 | 14.0 |
| Benzylalcohol | 43.5 |
| Magnesium Stearate | 2.5 |
Add up to 500mg
(table 3)
Capsule
| Mg/ capsule | |
| Formula (I) compound | 25 |
| Lactose powder | 573.5 |
| Magnesium Stearate | 1.5 |
Add up to 600mg
(table 4)
Aerosol
| Per 1 container | |
| Formula (I) compound | 24mg |
| Yelkin TTS, NF concentrated solution | 1.2mg |
| Trichlorofluoromethane, NF | 4.025g |
| Refrigerant 12, NF | 12.15g |
The compound of formula (I) not only can be used for disease relevant with type ii diabetes or symptom, and can be used in combination with the other medicines of the treatment/prevention/delay that is used for the type ii diabetes morbidity.Described other medicine can be by common used route of administration or dosage, with the administration at the same time or separately of formula (I) compound.
When the compound of formula (I) and one or more medicines use simultaneously, be preferably the pharmaceutical composition that contains formula (I) compound and these other drugs.Therefore, pharmaceutical composition of the present invention also contains one or more other activeconstituentss except that formula (I) compound.As the example of the activeconstituents that can be used in combination with formula (I) compound, can distinguish administration, perhaps equally with the pharmaceutical compositions administration, these examples are not limited to following substances.
(a) biguanides (for example W-37, N1,N1-Dimethylbiguanide, phenformin),
(b) PPAR agonist (for example troglitazone, pioglitazone, rosiglitazone),
(c) Regular Insulin,
(d) somatostatin,
(e) alpha-glucosidase inhibitor (for example voglibose, miglitol, acarbose) and
(f) insulin secretion stimulators (for example acetohexamide, carbutamide, P-607, glibornuride, gliclazide, glimepiride, Glipizide, gliquidone (gliquidine), glisoxepide, Glyburide, glyhexamide, glypinamide, R-131, tolazamide, tolbutamide, tolhexamide, metahexamide, nateglinide, repaglinide).
The weight ratio of formula (I) compound and second kind of activeconstituents can change in very wide scope, and depends on the significant quantity of each activeconstituents.Therefore, when for example formula (I) compound and PPAR agonist being used in combination, the weight ratio of formula (I) compound and PPAR agonist is generally about 1000: 1 to 1: 1000, preferred about 200: 1 to 1: 200.Formula (I) is though the combination of compound and other activeconstituents in above-mentioned scope, regardless of what situation, all should be to use the significant quantity of each activeconstituents.
Below The compounds of this invention (I) shown glucokinase activation energy and test method thereof are described.
The mensuration of the glucokinase activation of above-mentioned formula (I) excellence that compound had, method that can be by document record (for example Diabetes, the 45th volume, the 1671st page-1677 pages, 1996 etc.) or carry out based on its method.
The glucokinase activity is not directly to measure Robison ester, but under glucose-6-phosphate dehydrogenase effect as the report enzyme, when generating phosphogluconolactone, study the activation degree of glucokinase by the amount of measuring the Thio-NADH that is generated by Robison ester.
In this test used recombinant human liver GK with the FLAG fusion rotein at expression in escherichia coli, by ANTIFLAG M2 AFFINITY GEL (Sigma) purifying.
Test uses flat 96 orifice plates to carry out at 30 ℃.Dispensing 69 μ l test damping fluid (25mMHepes damping fluid: pH=7.2,2mM MgCl
2, 1mM ATP, 0.5mM TNAD, 1mM dithiothreitol (DTT)), add the DMSO solution of 1 μ l compound or DMSO in contrast.Dispensing 20 μ l cool off good enzyme mixture (FLAG-GK, 20U/mlG6PDH) in ice subsequently, add 10 μ l25mM glucose as substrate then, begin to react (the glucose final concentration=2.5mM).
After the reaction beginning, measure the increase of absorbancy under the 405nm, measured once, measure 10 minutes, use initial 5 minutes increasing amount that compound is estimated every 30 seconds.Add FLAG-GK, make in the absorbancy increasing amount in the presence of the 1%DMSO, after 5 minutes to reach 0.05-0.1.
OD value with the DMSO contrast is 100%, measures the OD value of compound to be evaluated under each concentration.Calculate Emax (%) and EC50 (μ M) by the OD value of each concentration, be used as the index of the GK activation energy of compound.
Measure the GK activation energy of The compounds of this invention by present method.Its result is as shown in table 5 below.
(table 5)
(the GK activation energy of The compounds of this invention)
| Compound number | Emax(％) | EC50(μM) |
| Preparation example 1 | 957 | 0.25 |
| Preparation example 7 | 844 | 0.08 |
| Preparation example 59 | 936 | 0.53 |
As above shown in the table 5, as index, The compounds of this invention has excellent GK activation energy with the value of Emax and EC50.
The best mode that carries out an invention
Below, by formulation example and preparation example, the present invention further is specifically described, but the present invention is not limited to these examples.
Formulation example 1
With the compound of 10 parts of preparation examples 1,15 parts of heavy-calcined magnesias and 75 parts of lactose uniform mixing, make the following Powdered or fine-grannular powder of 350 μ m.During this powder incapsulated, make capsule.
Formulation example 2
With the compound of 45 parts of preparation examples 1,15 parts of starch, 16 parts of lactose, 21 parts of crystallinity Mierocrystalline celluloses, 3 parts of polyvinyl alcohol and 30 parts of distilled water uniform mixing, pulverize granulation then, drying is sieved subsequently, makes the granule of diameter 1410-177 μ m size.
Formulation example 3
After making granule by the method the same with formulation example 2, add 3 parts of calcium stearates in 96 parts of these granules, the tablet of diameter 10mm is made in compressed moulding.
Formulation example 4
Add 10 parts of crystallinity Mierocrystalline celluloses and 3 parts of calcium stearates in 90 parts of granules that make by the method for formulation example 2, the tablet of diameter 8mm is made in compressed moulding, to wherein adding syrup gelatin, precipitation threshold lime carbonate mixing suspension, makes coated tablet then.
Below by formulation example, preparation example, reference example, the present invention is carried out more specific description, but the present invention is not subjected to any qualification of these examples.
The thin-layer chromatography of embodiment adopts Silicagel 60F
245(Merck), use the UV detector in the detection method as dull and stereotyped.Use Wakogel
TMC-300 (with the pure medicine of light) as post silica gel, uses LC-SORB
TMSP-B-ODS (Chemco) or YMC-GEL
TMODS-AQ120-S50 (mountain village chemistry institute) is as reversed-phase column silica gel.
The connotation of the suspension points among the following embodiment is as follows.
I-Bu: isobutyl-
N-Bu: normal-butyl
T-Bu: the tertiary butyl
Me: methyl
Et: ethyl
Ph: phenyl
I-Pr: sec.-propyl
N-Pr: n-propyl
CDCl
3: heavy chloroform
CD
3OD: heavy methyl alcohol
DMSO-d
6: heavy dimethyl sulfoxide (DMSO)
The connotation of the suspension points in the nuclear magnetic resonance spectrum is as follows.
S: unimodal
D: bimodal
Dd: double doublet
T: triplet
M: multiplet
Br: wide
Q: quartet
J: coupling constant
Hz: hertz
Preparation example 1
The system of 5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-N-(4-methylthiazol-2-yl)-benzamide
Be equipped with
To 20.0g (0.12mol) 3, the dichloromethane solution (1.2 of 5-methyl dihydroxy benzoate
1) add 29.0g molecular sieve 4A, 22.0g (0.13mol) in to methylthio phenyl ylboronic acid, 21.6g (0.13mol) venus crystals (II) and 83.0g (0.59mol) triethylamine, then under oxygen atmosphere one evening of stirring at room.Filtering reacting liquid, concentrating under reduced pressure then, (hexane: ethyl acetate=2: 1) purifying obtains 12.4g (yield: 36%) be the 5-hydroxyl-3-of yellow solid (4-methylthio group phenoxy group) methyl benzoate by silica gel column chromatography with the gained resistates.
To the N of 54.4mg (0.19mmol) gained phenolic compound, add 129mg (0.94mmol) salt of wormwood and 0.053ml (0.56mmol) 2-N-PROPYLE BROMIDE in the dinethylformamide solution (2.5ml), then reaction solution was stirred 4 hours at 80 degree.In reaction solution, add entry, use ethyl acetate extraction, use saturated common salt solution washing organic layer then, drying, concentrating under reduced pressure.(hexane: ethyl acetate=2: 1) purifying obtains 55.4mg (yield: 89%) be the 5-isopropoxy-3-of colorless oil (4-methylthio group phenoxy group) methyl benzoate with silica gel column chromatography with the gained resistates.In the chloroformic solution (2.0ml) of 41.0mg (0.12mmol) gained ester cpds, add 64.0mg (0.37mmol) metachloroperbenzoic acid down ice-cooled, reaction solution was stirred 20 minutes under ice-cooled condition.In reaction solution, add sodium thiosulfate solution, with saturated sodium bicarbonate aqueous solution, saturated common salt solution washing organic layer, dry back concentrating under reduced pressure.(hexane: ethyl acetate=1: 1) purifying obtains 3.9mg (yield: 98%) be the 5-isopropoxy-3-of colorless oil (4-methylsulfonyl phenoxy group) methyl benzoate by silica gel column chromatography with the gained resistates.
In the methanol solution (1.0ml) of 41.0mg (0.11mmol) gained sulphones, add 0.28ml (0.56mmol) 2N aqueous sodium hydroxide solution, reaction solution is stirred a night.In reaction solution, add the 2N aqueous hydrochloric acid, use ethyl acetate extraction,, obtain the crude product of carboxylic compound with saturated common salt solution washing organic layer, concentrating under reduced pressure after the drying.In the dichloromethane solution (0.5ml) of 12.0mg (0.034mmol) gained carboxylic compound, add 5.90mg (0.51mol) 2-amino-4-methylthiazol, 9.30mg (0.068mmol) I-hydroxybenzotriazole hydrate and 13.0mg (0.068mol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, at room temperature stir then and spend the night.The concentrating under reduced pressure reaction solution, (hexane: ethyl acetate=1: 1) purifying obtains the title compound into white solid by silica gel column chromatography with the gained resistates.The analytical data of the compound that makes by preparation example 1 is as follows.
1H NMR(CDCl
3)δ：1.34(6H，d，J＝6.0H z)，2.22(3H，d，J＝0.7H z)，3.08(3H，s)，4.53-4.57(1H，m)，6，57(1H，d，J＝0.7H z)，6.80(1H，t，J＝2.0H z)，7.11(1H，d，J＝2.0H z)，7.12(2H，d，J＝8.8H z)，7.27(1H，d，J＝2.0H z)，7.92(2H，d，J＝8.8Hz)
ESI-MS(m/e)：447[M＋H]
+
Preparation example 2
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzoyl
The preparation of amine
Add in the tetrahydrofuran solution (10ml) of gained 5-hydroxyl-3-in 1.20g (4.13mmol) preparation example 1 (4-methylthio group phenoxy group) methyl benzoate 1.40g (7.40mmol) (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2.00g (7.40mmol) triphenyl phosphine, at ice-cooled 3.20ml (7.40mmol) diethyl azodiformate that adds down, at room temperature stirred 2 hours then.In reaction solution, add entry, use ethyl acetate extraction, with saturated common salt solution washing organic layer, dry back concentrating under reduced pressure.(hexane: ethyl acetate=95: 5) purifying obtains 1.63g (yield: 95%) be the 5-of colorless oil ((1S)-2-(t-butyldimethylsilyloxy base)-1-methyl-oxyethyl group)-3-(4-methylthio group phenoxy group)-methyl benzoate by silica gel column chromatography with the gained resistates.In the chloroformic solution (40ml) of 1.84g (3.97mmol) gained ester cpds, add 2.06g (12.0mmol) metachloroperbenzoic acid down ice-cooled, reaction solution was stirred 0.5 hour down ice-cooled.In reaction solution, add sodium thiosulfate solution,, obtain the crude product of sulphones with saturated sodium bicarbonate aqueous solution, saturated common salt solution washing organic layer, concentrating under reduced pressure after the drying.
In the methanol solution (20ml) of gained sulphones, add 4.00ml (20.0mmol) 5N aqueous sodium hydroxide solution, reaction solution was stirred 1.5 hours.In reaction solution, add 5% aqueous citric acid solution (30ml), use ethyl acetate extraction,, obtain the crude product of carboxylic compound with saturated common salt solution washing organic layer, concentrating under reduced pressure after the drying.In the dichloromethane solution (40ml) of gained carboxylic compound, add 1.20g (12.0mmol) thiazolamine, 1.62g (12.0mmol) I-hydroxybenzotriazole hydrate and 1.53g (8.00mmol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, at room temperature stir then and spend the night.Reaction solution was stirred 1.5 hours.Add entry in reaction solution, use ethyl acetate extraction, with 5% aqueous citric acid solution, saturated common salt solution washing organic layer, drying is concentrating under reduced pressure afterwards, obtains the crude product of amide compound.
To 1 of gained amide compound, add 20ml 4N aqueous hydrochloric acid in the 4-dioxane solution (60ml), at room temperature stirred then 15 minutes.The concentrating under reduced pressure reaction solution adds triethylamine then, once more the concentrating under reduced pressure reaction solution.(hexane: ethyl acetate=1: 2) purifying obtains the title compound into white solid by silica gel column chromatography with the gained resistates.Provide the analytical data of preparation example 2 gained compounds below.
1H NMR(CDCl
3)δ：1.33(d，3H，J＝6.2H z)，3.10(s，3H)，3.80(m，2H)，4.56(m，1H)，6.88(m，1H)，7.03(d，1H，J＝3.6H z)，7.17(d，2H，J＝8.8H z)，7.22(m，1H)，7.38(m，2H)，7.96(d，2H，J＝8.8H z)，10.8(br，1H)
ESI-MS(m/e)：449[M+H]
+
By with above-mentioned preparation example 1 or 2 the same methods, make the compound of following preparation example 3-58.Provide the structure and the analytical data of these compounds below.
Preparation example 3
5-oxyethyl group-3-(4-methylsulfonyl phenoxy group)-N-(4-methoxymethyl-thiazol-2-yl) benzamide
Preparation
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, monobromethane, 2-amino-4-methoxymethyl thiazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 3 of colorless oil with preparation example 1.
1HNMR(CDCl
3)δ：1.45(1H，t，J＝7.0H z)，3.10(3H，s)，3.44(3H，s)，4.10(2H，q，J＝7.0Hz)，4.45(2H，s)，6.85(1H，t，J＝2.0H z)，6.92(1H，s)，7.14(1H，s)，7.15(2H，d，J＝8.8H z)，7.29(1H，s)，7.94(2H，d，J＝8.8Hz)
ESI-MS(m/e)：463[M+H]
+
Preparation example 4
The preparation of 5-cyclopentyloxy-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, cyclopentyl bromide, thiazolamine in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 4 of faint yellow oily thing with preparation example 1.
1HNMR(CDCl
3)δ：1.61-1.93(8H，m)，3.07(3H，s)，4.75-4.79(1H，m)，6.81(1H，d，J＝2.0H z)，6.97(1H，d，J＝3.6H z)，7.13(2H，d，J＝8.6Hz)，7.20(1H，s)，7.21(1H，d，J＝3.6H z)，7.33(1H，d，J＝2.0H z)，7.92(2H，d，J＝8.6Hz)
ESI-MS(m/e)：459[M+H]
+
Preparation example 5
3-(4-methylsulfonyl phenoxy group)-5-(tetrahydrofuran (THF)-3-base oxygen base)-N-thiazol-2-yl-benzamide
Preparation
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 3-hydroxyl tetrahydrofuran, thiazolamine in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 5 of faint yellow oily thing with preparation example 2.
1HNMR(CDCl
3)δ：2.14-2.27(2H，m)，3.08(3H，s)，3.91-3.99(4H，m)，4.96-4.97(1H，m)，6.82(1H，d，J＝1.7H z)，6.99(1H，d，J＝3.6H z)，7.13(2H，d，J＝8.9H z)，7.18(1H，d，J＝3.6H z)，7.25(1H，s)，7.30(1H，d，J＝1.7H z)，7.93(2H，d，J＝8.9H z)
ESI-MS(m/e)：461[M+H]
+
Preparation example 6
3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-1-methyl-oxyethyl group)-N-thiazol-2-yl-benzene first
The preparation of acid amides
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-methoxyl group-2-hydroxy propane and thiazolamine in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 6 with preparation example 2.
1HNMR(CDCl
3)δ：1.31(d、3H，J＝6.3H z)，3.07(s，3H)，3.38(s，3H)，3.55(m，2H)，4.59(m，1H)，6.89(m，1H)，6.98(d，1H，J＝3.6H z)，7.13(d，2H，J＝8.8H z)，7.22(m，1H)，7.25(d，1H，J＝3.6H z)，7.38(m，1H)，7.92(d，2H，J＝8.8Hz)
ESI-MS(m/e)：463[M+H]
+
Preparation example 7
3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-1-methoxymethyl-oxyethyl group)-N-thiazole-2-
The preparation of base-benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1 in the preparation example 1,3-dimethoxy-2-hydroxy propane and thiazolamine, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 7 with preparation example 2.
1HNMR(CDCl
3)δ：3.08(s，3H)，3.39(s，6H)，3.63(d，4H，J＝4.7Hz)，4.57(m，1H)，6.98(m，2H)，7.15(d，2H，J＝8.9H z)，7.27(m，2H)，7.45(m，1H)，7.93(d，2H，J＝8.9Hz)
ESI-MS(m/e)：493[M+H]
+
Preparation example 8
The preparation of 3-(2-fluoro-4-methylsulfonyl phenoxy group)-5-isopropoxy-N-thiazol-2-yl-benzamide
5-hydroxyl-3-(2-fluoro-4-methylsulfonyl phenoxy group) methyl benzoate, 2-N-PROPYLE BROMIDE and thiazolamine that use makes by the method the same with preparation example 1; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 8 of faint yellow oily thing with preparation example 1.
1HNMR(CDCl
3)δ：1.37(6H，d，J＝6.1Hz)，3.11(3H，s)，4.60-4.64(1H，m)，6.81(1H，t，J＝2.2H z)，7.02(1H，d，J＝3.6H z)，7.15(1H，t，J＝2.2H z)，7.21(1H，d d，J＝7，5，8.5H z)，7.31(1H，t，J＝2.2H z)，7.40(1H，d，J＝3.6H z)，7.72(1H，ddd，J＝1.2，2，2，7.5Hz)
ESI-MS(m/e)：451[M+H]
+
Preparation example 9
3-(4-methylsulfonyl phenoxy group)-5-(1-methoxymethyl-propoxy-)-N-(4-methyl-thiazole-2-
Base)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-hydroxyl-1-methyl butyl ether, 2-amino-4-methylthiazol in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 9 of white with preparation example 2.
1HNMR(CDCl
3)δ：0.97(t，3H，J＝7.3H z)，1.71(quintet，2H，J＝7.3Hz)，2.23(s，3H)，3.08(s，3H)，3.36(s，3H)，3.54(m，2H)，4.32(m，1H)，6.56(s，1H)，6.90(m，1H)，7.13(d，2H，J＝8.9H z)，7.15(m，1H)，7.35(m，1H)，7.92(d，2H，J＝8.9H z)，10.6(br，1H)
ESI-MS(m/e)：491[M+H]
+
Preparation example 10
The preparation of 5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-N-pyrazole-3-yl-benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-N-PROPYLE BROMIDE and 3-amino-pyrazol in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 10 of faint yellow oily thing with preparation example 1.
1HNMR(CDCl
3)δ：1.35(d，6H，J＝6.0H z)，3.06(s，3H)，4.58(septet，1H，J＝6.0H z)，6.00(d，1H，J＝3.0Hz)，6.78(m，1H)，7.15(d，2H，J＝8.9H z)，7.32(m，1H)，7.41(m，1H)，7.90(d，2H，J＝8.9H z)，8.14(d，1H，J＝3.0Hz)
ESI-MS(m/e)：416[M+H]
+
Preparation example 11
The preparation of 5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-N-pyrazine-2-base-benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate in the preparation example 1,2-N-PROPYLE BROMIDE, the amino pyrazine of 2-, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 11 of white with preparation example 1.
1HNMR(CDCl
3)δ：1.39(d，6H，J＝6.0H z)，3.09(s，3H)，4.62(septet，1H，J＝6.0H z)，6.82(m，1H)，7.14(m，1H)，7.17(d，2H，J＝8.6H z)，7.39(m，1H)，7.95(d，2H，8.6H z)，8.30(m，1H)，8.41(m，2H)，9.68(brs，1H)
ESI-MS(m/e)：428[M+H]
+
Preparation example 12
3-(4-methylsulfonyl phenoxy group)-5-(3-methoxyl group-1-methyl-propoxy-)-N-thiazol-2-yl-benzene first
The preparation of acid amides
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-bromo-4-methyl butyl ether, thiazolamine in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 12 of white with preparation example 1.
1HNMR(CDCl
3)δ：1.34(d，3H，J＝6.1H z)，1.87(m，1H)，2.02(m，1H)，3.07(s，3H)，3.32(s，3H)，3.50(m，2H)，4.61(m，1H)，6.87(m，1H)，6.98(d，1H，J＝3.4H z)，7.14(d，2H，J＝8.8H z)，7.21(m，1H)，7.25(d，1H，J＝3.4H z)，7.39(m，1H)，7.92(d，2H，J＝8.8H z)，11.6(br，1H)
ESI-MS(m/e)：477[M+H]
+
Preparation example 13
5-(3-hydroxyl-1-methyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzoyl
The preparation of amine
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-3-hydroxyl butane and thiazolamine in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 13 of white with preparation example 2.
1HNMR(CDCl
3)δ：1.39(d，3H，J＝6.1Hz)，1.88(m，1H)，2.02(m，1H)，3.10(s，3H)，3.84(m，2H)，4.71(m，1H)，6.88(m，1H)，7.01(d，1H，J＝3.5Hz)，7.17(d，2H，J＝8.9Hz)，7.24(m，1H)，7.35(d，1H，J＝3.5Hz)，7.48(m，1H)，7.95(d，2H，J＝8.9Hz)，11.0(b r，1H)
ESI-MS(m/e)：463[M+H]
+
Preparation example 14
The preparation of 5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-N-pyrimidine-4-base-benzamide
Use the amino pyrazine of gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-N-PROPYLE BROMIDE and 4-in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 14 of white with preparation example 1.
1HNMR(CDCl
3)δ：1.38(d，6H，J＝6.0H z)，3.90(s，3H)，4.63(septet，1H，J＝6.0H z)，6.83(m，1H)，7.16(m，1H)，7.16(d，2H，J＝8.9H z)，7.29(m，1H)，7.95(d，2H，J＝8.9H z)，8.31(dd，1H，J＝1.2，5.6H z)，8.61(br，1H)，8.70(d，1H，J＝5.6Hz)，8.90(d，1H，J ＝1.2Hz)
ESI-MS(m/e)：428[M+H]
+
Preparation example 15
The preparation of 5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-N-(pyrimidine-2-base)-benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate in the preparation example 1,2-N-PROPYLE BROMIDE, the amino pyrazine of 2-, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 15 of white with preparation example 1.
1HNMR(CDCl
3)δ：1.37(d，6H，J＝6.0Hz)，3.08(s，3H)，4.62(septet，1H，J＝6.0Hz)，6.79(t，1H，J＝2.2Hz)，7.05-7.20(m，4H).7.31(t，1H，J＝2.2Hz)，7.93(d，2H，J＝8.8Hz)，8.60(br，1H)，8.68(d，2H，J＝5.9Hz)
ESI-MS(m/e)：428[M+H]
+
Preparation example 16
N-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-benzoyl
The preparation of amine
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-N-PROPYLE BROMIDE and 2-amino-4-(t-butyldimethylsilyloxy ylmethyl) thiazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 16 of white with preparation example 1.
1HNMR(CDCl
3)δ：1.38(6H，d，J＝6.0Hz)，3.08(3H，s)，4.61-4.65(3H，m)，6.83(1H，t，J＝2.2Hz)，6.87(1H，s)，7.17(2H，d，J＝8.9Hz)，7.18(1H，d，J＝2.0Hz)，7.34(1H，d，J＝2.0Hz)，7.95(2H，d，J＝8.9Hz)
ESI-MS(m/e)：463[M+H]
+
Preparation example 17
N-(isoxazole-3-base)-3-(4-methylsulfonyl phenoxy group)-5-(1-methoxymethyl-propoxy-)-benzene first
The preparation of acid amides
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-hydroxyl-1-methyl butyl ether and 3-ammonia base oxazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 17 of colorless oil with preparation example 2.
1HNMR(CDCl
3)δ：0.99(t，3H，J＝7.5Hz)，1.74(quintet，2H，J＝7.5Hz)，3.01(s，3H)，3.38(s，3H)，3，57(m，2H)，4.39(m，1H)，6.89(m，1H)，7.16-7.12(m，2H)，7.14(d，2H，J＝8.8Hz)，7.32(m，1H)，7.93(d，2H，J＝8，8Hz)，8.33(s，1H，J＝1.9Hz)，8.64(br，1H)
ESI-MS(m/e)：461[M+H]
+
Preparation example 18
3-(4-methylsulfonyl phenoxy group)-5-(1-methoxymethyl-propoxy-)-N-[1,3,4] thiadiazoles-2-base-
The preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-hydroxyl-1-methoxyl group-butane and 2-amino-1 in the preparation example 1,3, the 4-thiadiazoles, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 18 of colorless oil with preparation example 2.
1HNMR(CDCl
3)δ：0.98(t，3H，J＝7.5H z)，1.75(quintet，2H，J＝7.5H z)，3.07(s，3H)，3.37(s，3H)，3.56(m，2H)，4.45(m，1H)，6.93(m，1H)，7.14(d，2H，J＝8.9H z)，7.44(m，1H)，7.53(m，1H)，7.91(d，2H，J＝8.9H z)，8.73(s，1H)，12.0(br，1H)
ESI-MS(m/e)：478[M+H]
+
Preparation example 19
5-(1-hydroxymethyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-(4-methyl-thiazol-2-yl)-
The preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxyl butane and 2-amino-4-methylthiazol in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 19 with preparation example 2.
1HNMR(CDCl
3)δ：0.99(t，3H，J＝7.3Hz)，1.68(m，2H)，2.28(d，3H，J＝1.0Hz)，3.09(s，3H)，3.82(m，2H)，4.36(m，1H)，6.57(d，1H，J＝1.0H z)，6.75(m，1H)，7.11(m，1H)，7.13(d，2H，J＝8.9H z)，7.28(m，1H)，7.93(d，2H，J＝8.9Hz)，10.8(br，1H)
ESI-MS(m/e)：477[M+H]
+
Preparation example 20
N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methylsulfonyl phenoxy group)-5-(1-methoxymethyl-third
The oxygen base)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-hydroxyl-1-methyl butyl ether and 2-amino-4-(t-butyldimethylsilyloxy ylmethyl) thiazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 20 of white with preparation example 2.
1HNMR(CDCl
3)δ：1.01(t，3H，J＝7.5H z)，1.76(quintet，2H，J＝7.5Hz)，3.10(s，3H)，3.40(s，3H)，3.59(m，2H)，4.43(m，1H)，4.64(s，2H)，6.89(s，1H)，6.94(m，1H)，7.18(d，2H，J＝9.0H z)，7.20(m，1H)，7.40(m，1H)，7.96(d，2H，J＝9.0Hz)，10.0(br，1H)
ESI-MS(m/e)：507[M+H]
+
Preparation example 21
5-(2-amino-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzoyl
The preparation of amine
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(tert-butoxycarbonyl amino)-2-hydroxy propane and thiazolamine in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 21 of white with preparation example 2.
1HNMR(CDCl
3)δ：1.30(d，3H，J＝6.0Hz)，2.92(d，2H，J＝6.0Hz)，3.09(s，3H)，4.41(sextet，1H，J＝6.0Hz)，6.86(m，1H)，6.98(d，1H，J＝3.5Hz)，7.14(d，2H，J＝8.9Hz)，7.21(d，1H，J＝3.5Hz)，7.25(m，1H)，7.42(m，1H)8.87(d，2H，J＝8.9Hz)
ESI-MS(m/e)：448[M+H]
+
Preparation example 22
5-(2-dimethylamino-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-
The preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-dimethylamino-2-hydroxy propane and thiazolamine in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 22 of faint yellow oily thing with preparation example 2.
1HNMR(CDCl
3)δ：1.28(d，3H，J＝6.2H z)，2.30(s，6H)，2.42(dd，1H，J＝4.4，13.0Hz)，2.68(dd，1H，J＝6.2Hz，13.0Hz)，3.09(s，3H)，4，56(dt，1H，J＝4.5，6.2Hz)，6.89(m，1H)，7.00(d，1H，J＝3.6H z)，7.15(d，2H，J＝8.9Hz)，7.22(m，1H)，7.28(d，1H，3.6Hz)，7.41(m，1H)，7.93(d，2H，J＝8.9Hz)，11.4(br，1H)
ESI-MS(m/e)：476[M+H]
+
Preparation example 23
5-(2-hydroxyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-(4-methyl-thiazol-2-yl)-benzene first
The preparation of acid amides
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-(t-butyldimethylsilyloxy base)-1-hydroxy propane and 2-amino-4-methylthiazol in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 23 of white with preparation example 2.
1HNMR(CDCl
3)δ：1.28(d，3H，J＝6.4Hz)，2.20(d，3H，J＝1.0Hz)，3.08(s，3H)，3.79(m，1H)，3.93(m，1H)，4.20(m，1H)，6.57(d，1H，J＝1.0Hz)，6.78(m，1H)，7.09(d，2H，J＝8.9Hz)，7.16(m，1H)，7.25(m，1H)，7.92(d，2H，J＝8.9Hz)，11.2(br，1H)
ESI-MS(m/e)：463[M+H]
+
Preparation example 24
3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-propoxy-)-N-(4-methyl-thiazol-2-yl)-benzene
The preparation of methane amide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-hydroxyl-2-methoxy propane and 2-amino-4-methylthiazol in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 24 of colorless oil with preparation example 2.
1NMR(CDCl
3)δ：1.26(d，3H，J＝6.3Hz)，2.22(d，3H，J＝1.1Hz)，3.08(s，3H)，3.43(s，3H)，3.72(m，1H)，3.93(m，2H)，6.57(d，1H，J＝1.1Hz)，6.86(m，1H)，7.12(d，2H，J＝8.6H z)，7.16(m，1H)，7.29(m，1H)，7.92(d，2H，J＝8.6Hz)，10.6(br，1H)
ESI-MS(m/e)：477[M+H]
+
Preparation example 25
5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-N-(thiazole is [5,4-b] pyridine-2-yl also)-benzoyl
The preparation of amine
Use in the preparation example 1 gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-N-PROPYLE BROMIDE and 2-amino-thiazolyl-also [5,4-b] pyridine, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 25 of faint yellow solid with preparation example 1.
1HNMR(CDCl
3)δ：1.37(6H，d，J＝6.0Hz)，3.09(3H，s)，4.59-4.63(1H，m)，6，84(1H，t，J＝1.8Hz)，7.14(2H，d，J＝8.9Hz)，7.19(1H，t，J＝1.8Hz)，7.34(1H，t，J＝1.8Hz)，7.38(1H，dd，J＝4.7，8.1Hz)，7.92(1H，dd，J＝1.5，8.1Hz)，7.94(2H，d，J＝8.9Hz)，8.53(1H，dd，J＝1.5，4.7Hz)
ESI-MS(m/e)：484[M+H]
+
Preparation example 26
5-(2-hydroxymethyl-allyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide
Preparation
1HNMR(CDCl
3)δ：3.08(3H，s)，3.49(2H，s)，4.06(2H，s)，4.91(1H，s)，5.19(1H，s)，7.00(1H，d，J＝3.3Hz)，7.11(2H，d，J＝9.0Hz)，7.13(1H，d，J＝3.3Hz)，7.20(1H，s)，7.55(1H，s)，7.67(1H，s)，7.92(2H，d，J＝9.0Hz)
ESI-MS(m/e)：445[M+H]
+
Preparation example 27
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazole also [5,4-b] pyridine-
The preparation of 2-base-benzamide
Use in the preparation example 1 gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-thiazolyl-also [5,4-b] pyridine, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 27 of faint yellow solid with preparation example 2.
1HNMR(CDCl
3)δ：1.34(6H，d，J＝6.2Hz)，3.11(3H，s)，3.74(2H，d，J＝4.6Hz)，4.57-4.62(1H，m)，6.92(1H，t，J＝1.8Hz)，7.19(2H，d，J＝8.9Hz)，7.36(1H，t，J＝1.8Hz)，7.43(1H，dd，J＝4.7，8.2Hz)，7.49(1H，t，J＝1.8Hz)，7.94(2H，d，J＝8.9Hz)，8.03(1H，dd，J＝1.4，8.2Hz)，8.49(1H，dd，J＝1.4，4.7Hz)
ESI-MS(m/e)：484[M+H]
+
Preparation example 28
5-(3-hydroxy-2-methyl-propyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide
Preparation
1HNMR(CDCl
3)δ：0.94(6H，d，J＝6.7H z)，1.97-2.05(1H，m)，2.50-2.94(2H，m)，3.08(3H，s)，3.50-3.56(2H，m)，7.03(1H，d，J＝3.5Hz)，7.13(2H，d，J＝8.8Hz)，7.17(1H，s)，7.42(1H，d，J＝3.5Hz)，7.52(1H，s)，7.63(1H，s)，7.93(2H，d，J＝8.8Hz)
ESI-MS(m/e)：447[M+H]
+
Preparation example 29
3-(4-methylsulfonyl phenoxy group)-N-(4-methyl-thiazol-2-yl)-5-(piperidin-4-yl-oxygen base)-benzene first
The preparation of amide hydrochloride
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(tert-butoxycarbonyl)-4-hydroxy piperidine and 2-amino-4-methylthiazol in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 29 of white crystals with preparation example 2.
1HNMR(CD
3OD)δ：1.93(m，2H)，2.11(m，2H)，2.31(s，3H)，2.99(s，3H)，3.13(m，2H)，3.30(m，2H)，4.75(m，1H)，6.89(s，1H)，7.11(m，2H，J＝8.9Hz)，7.27(m，1H)，7.52(m，1H)，7.84(d，2H，J＝8.9Hz)
Preparation example 30
5-(1-ethanoyl-piperidin-4-yl oxygen base)-3-(4-methylsulfonyl phenoxy group)-N-(4-methyl-thiazole-2-
Base)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-ethanoyl-4-hydroxy piperidine and 2-amino-4-thiazole in the preparation example 1; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 30 of white with preparation example 2.
1HNMR(CDCl
3)δ：1.80(m，3H)，2.20-2.00(m，2H)，2.14(s，3H)，2.51(s，3H)，3.10(s，3H)，3.50(m，1H)，3.75(m，1H)，4.01(m，1H)，4.84(m，1H)，4.84(m，1H)，6.71(s，1H)，6.92(m，1H)，7.18(d，2H，J＝8.9Hz)，7.43(m，1H)，7.76(m，1H)，7.96(d，2H，J＝8.9Hz)
ESI-MS(m/e)：530[M+H]
+
Preparation example 31
2-[3-(4-methylsulfonyl phenoxy group)-5-(4-methyl-thiazol-2-yl-formamyl)-phenoxy group] third
The preparation of acid
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, the 2 bromopropionic acid tert-butyl ester and 2-amino-4-methylthiazol in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 31 of white crystals with preparation example 1.In addition, when preparing this compound, method that can be by document record (Protective Groups in Organic Synthesis for example, T.W.Green work, the 2nd edition, John Wiley﹠amp; Sons company, 1991, etc.), based on its method or with the combination of these methods and ordinary method, remove the protecting group-tertiary butyl of decarboxylate.
1HNMR(DMSO-d
6)δ：1.53(d，3H，J＝6.8Hz)，2.28(s，3H)，3.27(s，3H)，5.03(septet，1H，J＝6.8Hz)，6.82(m，1H)，6.94(m，1H)，7.25(d，2H，J＝8.8Hz)，7.42(m，1H)，7.50(m，1H)，7.95(d，2H，J＝8.8Hz)
ESI-MS(m/e)：477[M+H]
+
Preparation example 32
5-(3-hydroxyl-1-methyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzoyl
The preparation of amine
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base-3-hydroxyl butane and thiazolamine in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 32 of white with preparation example 2.
1HNMR(CDCl
3)δ：1.35(d，3H，J＝6.0Hz)，1.83(m，1H)，2.00(m，1H)，3.08(s，3H)，3.78(m，2H)，4.65(m，1H)，6.86(m，1H)，6.98(m，1H，J＝3.5Hz)，7.13(d，2H，J＝8.8Hz)，7.21(d，1H，J＝3.5Hz)，7.23(m，1H)，7.45(m，1H，)，7.91(d，2H，J＝8.8Hz)，12.1(br，1H)
ESI-MS(m/e)：463[M+H]
+
Preparation example 33
3-(4-methylsulfonyl phenoxy group)-5-(1-methylamino formyl radical-oxyethyl group)-N-(4-methyl-thiazole-
The 2-yl)-preparation of benzamide
Make gained 2-[3-in the preparation example 31 (4-methylsulfonyl phenoxy group)-5-(4-methyl-thiazol-2-yl-formamyl)-phenoxy group] reaction of propionic acid and methylamine, obtain the compound of white unbodied preparation example 33.Preparation example 31 gained compounds are into the amido linkage reaction with the reaction of methylamine, method that can be by document record (for example, peptide synthetic basis and experiment, spring room letter husband etc., ball is kind, nineteen eighty-three, Comprehensive Organic Synthesis, the 6th volume, PergamonPress society, 1991, etc.), carry out based on its method or with the combination of these methods and ordinary method.
1HNMR(CDCl
3)δ：1.59(s，3H)，2.26(s，3H)，2.86(d，3H，J＝4.7Hz)，3.10(s，3H)，4.73(q，1H，J＝6.6H z)，6.47(br，1H)，6.57(m，1H)，6.83(m，1H)，7.12(d，2H，J＝8.8Hz)，7.22(m，1H)，7.31(m，1H)，7.93(d，2H，J＝8.8H z)，11.0(br，1H)
ESI-MS(m/e)：490[M+H]
+
Preparation example 34
5-(2-acetylamino-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group) N-thiazol-2-yl-
The preparation of benzamide
Convert preparation example 2 gained 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-hydroxyl that (4-methylsulfonyl-phenoxy group)-the N-thiazol-2-yl-benzamide is had to amino; obtain 5-(2-amino-1-methyl-oxyethyl group)-3-(4-methylsulfonyl-phenoxy group)-N-thiazol-2-yl-benzamide thus; make itself and acetic acidreaction, obtain compound into the unbodied preparation example 34 of white.
Hydroxyl can make this methylsulfonyl compound and reaction of sodium azide by converting hydroxyl to methylsulfonyl then to amino conversion reaction, forms trinitride, is undertaken by reduction azido-s such as triphenyl phosphines afterwards.This conversion reaction can pass through Comprehensive OrganicTransformations, Richard C.Larock work, the 2nd edition, John Wiley ﹠amp; Sons company, carries out based on its method or with these methods and ordinary method combination at the method for record such as 1999.
3-(2-amino-1-methyl-oxyethyl group)-5-(4-methylsulfonyl-phenoxy group)-N-thiazol-2-yl-benzamide and the reaction of acetate are into the amido linkage reaction, can make up by the method the same with the one-tenth amido linkage reaction adopted in step 1 or other step, based on its method or with these methods and ordinary method and carry out.
1HNMR(CDCl
3)δ：1.33(d，3H，J＝6.0Hz)，2.03(s，3H)，3.10(s，3H)，3.49(t，2H，J＝5.8Hz)，4.56(sextet，1H，J＝6.0Hz)，5.98(t，1H，J＝5.8Hz)，6.87(m，1H)，7.00(d，1H，J＝3.6Hz)，7.15(d，2H，J＝8.7Hz)，7.28(m，2H)，7.54(m，1H)，7.94(d，2H，J＝8.7Hz)，11.9(br，1H)
ESI-MS(m/e)：490[M+H]
+
Preparation example 35
N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-benzene
The preparation of methane amide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-N-PROPYLE BROMIDE and 2-amino-4-(1-t-butyldimethylsilyloxy base ethyl)-thiazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 35 of white solid with preparation example 1.
1HNMR(CDCl
3)δ：1.38(6H，d，J＝6.0Hz)，1.55-1.60(3H，br)，3.08(3H，s)，4.63(1H，quint，J＝6.0Hz)，4.90(1H，q，J＝6.6Hz)，6.79-6.85(2H，m)，7.16(2H，d，J＝8.8Hz)，7.20(1H，br)，7.36(1H，br)，7.94(2H，d，J＝8.8Hz)
ESI-MS(m/e)：477[M+H]
+
Preparation example 36
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-pyridine-2-base-benzoyl
The preparation of amine
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-aminopyridine in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 36 of white crystals with preparation example 2.
1HNMR(CDCl
3)δ：1.32(3H，d，J＝3.2Hz)，3.08(3H，s)，3.76-3.79(2H，m)，4.57-4.63(1H，m)，6.48(1H，t，J＝2.0Hz)，7.13-7.17(1H，m)，7.15(2H，d，J＝8.8Hz)，7.18(1H，d，J＝2.0Hz)，7.35(1H，d，J＝2.0Hz)，7.76(1H，ddd，J＝1.6，5.1，8.4Hz)，7.93(2H，d，J＝8.8Hz)，8.30(1H，d，J＝5.1Hz)，8.34(1H，d，J＝8.4Hz)
ESI-MS(m/e)：443[M+H]
+
Preparation example 37
The system of 5-(2-hydroxyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide
Be equipped with
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxyl ethane and thiazolamine in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 37 of white with preparation example 2.
1HNMR(CDCl
3)δ：3.10(s，3H)，4.01(t，2H，J＝4.5Hz)，4.14(t，2H，J＝4.5Hz)，6.87(m，1H)，7.02(d，1H，J＝3.0Hz)，7.16(d，2H，J＝8.4Hz)，7.30(m，2H)，7.38(m，1H)，7.95(d，2H，J＝8，4Hz)，11.3( r，1H)
ESI-MS(m/e)：435[M+H]
+
Preparation example 38
5-(2-hydroxyl-cyclopentyloxy)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide
Preparation
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(tert-butyl diphenyl siloxy-)-2-hydroxy-cyclopentane and thiazolamine in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 38 of faint yellow oily thing with preparation example 2.
1HNMR(CDCl
3)δ：1.62-2.08(6H，m)，3.08(3H，s)，4.24-4.30(1H，m)，4.55-4.60(1H，m)，6.87(1H，t，J＝2.0H z)，7.00(1H，d，J＝3.6H z)，7.14(2H，d，J＝8.8H z)，7.25(1H，t，J＝2.0Hz)，7.25(1H，d，J＝3.6Hz)，7.40(1H，t，J＝2.0Hz)，7.93(2H，d，J＝8.8Hz)
ESI-MS(m/e)：475[M+H]
+
Preparation example 39
N-(4-ethanoyl-thiazol-2-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl benzene oxygen
Base)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 4-ethanoyl-thiazolamine in the preparation example 1; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 39 of white with preparation example 2.
1HNMR(CDCl
3)δ：1.32(3H，d，J＝6.2Hz)，2.58(3H，s)，3.10(3H，s)，3.80(2H，d，J＝5.2Hz)，4.63(1H，q，J＝5.6Hz)，6.81-6.89(1H，m)，7.12-7.19(3H，m)，7.38(1H，br)，7.83(1H，d，J＝2.0Hz)，7.95(2H，dd，J＝8.9Hz)
ESI-MS(m/e)：491[M+H]
+
Preparation example 40
5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methylsulfonyl benzene
The oxygen base)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-4-t-butyldimethylsilyloxy ylmethyl thiazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 40 of white solid with preparation example 2.
1HNMR(CDCl
3)δ：1.31(3H，d，J＝6.2Hz)，3.09(3H，s)，3.75-3.80(2H，m)，4.55-4.66(3H，m)，6.83-6.86(1H，m)，6.88(1H，s)，7.12-7.20(3H，m)，7.33-7.36(1H，m)，7.94(2H，d，J＝8.6Hz)
ESI-MS(m/e)：479[M+H]
+
Preparation example 41
N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl
Phenoxyl)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-4-(1-t-butyldimethylsilyloxy base ethyl) thiazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 41 of faint yellow oily thing with preparation example 2.
1HNMR(CDCl
3)δ：1.31(3H，d，J＝6.2Hz)，1.49(3H，d，J＝6.5Hz)，3.12(3H，s)，3.68(2H，d，J＝5.0Hz)，4.60(1H，q，J＝6.2Hz)，4.80-4.90(1H，m)，6.94(1H，s)，6.96-6.99(1H，m)，7.23(2H，d，J＝8.9Hz)，7.29-7.32(1H，m)，7.47-7.50(1H，m)，7.89(1H，s)，7.96(2H，d，J＝8.9Hz)
ESI-MS(m/e)：493[M+H]
+
Preparation example 42
3-(3-fluoro-4-methylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-thiazol-2-yl-benzene
The preparation of methane amide
In the pyridine solution (50.0ml) of 9.00g (0.43mol) 5-hydroxyl-3-methoxymethoxy methyl benzoate, add 20.4g (0.68mol) 1-bromo-2-fluoro-4-iodobenzene, 20.8g (0.64mol) cesium carbonate and 5.07g (0.64mol) cupric oxide (II), under nitrogen atmosphere, stirred 8 hours then in 130 degree.Filtering reacting liquid, concentrating under reduced pressure adds ethyl acetate and saturated aqueous ammonium chloride in the gained resistates then, with saturated common salt solution washing organic layer, dry back concentrating under reduced pressure.(hexane: ethyl acetate=9: 1) purifying obtains 10.6g (yield: 65%) be the 3-of yellow oil (4-bromo-3-fluoro-phenoxy group)-5-methoxymethoxy methyl benzoate by silica gel column chromatography with the gained resistates.
In the dimethyl sulphoxide solution (6.0ml) of 357mg (0.93mmol) gained ester cpds, add 757mg (7.41mmol) methyl-sulfinic acid sodium and 1.41g (7.41mmol) cupric iodide, then reaction solution was stirred 6 hours at 120 degree.In reaction solution, add sodium chloride aqueous solution/ammoniacal liquor (9: 1), use ethyl acetate extraction, with saturated common salt solution washing organic layer, dry back concentrating under reduced pressure.(hexane: ethyl acetate=2: 1) purifying obtains 170mg (yield: 48%) be the 3-of colorless oil (3-fluoro-4-methylsulfonyl-phenoxy group)-5-methoxymethoxy methyl benzoate by silica gel column chromatography with the gained resistates.
In the dichloromethane solution (60.0ml) of 3.34g (8.69mmol) gained ester cpds, add the 30.0ml trifluoroacetic acid, reaction solution was at room temperature stirred 2 hours.The concentrating under reduced pressure reaction solution, (hexane: ethyl acetate=3: 7) purifying obtains 2.59g (yield: 88%) be the 3-of colorless oil (3-fluoro-4-methylsulfonyl-phenoxy group)-5-methyl hydroxybenzoate by silica gel column chromatography with the gained resistates.
In the tetrahydrofuran solution (1.0ml) of 77.5mg (0.23mmol) gained phenolic compound, add 87.0mg (0.46mmol) (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 119mg (0.46mmol) triphenyl phosphine, 40% toluene solution that adds 0.25ml (0.57mmol) diethyl azodiformate then at room temperature stirs and spends the night.The concentrating under reduced pressure reaction solution; (hexane: ethyl acetate=2: 1) purifying obtains 80.0mg (yield: 69%) be the 5-of colorless oil ((1S)-2-(t-butyldimethylsilyloxy base)-1-methyl-oxyethyl group)-3-(3-fluoro-4-methylsulfonyl-phenoxy group)-methyl benzoate by silica gel column chromatography with the gained resistates.
Use gained 5-((1S)-2-(t-butyldimethylsilyloxy base)-1-methyl-oxyethyl group)-3-(3-fluoro-4-methylsulfonyl-phenoxy group)-methyl benzoate and thiazolamine; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 42 of colorless oil with preparation example 2.
1HNMR(CDCl
3)δ：1.32(3H，d，J＝6.3Hz)，3.23(3H，s)，3.78-3.80(2H，m)，4.56-4.61(1H，m)，6.83-6.94(3H，m)，7.01(1H，d，J＝3.5Hz)，7.23(1H，t，J＝1.8Hz)，7.37(1H，d，J＝3.5Hz)，7.41(1H，t，J＝1.8Hz)，7.94(1H，t，J＝8.2Hz)ESI-MS(m/e)：467[M+H]
+
Preparation example 43
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(5-methyl-thiazol-2-yl)
The preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-5-methylthiazol in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 43 of faint yellow oily thing with preparation example 2.
1HNMR(CDCl
3)δ：1.29(3H，d，J＝6.2Hz)，2.37(3H，s)，3.08(2H，s)，3.69-3.76(2H，m)，4.52-4.57(1H，m)，6.82(1H，t，J＝2.0Hz)，6.88(1H，s)，7.12(2H，d，J＝8.8Hz)，7.20(1H，d，J＝2.0Hz)，7.35(1H，d，J＝2.0Hz)，7.92(2H，d，J＝8.8Hz)
ESI-MS(m/e)：463[M+H]
+
Preparation example 44
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-([1,2,4] thiadiazoles-5-
Base)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 5-amino-1 in the preparation example 1,2, the 4-thiadiazoles, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 44 of faint yellow oily thing with preparation example 2.
1HNMR(CDCl
3)δ：1.30(3H，d，J＝6.2Hz)，3.12(3H，s)，3.68(2H，d，J＝5.1Hz)，4.58-4.85(1H，m)，7.00(1H，s)，7.23(2H，d，J＝8.9Hz)，7.37(1H，s)，7.56(1H，s)，7.95(2H，d，J＝8.9Hz)，8.37(1H，s)
ESI-MS(m/e)：450[M+H]
+
Preparation example 45
N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-1-methyl-
Oxyethyl group)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-hydroxyl-1-methoxy propane and 2-amino-4-t-butyldimethylsilyloxy ylmethyl thiazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 45 with preparation example 2.
1HNMR(CDCl
3)δ：1.35(3H，d，J＝6.3Hz)，3.09(3H，s)，3.41(3H，s)，3.49-3.64(2H，m)，4.58-4.67(3H，m)，6.87-6.92(2H，m)，7.13-7.20(3H，m)，7.35-7.38(1H，br)，7.94(2H，d，J＝8.8Hz)
ESI-MS(m/e)：493[M+H]
+
Preparation example 46
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(5-methoxycarbonyl-pyrrole
Pyridine-2-yl)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-5-methoxycarbonyl pyridine in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 46 of white with preparation example 2.
1HNMR(CDCl
3)δ：1.34(d，3H，J＝6.0Hz)，3.10(s，3H)，3.80(m，2H)，3.96(s，3H)，4.61(m，1H)，6.80(m，1H)，7.16(d，2H，J＝8.8Hz)，7.20(m，1H)，7.37(m，1H)，7.94(d，2H，J＝8.8Hz)，8.33-8.46(m，2H)，8.80(br，1H)，8.93(m，1H)
ESI-MS(m/e)：501[M+H]
+
Preparation example 47
6-[5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-benzoyl-amido] preparation of nicotinic acid
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 6-amino-nicotinic acid in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 47 of white solid with preparation example 2.
1HNMR(DMSO-d
6)δ：1.29(d，6H，J＝6.0Hz)，3.20(s，3H)，4.76(septet，1H，J＝6.0Hz)，6.94(m，1H)，7.23(d，2H，J＝8.8Hz)，7.33(m，1H)，7.49(m，1H)，7.94(d，2H，J＝8.8Hz)，8.29(m，2H)，8.87(m，1H)，11.2(s，1H)
ESI-MS(m/e)：471[M+H]
+
Preparation example 48
5-(2-hydroxyl-1-methyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzoyl
The preparation of amine
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-(t-butyldimethylsilyloxy base-3-hydroxyl) butane and thiazolamine in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 48 of faint yellow oily thing with preparation example 2.
1HNMR(CDCl
3)δ：1.25(s，3H，J＝6.2Hz)，1.28(s，3H，J＝6.2Hz)，3.08(s，3H)，3.87(m，1H)，4.22(m，1H)，6.85(m，1H)，6.99(m，1H)，7.13(d，2H，J＝8.8Hz)，7.23(m，2H)，7.38(m，1H)，7.92(d，2H，J＝8.8Hz)，12,0(br，1H)
ESI-MS(m/e)：463[M+H]
+
Preparation example 49
5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(isoxazole-3-base)-3-(4-methylsulfonyl phenoxy group)-benzene
The preparation of methane amide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-ammonia base oxazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 49 of white with preparation example 2.
1HNMR(CDCl
3)δ：1.32(d，3H，J＝6.0Hz)，2.04(br，1H)，3.08(s，3H)，3.77(m，2H)，4.60(m，1H)，6.87(m，1H)，7.15(d，2H，J＝8.8Hz)，7.19(m，2H)，7.35(m，1H)，7.94(d，2H，J＝8.8Hz)，8.30(d，1H，J＝1.6Hz)，9.24(br，1H)
ESI-MS(m/e)：433[M+H]
+
Preparation example 50
N-(5-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methylsulfonyl phenoxy group)-benzoyl
The preparation of amine
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-N-PROPYLE BROMIDE and 2-amino-5-formyl thiazole in the preparation example 1; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 50 of faint yellow oily thing with preparation example 1.
1HNMR(CDCl
3)δ：1.36(d，6H，J＝6.0Hz)，3.08(s，3H)，4.59(septet，1H，J＝6.0Hz)，4.79(s，2H)，6.82(s，1H)，7.14(d，2H，J＝8.4Hz)，7.13-1.18(m，2H)，7.31(s，1H)，7.92(d，2H，J＝8.4Hz)，11.2(br，1H)
ESI-MS(m/e)：463[M+H]
+
Preparation example 51
N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-1-
Methyl-oxyethyl group)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-methoxyl group-2-hydroxy propane and 2-amino-4-(1-t-butyldimethylsilyloxy base ethyl) thiazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 51 with preparation example 2.
1HNMR(CDCl
3)δ：1.35(3H，d，J＝6.3Hz)，1.55(3H，d，J＝6.3Hz)，3.08(3H，s)，3.41(3H，s)，3.49-3.64(2H，m)，4.59-4.70(1H，m)，4.90(1H，q，J＝6.3Hz)，6.80(1H，brs)，6.90(1H，br)，7.16(2H，d，J＝8.9Hz)，7.23-7.26(1H，br)，7.42(1H，brs)，7.94(2H，d，J＝8.9Hz)
ESI-MS(m/e)：507[M+H]
+
Preparation example 52
N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methylsulfonyl phenoxy group)-5-(tetrahydrofuran (THF)-3-base-oxygen
Base)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 3-hydroxyl tetrahydrofuran and 2-amino-4-t-butyldimethylsilyloxy ylmethyl thiazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 52 with preparation example 2.
1HNMR(CDCl
3)δ：2.10-2.36(2H，m)，3.09(3H，s)，3.39-4.07(4H，m)，4.66(2H，s)，4.96-5.05(1H，m)，6.84(1H，t，J＝2.0Hz)，7.15-7.20(3H，m)，7.30(1H，br)，7.96(2H，d，J＝8.8Hz)
ESI-MS(m/e)：491[M+H]
+
Preparation example 53
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(2-methylthiazol-4-yl)-
The preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 4-amino-2-methyl thiazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 53 of white with preparation example 2.
1HNMR(CDCl
3)δ：1.32(d，3H，J＝6.0Hz)，2.31(br，1H)，2.66(s，3H)，3.09(s，3H)，3.78(m，2H)，4.59(m，1H)，7.13-7.16(m，1H)，7.15(d，2H，J＝8.8Hz)，7.32(m，1H)，7.60(s，1H)，7.94(d，2H，J＝8.8Hz)，8.90(br，1H)
ESI-MS(m/e)：463[M+H]
+
Preparation example 54
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(4-methoxymethyl-thiophene
Azoles-2-yl)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-4-methoxymethyl thiazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 54 of white with preparation example 2.
1HNMR(CDCl
3)δ：1.31(d，3H，J＝6.0Hz)，3.09(s，3H)，3.42(s，3H)，3.78(m，2H)，4.44(m，2H)，4.57(m，1H)，6.86(m，1H)，6，91(s，1H)，7.10-7.26(m，3H)，7.31(m，1H)，7.97(d，2H，J＝8.9Hz)，9.67(br，1H)
ESI-MS(m/e)：493[M+H]
+
Preparation example 55
N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-1-
Methyl-oxyethyl group)-preparation of benzamide (diastereomer of preparation example 51)
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 2-hydroxyl-1-methoxy propane and 2-amino-4-(1-t-butyldimethylsilyloxy base ethyl) thiazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 55 of white with preparation example 2.
1H NMR(CDCl
3)δ：1.35(3H，d，J＝6.3Hz)，1.55(3H，d，J＝6.3Hz)，3.08(3H，s)，3.41(3H，s)，3.49-3.64(2H，m)，4.59-4.70(1H，m)，4.90(1H，q，J＝6.3Hz)，6.80(1H，brs)，6.90(1H，br)，7.16(2H，d，J＝8.9Hz)，7.23-7.26(1H，br)，7.42(1H，brs)，7.94(2H，d，J＝8.9Hz)
ESI-MS(m/e)：507[M+H]
+
Preparation example 56
N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-3-(4-methylsulfonyl phenoxy group)-5-(tetrahydrofuran (THF)-3-
Base-oxygen base)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 3-hydroxyl tetrahydrofuran and 2-amino-4-(1-t-butyldimethylsilyloxy base ethyl) thiazole in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 56 of white solid with preparation example 2.
1H NMR(CDCl
3)δ：2.10-2.36(2H，m)，0.39(3H，s)，3.89-4.07(4H，m)，4.85-4.95(1H，m)，4.97-5.04(1H，m)，6.81-6.85(2H，m)，7.16(2H，d，J＝8.7Hz)，7.23(1H，brs)，7.34(1H，brs)，7.96(2H，d，J＝8.7Hz)
ESI-MS(m/e)：505[M+H]
+
Preparation example 57
N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-3-(4-methylsulfonyl phenoxy group)-5-(tetrahydrofuran (THF)-3-
Base-oxygen base)-preparation of benzamide (diastereomer of preparation example 56)
By the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 57 of white solid with preparation example 56.
1H NMR(CDCl
3)δ：2.10-2.35(2H，m)，3.09(3H，s)，3.89-4.06(4H，m)，4.86-4.95(1H，m)，4.97-5.05(1H，m)，6.81-6.85(2H，m)，7.16(2H，d，J＝8.7Hz)，7.22(1H，b r s)，7.34(1H，brs)，7.96(2H，d，J＝8.7Hz)
ESI-MS(m/e)：505[M+H]
+
Preparation example 58
N-(2,5-dimethylthiazole-4-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl benzene oxygen
Base)-preparation of benzamide
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 4-amino-2 in the preparation example 1, the 5-dimethylthiazole, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 58 of faint yellow oily thing with preparation example 2.
1H NMR(CDCl
3)δ：1.28(d，3H，J＝6.0Hz)，2.32(s，3H)，2.56(s，3H)，3.07(s，3H)，3.72(m，2H)，4.53(m，1H)，6.79(t，1H，J＝2.0Hz)，7.08(dd，2H，J＝2.0，6.8Hz)，7.18(s，1H)，7.32(s，1H)，7.89(dd，2H，J＝2.0，6.8Hz)，8.67(br，1H)
ESI-MS(m/e)：477[M+H]
+
Preparation example 59
5-isopropoxy-3-(4-methoxycarbonyl amino methyl phenoxy group)-N-thiazol-2-yl-benzamide
Preparation
To 25.0g (0.15mol) 3, add 41.0g (0.30mmol) salt of wormwood and 23.8g (0.19mmol) 2-N-PROPYLE BROMIDE among the N of 5-methyl dihydroxy benzoate, dinethylformamide solution (250ml), then reaction solution was stirred 4 hours at 80 degree.In reaction solution, add entry, use ethyl acetate extraction, use saturated common salt solution washing organic layer then, dry back concentrating under reduced pressure.(hexane: ethyl acetate=5: 1) purifying obtains 12.0g (yield: 38%) be the 5-hydroxyl of colorless oil-3-isopropoxy methyl benzoate with silica gel column chromatography with the gained resistates.
In the dichloromethane solution (30ml) of 700mg (3.30mmol) gained phenolic compound, add 1.05g molecular sieve 4A, 1.00g (6.70mol) to formyl radical phenyl-boron dihydroxide, 605mg (3.30mol) venus crystals (II) and 2.32ml (16.6mol) triethylamine, then under oxygen atmosphere one evening of stirring at room.Filtering reacting liquid, concentrating under reduced pressure then, (hexane: ethyl acetate=5: 1) purifying obtains 593mg (yield: 57%) be the 3-of colorless oil (4-formyl radical phenoxy group)-5-isopropoxy methyl benzoate by silica gel column chromatography with the gained resistates.
In the methanol solution (20ml) of 590mg (1.88mmol) gained formylation compound, add 85.0mg (2.25mmol) sodium borohydride, then reaction solution was at room temperature stirred 16 hours.Concentration of reaction solution adds saturated sodium bicarbonate aqueous solution then, uses chloroform extraction, with concentrating under reduced pressure after the organic layer drying.(hexane: ethyl acetate=2: 1) purifying obtains 567mg (yield: 95%) be the 3-of colorless oil (4-hydroxymethyl phenoxy group)-5-isopropoxy methyl benzoate by silica gel column chromatography with the gained resistates.
In the chloroformic solution (10ml) of 200mg (0.63mmol) gained alkylol cpd, add 0.18ml (1.26mmol) triethylamine and 0.073ml (0.95mmol) methylsulfonyl chloride, reaction solution was stirred 15 minutes at 50 degree.In reaction solution, add saturated sodium bicarbonate aqueous solution, use chloroform extraction, with concentrating under reduced pressure after the organic layer drying.In the gained resistates, add 5.0ml DMF and dissolving, add 123mg (1.90mmol) sodiumazide, stirred 1 hour at 80 degree.In reaction solution, add entry, use ethyl acetate extraction,, obtain the crude product of trinitride concentrating under reduced pressure after the organic layer drying.
In tetrahydrofuran (THF)/water (10: 1) solution (11ml) of gained trinitride, add 247mg (1.26mmol) triphenyl phosphine, reaction solution was stirred 14 hours at 90 degree.In reaction solution, add the 2N aqueous hydrochloric acid, form acidic aqueous solution.With the ethyl acetate washing, in water layer, add the 4N aqueous sodium hydroxide solution then, form alkaline aqueous solution, use chloroform extraction afterwards, dry organic layer, concentrating under reduced pressure obtains 67.8mg (yield: the crude product of amine compound 34%) afterwards.
In the chloroformic solution (5.0ml) of gained amine compound, add 0.057ml (0.41mmol) triethylamine and 0.024ml (0.31mmol) methyl-chloroformate, at room temperature stirred 1 hour.In reaction solution, add saturated sodium bicarbonate aqueous solution, use chloroform extraction then, dry organic layer, concentrating under reduced pressure afterwards obtains the methoxycarbonyl amino methyl compound of crude product form.
In tetrahydrofuran (THF)/methyl alcohol (5: 3) solution (8.0ml) of gained methoxycarbonyl amino methyl compound, add 1.0ml (4.00mmol) 4N aqueous sodium hydroxide solution, reaction solution is stirred at 50 degree spend the night.In reaction solution, add saturated aqueous ammonium chloride, use chloroform extraction, dry organic layer, concentrating under reduced pressure then, (chloroform: purifying methyl alcohol=30: 1) obtains 63.1mg (yield: 85) be the 5-isopropoxy-3-of white solid (4-methoxycarbonyl amino methyl phenoxy group)-phenylformic acid by silica gel column chromatography with the gained resistates.
N to the gained carboxylic compound, add 33.0mg (0.33mol) thiazolamine, 76.0mg (0.49mmol) I-hydroxybenzotriazole hydrate and 63.0mg (0.33mol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride in the dinethylformamide solution (3.0ml), at room temperature stir then and spend the night.In reaction solution, add entry, use ethyl acetate extraction, the concentrating under reduced pressure reaction solution, (chloroform: purifying methyl alcohol=100: 1) obtains the title compound into white solid by silica gel column chromatography with the gained resistates.The analytical data of the compound that makes by preparation example 59 is as follows.
1H NMR(CDCl
3)δ：1.34(6H，d，J＝6.0Hz)，3.71(3H，s)，4.36(2H，d，J＝5.5Hz)，4.57(1H，m)，4.99-5.10(1H，br)，6.75(1H，brs)，6.96-7.05(4H，m)，7.20(1H，br)，7.27-7.34(3H，m)，10.70-10.88(1H，br)
ESI-MS(m/e)：442[M+H]
+
By the method the same, make the compound of preparation example 60-64 with above-mentioned preparation example 59.The structure and the analytical data of these compounds are as follows.
Preparation example 60
The system of 5-isopropoxy-3-(4-methylamino formyl radical-phenoxy group)-N-thiazol-2-yl-benzamide
Be equipped with
Formyl radical oxidation with gained 3-in the preparation example 59 (4-formyl radical phenoxy group)-5-isopropoxy methyl benzoate; make gained 3-(4-carboxyl phenoxy group)-5-isopropoxy methyl benzoate and methylamine carry out condensation reaction; use 3-(4-methylamino formyl radical phenoxy group)-5-isopropoxy methyl benzoate and the thiazolamine that obtains thus; by the method the same, based on its method or the method identical, make compound into colourless unbodied preparation example 60 with these methods with preparation example 2.
1H NMR(CDCl
3)δ：1.36(6H，d，J＝6.1Hz)，3.00(3H，d，J＝4.8Hz)，4.58(1H，m)，6.12-6.21(1H，br)，6.79(1H，t.J＝2.2Hz)，6.99-7.06(4H，m)，7.24-7.27(1H，m)，7.34(1H，d，J＝3.6Hz)，7.72(2H，m)
ESI-MS(m/e)：412[M+H]
+
Preparation example 61
3-(4-formyl-dimethylamino-phenoxy group)-5-isopropoxy-N-thiazol-2-yl-benzamide
Preparation
Use preparation example 60 gained 3-(4-carboxyl phenoxy group)-5-isopropoxy methyl benzoate, dimethylamine and thiazolamine, by the method the same, based on its method or the method identical, make compound into colourless unbodied preparation example 61 with these methods with preparation example 60.
1H NMR(CDCl
3)δ：1.34(6H，d，J＝6.0Hz)，2.98-3.15(6H，br)，4.56(1H，m)，6.78(1H，t，J＝2.3Hz)，6.98(1H，d，J＝3.6Hz)，7.00-7.06(2H，m)，7.14-7.17(1H，m)，7.24-7.28(2H，m)，7.40-7.47(2H，m)
ESI-MS(m/e)：426[M+H]
+
Preparation example 62
5-isopropoxy-3-(4-methyl carbonylamino methyl-phenoxy group)-N-thiazol-2-yl-benzamide
Preparation
Use preparation example 59 gained 3-(4-amino methyl phenoxy group)-5-isopropoxy methyl benzoate, Acetyl Chloride 98Min. and thiazolamine, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 62 with preparation example 59.
1H NMR(CDCl
3)δ：1.35(6H，d，J＝6.0Hz)，2.05(3H，s)，4.40(2H，d，J＝5.6Hz)，4.57(1H，m)，5.95-6.07(1H，br)，6.78(1H，t，J＝2.2Hz)，6.93-7.02(4H，m)，7.20-7.32(4H，m)
ESI-MS(m/e)：426[M+H]
+
Preparation example 63
5-isopropoxy-3-(4-methylsulfonyl amino methyl-phenoxy group)-N-thiazol-2-yl-benzamide
Preparation
Use preparation example 59 gained 3-(4-amino methyl phenoxy group)-5-isopropoxy methyl benzoate, methylsulfonyl chloride and thiazolamine, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 63 with preparation example 59.
1H NMR(CDCl
3)δ：1.36(6H，d，J＝6.0Hz)，2.94(3H，s)，4.32(2H，d，J＝6.1Hz)，4.60(1H，m)，4.79-4.88(1H，m)，6.77(1H，m)，6.98-7.38(8H，m)
ESI-MS(m/e)：462[M+H]
+
Preparation example 64
3-[4-(1-hydroxyl-propyl group)-phenoxy group]-preparation of 5-isopropoxy-N-thiazol-2-yl-benzamide
Use preparation example 59 gained 3-(4-formyl radical phenoxy group)-5-isopropoxy methyl benzoate, ethyl-magnesium-bromide and thiazolamine; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 64 with preparation example 59.The reaction of 3-(4-formyl radical phenoxy group)-5-isopropoxy methyl benzoate and ethyl-magnesium-bromide is so-called Grignard reaction; method that can be by document record (Comprehensive Organic Transformations for example; works such as Richard L; VCHPblishers; 1988, etc.), carry out based on its method or with the combination of these methods and ordinary method.
1H NMR(CDCl
3)δ：0.92(3H，t，J＝7.4Hz)，1.34(6H，d，J＝6.1Hz)，1.67-1.88(2H，m)，4.51-4.63(2H，m)，6.76(1H，t，J＝2.3Hz)，6.95-7.07(3H，m)，7.04-7.07(1H，m)，7.20-7.24(2H，m)，7.32(2H，d，J＝8.5Hz)
ESI-MS(m/e)：413[M+H]
+
Preparation example 65
6-[3-isopropoxy-5-(thiazol-2-yl formamyl)-phenoxy group]-preparation of nicotinic acid methyl ester
In the methanol solution (50ml) of 3.0g (14.3mmol) preparation example 59 gained 5-hydroxyls-3-isopropoxy methyl benzoate, add 10ml 4N aqueous sodium hydroxide solution, at room temperature stirred 12 hours.The concentrating under reduced pressure reaction solution adds saturated aqueous ammonium chloride then, uses chloroform extraction, with concentrating under reduced pressure after the organic layer drying.(chloroform: purifying methyl alcohol=50: 1) obtains 2.44g (yield: 87%) be the 5-hydroxyl of white solid-3-isopropoxy phenylformic acid by silica gel column chromatography with the gained resistates.
Under ice-cooled, in the chloroformic solution (50ml) of 2.40g (12.2mmol) gained carboxylic acid, add 2.45g (24.5mmol) thiazolamine, 3.40ml (24.5mmol) triethylamine, 4.14g (24.5mmol) chlorination 2-chloro-1, the 3-methylimidazole at room temperature stirred 13 hours.In reaction solution, add saturated aqueous ammonium chloride, use chloroform extraction, concentrating under reduced pressure behind the dry organic layer.In the methanol solution (40ml) of gained resistates, add 10ml 4N aqueous sodium hydroxide solution, at room temperature stirred 1 hour.Behind the concentrating under reduced pressure reaction solution, add saturated aqueous ammonium chloride, use chloroform extraction, dry organic layer, concentrating under reduced pressure then.(chloroform: purifying methyl alcohol=100: 1) obtains 1.81g (yield: 53%) be the 5-hydroxyl of white solid-3-isopropoxy-N-thiazol-2-yl-benzamide by silica gel column chromatography with the gained resistates.
To the N of 100mg (0.36mmol) gained amide compound, add 123mg (0.72mmol) 6-chlorine apellagrin methyl esters, 199mg (1.44mmol) salt of wormwood in the dinethylformamide solution (10.0ml), under nitrogen atmosphere, stirred 18 hours in 80 degree.In reaction solution, add entry, use ethyl acetate extraction, with concentrating under reduced pressure after the organic layer drying.(hexane: ethyl acetate=3: 1) purifying obtains the title compound into white solid by silica gel column chromatography with the gained resistates.The analytical data of the compound that makes by preparation example 65 is as follows.
1H NMR(CDCl
3)δ：1.36(6H，d，J＝6.0Hz)，3.93(3H，s)，4.60(1H，m)，6.91-7.02(3H，m)，7.29-7.40(3H，m)，8.31(1H，dd，J＝8.6，2.4Hz)，8.81(1H，d，J＝2.4Hz)
ESI-MS(m/e)：414[M+H]
+
Preparation example 66
3-(5-hydroxymethyl-pyridine-2-base-oxygen base)-5-isopropoxy-N-thiazol-2-yl-benzamide
Preparation
Under ice-cooled; to 60.0mg (0.15mmol) preparation example 65 gained 6-[3-isopropoxy-5-(thiazol-2-yl formamyl)-phenoxy groups]-add 6.0mg (0.16mmol) lithium aluminum hydride in the tetrahydrofuran solution (5.0ml) of nicotinic acid methyl ester, stirred 1 hour at 0 degree.In reaction solution, add saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction, concentrating under reduced pressure behind the dry organic layer.(chloroform: purifying methyl alcohol=30: 1) obtains the title compound into white solid by silica gel column chromatography with the gained resistates.The analytical data of the compound that obtains by preparation example 66 is as follows.
1H NMR(CDCl
3)δ：1.36(6H，d，J＝6.0Hz)，4.54-4.64(1H，m)，4.68(2H，s)，6.90(1H，t，J＝2.1Hz)，6.92-6.98(2H，m)，7.22(1H，t，J＝1.7Hz)，7.31-7.37(2H，m)，7.77(1H，dd，J＝2.8，8.3Hz)，8.14(1H，br)
ESI-MS(m/e)：386[M+H]
+
By with above-mentioned preparation example 65 or 66 the same methods, obtained the compound of Production Example 67-73.The analytical data of these compounds is as follows.
Preparation example 67
The preparation of 5-isopropoxy-3-(5-methylsulfonyl pyridine-2-yl)-N-thiazol-2-yl-benzamide
Use preparation example 65 gained 5-hydroxyls-3-isopropoxy-N-thiazol-2-yl-benzamide and 2; 5-diformazan sulfonyl pyridine; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 67 of faint yellow oily thing with preparation example 65.
2,5-diformazan sulfonyl pyridine can be by making 2, and 5-dibromo pyridine and the reaction of sulfo-sodium methoxide form 2, behind the 5-methyl-sulfide yl pyridines, obtain with the metachloroperbenzoic acid oxidation.2, the reaction of 5-dibromo pyridine and sodium methoxide and with metachloroperbenzoic acid oxidation 2, the reaction of 5-methyl-sulfide yl pyridines all can be undertaken by ordinary method.
1H NMR(CDCl
3)δ：1.37(6H，d，J＝6.1Hz)，3.11(3H，s)，4.58-4.66(1H，m)，6.93(1H，t，J＝1.8Hz)，6.99(1H，d，J＝3.6Hz)，7.12(1H，d，J＝8.7Hz)，7.29(1H，d，J＝1.8Hz)，7.36(1H，d，J＝3.6H z)，7.40(1H，d，J＝1.8Hz)，8.21(1H，dd，J＝2.6，8.7H z)，8.71(1H，d，J＝2.6Hz)
ESI-MS(m/e)：434[M+H]
+
Preparation example 68
The system of 3-(5-ethanoyl-pyridine-2-base-oxygen base)-5-isopropoxy-N-thiazol-2-yl-benzamide
Be equipped with
5-hydroxyl-3-isopropoxy-N-thiazol-2-yl-benzamide and 2-chloro-5-acetylpyridine that use makes by the method the same with preparation example 65; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 68 of white solid with preparation example 65.
1H NMR(CDCl
3)δ：1.37(6H，d，J＝6.0Hz)，2.59(3H，s)，4.61(1H，m)，6.93(1H，t，J＝2.1Hz)，6.98(1H，d，J＝3.6Hz)，7.04(1H，d，J＝8.6Hz)，7.29(1H，t，J＝2.1Hz)，7.38(2H，m)，8.30(1H，dd，J＝2.5，8.6Hz)，8.75(1H，d，J＝2.5Hz)
ESI-MS(m/e)：398[M+H]
+
Preparation example 69
5-isopropoxy-3-(5-methoxycarbonyl-pyrazine-2-base-oxygen base)-N-thiazol-2-yl-benzamide
Preparation
5-hydroxyl-3-isopropoxy-N-thiazol-2-yl-benzamide and 2-chloro-5-methoxycarbonyl pyrazine that use makes by the method the same with preparation example 65, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 69 with preparation example 65.
1H NMR(CDCl
3)δ：1.38(6H，d，J＝6.0Hz)，4.03(3H，s)，4.57-4.65(1H，m)，6.95(1H，t，J＝2.1Hz)，7.00(1H，d，J＝3.6H z)，7.33-7.35(1H，m)，7.37-7.42(2H，m)，8.54(1H，d，J＝1.2Hz)，8.85(1H，d，J＝1.2Hz)
ESI-MS(m/e)：415[M+H]
+
Preparation example 70
The preparation of 3-(5-cyano group-pyridine-2-base-oxygen base)-5-isopropoxy-N-thiazol-2-yl-benzamide
5-hydroxyl-3-isopropoxy-N-thiazol-2-yl-benzamide and 2 that use makes by the method the same with preparation example 65, the 5-dibromo pyridine, make 3-(5-bromo-pyridine-2-base-oxygen base)-5-isopropoxy-N-thiazol-2-yl-benzamide and cupric cyanide (I) reaction that make by the method the same, make compound into colourless unbodied preparation example 70 with preparation example 65.
The reaction of 3-(5-bromo-pyridine-2-base-oxygen base)-5-sec.-propyl-N-thiazol-2-yl-benzamide and cupric cyanide, method that can be by document record (Comprehensive OrganicTransformations for example, works such as Richard L, VCH Publishers company, 1988, etc.), carry out based on its method or with the combination of these methods and ordinary method.
1H NMR(CDCl
3)δ：1.37(6H，d，J＝6.1Hz)，4.61(1H，m)，6.89-6.92(1H，m)，6.97-7.01(1H，m)，7.06-7.09(1H，m)，7.26-7.29(1H，m)，7.35-7.40(1H，m)，7.93-7.98(1H，m)，8.47-8.49(1H，m)
ESI-MS(m/e)：381[M+H]
+
Preparation example 71
5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-4-yl-oxygen base)-N-thiazol-2-yl-benzoyl
The preparation of amine
5-hydroxyl-3-isopropoxy methyl benzoate, 4-bromopyridine hydrochloride and thiazolamine that use makes by the method the same with preparation example 59, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 71 of white solid with preparation example 65.
1H NMR(CDCl
3)δ：1.31(6H，d，J＝6.0Hz)，4.73-4.83(1H，m)，5.51(1H，d，J＝2.6Hz)，6.03(1H，dd，J＝2.5，7.4Hz)，6.99(1H，t，J＝2.2Hz)，7.30(1H，d，J＝3.6Hz)，7.38-7.44(2H，m)，7.55-7.59(2H，m)
ESI-MS(m/e)：372[M+H]
+
Preparation example 72
5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxygen base)-N-thiazol-2-yl-benzoyl
The preparation of amine
5-hydroxyl-3-isopropoxy methyl benzoate, 3-bromo-2 hydroxy pyrimidine and thiazolamine that use makes by the method the same with preparation example 59, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 72 of white crystals with preparation example 65.
1H NMR(CDCl
3)δ：1.34(6H，d，J＝6.0Hz)，4.62-4.72(1H，m)，6.41(1H，dd，J＝6.7，7.2Hz)，6.76(1H，t，J＝2.3Hz)，7.10-7.13(1H，dd，J＝1.5，2.2Hz)，7.14(1H，d，J＝3.6Hz)，7.27-7.29(1H，m)，7.30-7.37(2H，m)，7.48(2H，d，J＝3.6Hz)
ESI-MS(m/e)：372[M+H]
+
Preparation example 73
5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxygen base)-N-thiazole also [5,4-b] pyridine-
The preparation of 2-base-benzamide
5-hydroxyl-3-isopropoxy methyl benzoate, 3-bromo-2 hydroxy pyrimidine and the thiazolamine that use makes by the method the same with preparation example 59 also [5,4-b] pyridine, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 73 of white solid with preparation example 65.
1H NMR(CDCl
3)δ：1.31(6H，d，J＝6.0Hz)，4.68-4.81(1H，m)，6.25(1H，t，J＝6.9Hz)，6.68-6.72(1H，m)，7.13-7.16(1H，m)，7.31-7.40(2H，m)，7.44-7.54(2H，m)，8.12(1H，d，J＝7.8Hz)，8.46-8.52(1H，m)
ESI-MS(m/e)：423[M+H]
+
Preparation example 74
5-isopropoxy-3-([1,3,4] thiadiazoles-2-base sulfenyl)-N-thiazole is [5,4-b]-pyridine-2-base-benzene also
The preparation of methane amide
To the N of 120mg (0.43mol) 3-hydroxyl-5-iodo-benzoic acid methyl esters, add 298mg (2.16mmol) salt of wormwood and 0.12ml (1.29mmol) 2-N-PROPYLE BROMIDE in the dinethylformamide solution (4.0ml), reaction solution is stirred at 80 degree spend the night then.In reaction solution, add entry, use ethyl acetate extraction, with saturated common salt solution washing organic layer, dry back concentrating under reduced pressure.(hexane: ethyl acetate=5: 1) purifying obtains 133mg (yield: 96%) be the 5-iodo-3-isopropoxy methyl benzoate of colorless oil by silica gel column chromatography with the gained resistates.
N to 132mg (0.41mmol) gained iodine compound, add 292mg (2.47mol) 2-sulfydryl-1 in the dinethylformamide solution (10ml), 3,4-thiadiazoles, 456mg (3.30mol) salt of wormwood, 27.0mg (0.25mmol) quinhydrones and 35.0mg (0.25mmol) cupric bromide (I) stirred 40 minutes in 130 degree under nitrogen atmosphere then.In reaction solution, add entry, use ethyl acetate extraction, with saturated common salt solution washing organic layer, dry back concentrating under reduced pressure.(hexane: ethyl acetate=1: 1) purifying obtains 8.90mg (yield: 7%) be the 5-isopropoxy-3-of colorless oil (1,3,4-thiadiazoles-2-base-sulfo-) methyl benzoate by silica gel column chromatography with the gained resistates.
In the methanol solution (1.0ml) of gained ester cpds, add 0.14ml (0.29mmol) 2N aqueous sodium hydroxide solution, reaction solution was at room temperature stirred 5 hours.In reaction solution, add the 2N aqueous hydrochloric acid, use ethyl acetate extraction,, obtain the crude product of carboxylic compound with saturated common salt solution washing organic layer, concentrating under reduced pressure after the drying.
N to the gained carboxylic compound, add 8.20mg (0.054mol) 2-amino-thiazolyl-also [5 in the dinethylformamide solution (1.2ml), 4-b]-pyridine, 5.00mg (0.037mmol) I-hydroxybenzotriazole hydrate and 7.10mg (0.037mol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, at room temperature stir then and spend the night.The concentrating under reduced pressure reaction solution, (hexane: ethyl acetate=1: 1) purifying obtains the title compound into white solid by silica gel column chromatography with the gained resistates.The analytical data of the compound that makes by preparation example 74 is as follows.
1H NMR(CDCl
3)δ：1.32(6H，d，J＝6.0Hz)，4.54-4.62(1H，m)，7.32(1H，dd，J＝4.6，8.2Hz)，7.37(1H，t，J＝1.8Hz)，7.56(1H，t，J＝1.8Hz)，7.74(1H，dd，J＝1.4，8.2Hz)，7.79(1H，t，J＝1.8Hz)，8.52(1H，dd，J＝1.4，4.6Hz)，9.07(1H，s)
ESI-MS(m/e)：430[M+H]
+
By the method the same, obtain the compound of preparation example 75-88 with above-mentioned preparation example 74.The analytical data of the representative compounds in these compounds is as follows.
Preparation example 75
5-isopropoxy-3-(4-methyl-[1,2,4] triazole-3-base sulfenyl)-N-thiazol-2-yl-benzamide
Preparation
Use preparation example 74 gained 5-iodo-3-isopropoxy methyl benzoate, thiazolamine and 3-sulfydryl-4-methyl-[1,2,4] triazole, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 75 with preparation example 74.
1H NMR(CDCl
3)δ：1.31(6H，d，J＝5.9Hz)，3.65(3H，s)，4.53-4.57(1H，m)，6.98(1H，q，J＝3.5Hz)，7.06(1H，s)，7.20(1H，d，J＝3.5Hz)，7.41(1H，s)，7.53(1H，s)，8.29(1H，s)
ESI-MS(m/e)：374[M-H]
-
Preparation example 76
The preparation of 5-isopropoxy-3-thiazol-2-yl sulfenyl-N-thiazol-2-yl-benzamide
Use preparation example 75 gained 5-iodo-3-isopropoxy methyl benzoate, thiazolamine and 2-thyroidan, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 76 with preparation example 74.
1H NMR(CDCl
3)δ：1.33(6H，d，J＝6.0Hz)，4.54-4.62(1H，m)，6.95(1H，d，J＝3.6Hz)，7.15(1H，d，J＝3.6Hz)，7.29-7.32(2H，m)，7.50(1H，dd，J＝1.5，2.2Hz)，7.69(1H，d，J＝1.5Hz)，7.77(1H，d，J＝3.4Hz)
Preparation example 77
The preparation of 5-isopropoxy-3-(4H-[1,2,4] triazole-3-base sulfenyl)-N-thiazol-2-yl-benzamide
Use preparation example 74 gained 5-iodo-3-isopropoxy methyl benzoate, thiazolamine and 3-sulfydryl-[1,2,4] triazole, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 77 with preparation example 74.
1H NMR(CDCl
3)δ：1.34(6H，d，J＝6.0Hz)，4.59-4.63(1H，m)，7.04(1H，d，J＝2.5Hz)，7.44(1H，dd，J＝1.0Hz)，7.49(1H，t，J＝1.0Hz)，7.49(1H，d，J＝2.5Hz)，7.67(1H，t，J＝1.0Hz)，8.24(1H，s)
ESI-MS(m/e)：362[M+H]
+
Preparation example 78
The preparation of 5-isopropoxy-3-([1,3,4] thiadiazoles-2-base sulfenyl)-N-thiazol-2-yl-benzamide
Use preparation example 74 gained 5-iodo-3-isopropoxy methyl benzoate, thiazolamine and 2-sulfydryl-[1,3,4] triazole, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 78 with preparation example 74.
1H NMR(CD
3OD)δ：1.37(6H，d，J＝6.0Hz)，4.71-4.81(1H，m)，7.14(1H，d，J＝3.7Hz)，7.45(1H，t，J＝1.8Hz)，7.50(1H，d，J＝3.7Hz)，7.68(1H，t，J＝1.8Hz)，7.89(1H，t，J＝1.8Hz)，9.32(1H，s)
ESI-MS(m/e)：379[M+H]
+
Preparation example 79
5-isopropoxy-3-(5-methyl sulfenyl-[1,3,4] thiadiazoles-2-base sulfenyl)-N-thiazol-2-yl-benzene first
The preparation of acid amides
Use preparation example 74 gained 5-iodo-3-isopropoxy methyl benzoate, thiazolamine and 2-sulfydryl-5-methyl sulfenyl-[1,3,4] thiadiazoles, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 79 of colorless oil with preparation example 74.
1H NMR(CDCl
3)δ：1.34(6H，d，J＝6.0Hz)，2.75(3H，s)，4.55-4.63(1H，m)，6.97(1H，d，J＝3.6Hz)，7.13(1H，d，J＝3.6Hz)，7.32(1H，t，J＝1.8Hz)，7.53(1H，t，J＝1.8Hz)，7.72(1H，t，J＝1.8Hz)
ESI-MS(m/e)：425[M+H]
+
Preparation example 80
5-isopropoxy-3-(5-methyl-[1,3,4] thiadiazoles-2-base sulfenyl)-N-thiazol-2-yl-benzamide
Preparation
Use preparation example 74 gained 5-iodo-3-isopropoxy methyl benzoate, thiazolamine and 2-sulfydryl-5-methyl-[1,3,4] thiadiazoles, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 80 with preparation example 74.
1H NMR(CDCl
3)δ：1.35(6H，d，J＝6.0Hz)，2.72(3H，s)，4.56-4.64(1H，m)，6.97(1H，d，J＝3.6Hz)，7.17(1H，d，J＝3.6Hz)，7.35(1H，t，J＝1.8Hz)，7.54(1H，t，J＝1.8Hz)，7.73(1H，t，J＝1.8Hz)
ESI-MS(m/e)：393[M+H]
+
Preparation example 81
5-(tetrahydrofuran (THF)-3-base-oxygen base)-N-thiazol-2-yl-3-(4H-[1,2,4] triazole-3-base sulfenyl)-benzene
The preparation of methane amide
Replace the 2-N-PROPYLE BROMIDE with (3R)-3-N-PROPYLE BROMIDE, and use 5-iodo-3-(the basic oxygen base of tetrahydrofuran (THF)-3-) methyl benzoate, thiazolamine and the 3-sulfydryl-[1 that makes by the method the same with preparation example 74,2,4] triazole, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 81 of colorless oil with preparation example 74.
1H NMR(CDCl
3)δ：2.05-2.24(2H，m)，3.89-4.02(4H，m)，4.94-4.98(1H，m)，7.06(1H，d，J＝3.6Hz)，7.23(1H，t，J＝1.8Hz)，7.40(1H，d，J＝1.8Hz)，7.48(1H，d，J＝3.6Hz)，7.68(1H，d，J＝1.8Hz)，8.32(1H，s)
ESI-MS(m/e)：390[M+H]
+
Preparation example 82
5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4] thiadiazoles-2-base
Sulfenyl)-preparation of benzamide
With 3-hydroxyl-5-iodo-methyl benzoate, uncle's 1-dimethylsilane oxygen base-2-hydroxy propane and 2-amino-4-methyl-thiazole, make 3-(the 2-tertiary butyl-dimethylsilane Oxy-1-methyl-oxyethyl group)-5-iodo-N-(4-methyl-thiazol-2-yl)-benzamide by the method the same with preparation example 65, use this compound and 2-sulfydryl-[1,3,4] thiadiazoles, by the method the same, based on its method or with these methods and ordinary method combination, obtain compound into the preparation example 82 of colorless oil with preparation example 74.Removing of hydroxyl protecting group-t-butyldimethylsilyloxy base wherein can be by the method the same with preparation example 2, carry out based on its method or with these methods and ordinary method combination.
1H NMR(CDCl
3)δ：1.32(d，3H，J＝6.2Hz)，2.38(s，3H)，4.79(m，2H)，4.65(m，1H)，6.63(s，1H)，7.38(m，1H)，7.72(m，1H)，7.82(m，1H)，9.08(s，1H)
ESI-MS(m/e)：409[M+H]
+
Preparation example 83
5-(3-hydroxyl-1-methyl-propoxy-)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4] thiadiazoles-2-base
Sulfenyl)-preparation of benzamide
With 3-hydroxyl-5-iodo-methyl benzoate, the pure and mild 2-amino of 5-t-butyldimethylsilyloxy base-penta-2--4-methyl-thiazole, make 3-(the 3-tertiary butyl-dimethylsilane Oxy-1-methyl-propoxy-)-5-iodo-N-(4-methyl-thiazol-2-yl)-benzamide by the method the same with preparation example 65, use this compound and 2-sulfydryl-[1,3,4] thiadiazoles, by the method the same, based on its method or with these methods and ordinary method combination, obtain compound into the unbodied preparation example 83 of white with preparation example 74.Removing of hydroxyl protecting group-t-butyldimethylsilyloxy base wherein can be by the method the same with preparation example 2, carry out based on its method or with these methods and ordinary method combination.
1H NMR(CDCl
3)δ：1.33(d，3H，J＝6.1Hz)，2.10-1.75(m，4H)，2.18(d，1H，J＝1.0Hz)，3.78(m，2H)，4.63(m，1H)，6.56(d，1H，J＝1.0Hz)，7.38(m，1H)，7.61(m，1H)，7.73(m，1H)，9.05(s，1H)，11.1(br，1H)
ESI-MS(m/e)：423[M+H]
+
Preparation example 84
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-([1,3,4] thiadiazoles-2-base sulfenyl)-N-thiazol-2-yl-benzene
The preparation of methane amide
With 3-hydroxyl-5-iodo-methyl benzoate, the pure and mild thiazolamine of 1-tert.-butoxy-2-, make 3-(the 2-tertiary butyl-dimethylsilane Oxy-1-methyl-propoxy-)-5-iodo-N-(thiazol-2-yl)-benzamide by the method the same with preparation example 65, use this compound and 2-sulfydryl-[1,3,4] thiadiazoles, by the method the same, based on its method or with these methods and ordinary method combination, obtain compound into the preparation example 84 of colorless oil with preparation example 74.Removing of hydroxyl protecting group one t-butyldimethylsilyloxy base wherein can be by the method the same with preparation example 2, carry out based on its method or with these methods and ordinary method combination.
1H NMR(CDCl
3)δ：1.30(d，3H，J＝6.0Hz)，3.80(m，2H)，4.62(sextet，1H，J＝6.0Hz)，7.00(d，1H，J＝3.6Hz)，7.27(d，1H，J＝3.6Hz)，7.40(m，1H)，7.62(m，1H)，7.81(m，1H)，9.09(s，1H)
ESI-MS(m/e)：395[M+H]
+
Preparation example 85
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenyl sulfenyl)-N-thiazol-2-yl-benzene first
The preparation of acid amides
With 3-hydroxyl-5-iodo-methyl benzoate, the 1-t-butyldimethylsilyloxy Ji-Ding-pure and mild thiazolamine of 2-, make 3-(the 2-tertiary butyl-dimethylsilane Oxy-1-methyl-propoxy-)-5-iodo-N-(thiazol-2-yl)-benzamide by the method the same with preparation example 65, use this compound and 2-sulfydryl-[1,3,4] thiadiazoles, by the method the same, based on its method or with these methods and ordinary method combination, obtain compound into the preparation example 85 of colorless oil with preparation example 74.Removing of hydroxyl protecting group-t-butyldimethylsilyloxy base wherein can be by the method the same with preparation example 2, carry out based on its method or with these methods and ordinary method combination.
1H NMR(CDCl
3)δ：1.31(d，3H，J＝6.2Hz)，3.07(s，3H)，3.78(m，2H)，4.58(m，1H)，7.01(d，1H，J＝3.6Hz)，7.24(m，2H)，7.37(d，2H，J＝8.6Hz)，7.55(m，1H)，7.61(m，1H)，7.84(d，2H，J＝8.6Hz)，11.3(br，1H)
ESI-MS(m/e)：465[M+H]
+
Preparation example 86
The system of 3-(3-fluoro-thiophenyl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-thiazol-2-yl-benzamide
Be equipped with
With 3-hydroxyl-5-iodo-methyl benzoate, 1-(uncle's dimethylsilane oxygen base)-2-hydroxy propane and thiazolamine, make 3-(the 2-tertiary butyl-dimethylsilane Oxy-1-methyl-oxyethyl group)-5-iodo-N-(thiazol-2-yl)-benzamide by the method the same with preparation example 65, use this compound and 3-fluorobenzene thiophenol, by the method the same, based on its method or with these methods and ordinary method combination, obtain compound into the unbodied preparation example 86 of white with preparation example 74.Removing of hydroxyl protecting group-t-butyldimethylsilyloxy base wherein can be by the method the same with preparation example 2, carry out based on its method or with these methods and ordinary method combination.
1H NMR(CDCl
3)δ：1.27(d，3H，J＝6.2Hz)，3,75(m，2H)，4.54(m，1H)，7.18-6.95(m，4H)，7.21(m，1H)，7.30(m，1H)，7.52-7.40(m，2H)
ESI-MS(m/e)：405[M+H]
+
Preparation example 87
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(pyridin-4-yl sulfenyl)-N-thiazol-2-yl-benzamide
Preparation
With 3-hydroxyl-5-iodo-methyl benzoate, 1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and thiazolamine, make 3-(the 2-tertiary butyl-dimethylsilane Oxy-1-methyl-oxyethyl group)-5-iodo-N-(thiazol-2-yl)-benzamide by the method the same with preparation example 65, use this compound and 4-mercaptopyridine, by the method the same, based on its method or with these methods and ordinary method combination, obtain compound into the preparation example 87 of yellow oil with preparation example 74.Removing of hydroxyl protecting group-t-butyldimethylsilyloxy base wherein can be by the method the same with preparation example 2, carry out based on its method or with these methods and ordinary method combination.
1H NMR(CDCl
3)δ：1.36(d，3H，J＝6.1Hz)，3.72(d，2H，J＝6.1Hz)，4.68(sextet，1H，J＝6.1Hz)，7.20(m，3H)，7.45(m，1H)，7.54(m，1H)，7.75(m，1H)，7.85(m，1H)，8.36(m，2H)
ESI-MS(m/e)：388[M+H]
+
Preparation example 88
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(6-methyl-pyridin-3-yl sulfenyl)-N-thiazol-2-yl-benzene first
The preparation of acid amides
With 3-hydroxyl-5-iodo-methyl benzoate, 1-(uncle's dimethylsilane oxygen base)-2-hydroxy propane and thiazolamine, make 3-(2-t-butyldimethylsilyloxy base-1-methyl-oxyethyl group)-5-iodo-N-(thiazol-2-yl)-benzamide by the method the same with preparation example 65, use this compound and 3-sulfydryl-6-picoline, by the method the same, based on its method or with these methods and ordinary method combination, obtain compound into the unbodied preparation example 88 of white with preparation example 74.Removing of hydroxyl protecting group-t-butyldimethylsilyloxy base wherein can be by the method the same with preparation example 2, carry out based on its method or with these methods and ordinary method combination.
1H NMR(CDCl
3)δ：1.24(d，3H，J＝6.2Hz)，2.54(s、3H)，3.72(m，2H)，4.52(m，1H)，6.97(m，2H)，7.16(m，2H)，7.33(m，1H)，7.59(m，1H)，8.52(m，1H)，12.0(br，1H)
ESI-MS(m/e)：402[M+H]
+
Preparation example 89
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(3-methyl-[1,2,4]-thiophene
Diazole-5-yl)-preparation of benzamide
In the toluene solution (375ml) of 25.0g (119mmol) 5-hydroxyl-3-methoxymethoxy methyl benzoate, add 33.4g (142mmol) 4-methylsulfonyl-bromobenzene, 2.67g (11.9mmol) acid chloride, 5.31g (17.8mmol) 2-(di-t-butyl phosphino-) biphenyl, 50.3g (237mmol) potassiumphosphate; closed reaction vessel stirred 6 hours at 130 degree afterwards then.In reaction solution, add ethyl acetate, filter the back concentrating under reduced pressure.(hexane: ethyl acetate=2: 1) purifying obtains 31.0g (yield: 69%) be the 3-of white solid (4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate by silica gel column chromatography with the gained resistates.
In the dichloromethane solution (100ml) of 30.9g (84.3mmol) gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, add the 60ml trifluoroacetic acid down ice-cooled, at room temperature reaction solution was stirred 4 hours then.The concentrating under reduced pressure reaction solution, (hexane: ethyl acetate=1: 1) purifying obtains 15.2g (yield: 56%) be the 5-hydroxyl-3-of white solid (4-methylsulfonyl-phenoxy group) methyl benzoate by silica gel column chromatography with the gained resistates.
In the tetrahydrofuran solution (200ml) of 10.0g (31.0mmol) gained 5-hydroxyl-3-(4-methylsulfonyl-phenoxy group) methyl benzoate, add 11.8g (62.1mmol) (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 16.3g (62.1mmol) triphenyl phosphine; at ice-cooled 40% toluene solution that adds 33.8ml (77.6mmol) diethyl azodiformate down, at room temperature stirred 12 hours then.The concentrating under reduced pressure reaction solution; (hexane: ethyl acetate=8: 2) purifying obtains 5-((1S)-2-(t-butyldimethylsilyloxy base)-1-methyl-oxyethyl group)-3-(4-methylsulfonyl-phenoxy group)-methyl benzoate into yellow oil by silica gel column chromatography with the gained resistates.
Use 200mg (0.40mmol) gained 5-((1S)-2-(t-butyldimethylsilyloxy base)-1-methyl-oxyethyl group)-3-(4-methylsulfonyl-phenoxy group)-methyl benzoate and 5-amino-3-methyl-[1; 2; 4] thiadiazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 89 with preparation example 2.
1H NMR(CD
3OD)δ：1.30(d，6H，J＝6.2Hz)，2.50(s，3H)，3.12(s，3H)，3.68(d，2H，J＝5.0Hz)，4.58-4.63(m，1H)，7.01(s，1H)，7.23(d，2H，J＝8.8Hz)，7.36(s，1H)，7.54(s，1H)，7.97(d，2H，J＝8.8Hz)
ESI-MS(m/e)：464[M+H]
+
Preparation example 90
N-[3-hydroxymethyl-1,2,4-thiadiazoles-5-yl]-3-(4-methylsulfonyl phenoxy group)-5-(the 2-methoxyl group-
1-methyl-oxyethyl group) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-methoxyl group-2-propyl alcohol and 5-amino-3-(t-butyldimethylsilyloxy ylmethyl)-[1; 2; 4] thiadiazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 90 with preparation example 89.
1H NMR(CDCl
3)δ：1.34(3H，d，J＝6.3Hz)，3.09(3H，s)，3.41(3H，s)，3.49-3.64(2H，m)，4.60-4.72(1H，m)，4.79(2H，s)，6.92(1H，t，J＝2.0Hz)，7.16(2H，d，J＝8.7Hz)，7.43(1H，br)，7.93(2H，d，J＝8.7Hz)
ESI-MS(m/e)：494[M+H]
+
Preparation example 91
5-(3-hydroxyl-1-methyl ethoxy)-3-(4-methylsulfonyl phenoxy group)-N-[5-methyl isophthalic acid, 2,4-thiophene two
Azoles-3-yl] preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-5-methyl-[1; 2; 4] thiadiazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 91 of white with preparation example 89.
1H NMR(CDCl
3)δ：1.29(d，3H，J＝6.3Hz)，2.76(s，3H)，3.07(s，3H)，3.79(m，2H)，4.57(m，1H)，6.81(m，1H)，7.12(d，2H，J＝8.8Hz)，7.17(m，1H)，7.33(m 1H)，7.91(d，2H，J＝8.8Hz)，9.27(br，1H)
ESI-MS(m/e)：464[M+H]
+
Preparation example 92
5-(hydroxyl-1-methyl ethoxy)-3-(4-methylsulfonyl phenoxy group)-N-(3-methoxyl group-1,2,4-thiophene two
Azoles-5-yl) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 5-amino-3-methoxyl group-[1; 2; 4] thiadiazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 92 of white with preparation example 89.
1H NMR(CDCl
3)δ：1.32(d，3H，J＝6.3Hz)，3.12(s，3H)，3.80(d，2H，J＝5.5Hz)，3.99(s，3H)，4.61(m，1H)，6.87(m，1H)，7.17(d，2H，J＝8.8Hz)，7.23(m，1H)，7.35(m，1H)，7.96(d，2H，J＝8.8Hz)，11.2(br，1H)
ESI-MS(m/e)：480[M+H]
+
Preparation example 93
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(1,2,5-thiadiazoles-3-yl)
The preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-[1; 2; 5] thiadiazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into faint yellow unbodied preparation example 93 with preparation example 89.
1H NMR(CDCl
3)δ：1.34(d，3H，J＝6.3Hz)，1.91(t，1H，J＝5.7Hz)，3.09(s，3H)，3.80(m，2H)，4.60(m，1H)，6.89(m，1H)，7.17(d，2H)，7.18(m，1H)，7.35(m，1H)，7.96(d，2H，J＝8.8Hz)，8.92(br，1H)，9.32(s，1H)
ESI-MS(m/e)：450[M+H]
+
Preparation example 94
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(4-trifluoromethyl-thiazole-
The 2-yl) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-4-trifluoromethyl-thiazole; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 94 with preparation example 89.
1H NMR(CDCl
3)δ：1.32(d，3H，J＝6.2Hz)，3.11(s，3H)，3.78(d，2H，J＝5.1Hz)，4.57-4.63(m，1H)，6.91(s，1H)，7.16-7.17(m，1H)，7.17(d，2H，J＝8.8Hz)，7.34-7.36(m，1H)，7.44-7.46(m，1H)，7.96(d，2H，J＝8.8Hz)
ESI-MS(m/e)：517[M+H]
+
Preparation example 95
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(4,5,6, the 7-tetrahydro benzo
Thiazol-2-yl) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-4; 5; 6; the 7-tetrahydro benzothiazol; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 95 of colorless oil with preparation example 89.
1H NMR(CDCl
3)δ：1.26-1.29(m，3H)，1.82-1.86(m，4H)，2.57-2.72(m，4H)，3.09(s，3H)，3.73-3.78(m，2H)，4.54-4.56(m，1H)，6.78-6.81(m，1H)，7.09-7.14(m，3H)，7.22-7.29(m，1H)，7.90-7.95(m，2H)
ESI-MS(m/e)：503[M+H]
+
Preparation example 96
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(pyridazine-3-yl)-benzene first
The preparation of acid amides
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino pyridazine; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 96 with preparation example 89.
1H NMR(CDCl
3)δ：1.30(d，3H，J＝5.9Hz)，2.55(brs，1H)，3.07(s，3H)，3.76(m，2H)，4.59(qt，1H，J＝5.9，5.5Hz)，6.83(s，1H)，7.11(d，2H，J＝8.4Hz)，7.24(s，1H)，7.39(s，1H)，7.52(dd，1H，9.2，J＝4.8Hz)，7.90(d，2H，J＝8.4Hz)，8.55(d，1H，J＝9.2Hz)，8.93(m，1H)，9.54(brs，1H)
ESI-MS(m/e)：444[M+H]
+，442[M-H]
-
Preparation example 97
5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(3-sec.-propyl-[1,2,4]-triazole-5-yl)-3-(4-methylsulfonyl
Phenoxyl) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 5-amino-3-sec.-propyl-[1; 2; 4] triazole; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 97 with preparation example 89.
1H NMR(CDCl
3)δ：1.33(d，6H，J＝7.3Hz)，1.35(d，6H，J＝7.0Hz)，3.10(s，3H)，3.16-3.21(m，1H)，3.77-3.79(m，2H)，4.57-4.62(m，1H)，6.91(s，1H)，7.16(d，2H，J＝8.9Hz)，7.17(d，1H，J＝1.7Hz)，7.35(d，1H，J＝1.7Hz)，7.95(d，2H，J＝8.9Hz)
ESI-MS(m/e)：492[M+H]
+
Preparation example 98
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(3-methyl-[1,2,4]-Evil
Diazole-5-yl) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 5-amino-3-methyl-[1; 2; 4] oxadiazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 98 with preparation example 89.
1H NMR(CDCl
3)δ：1.28(d，3H，J＝5.9Hz)，2.31(s，3H)，3.08(s，3H)，3.75-3.76(m，2H)，4.57-4.58(m，1H)，5.60(brs，1H)，6.84(s，1H)，7.09(d，2H，J＝8.6Hz)，7.24(s，1H)，7.35(s，1H)，7.87(d，2H，J＝8.6Hz)，10.52(brs，1H)ESI-MS(m/e)：448[M+H]
+，446[M-H]
-
Preparation example 99
5-(2-hydroxyl-1-methyl-oxyethyl group)-N-[4-(1-hydroxyl-1-methyl-ethyl)-thiazol-2-yl]-3-(4-
The methylsulfonyl phenoxy group) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-4-(1-hydroxyl-1-methyl-ethyl)-thiazole; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 99 of white solid with preparation example 89.
1H NMR(CDCl
3)δ：1.33(3H，d，J＝6.2Hz)，1.61(6H，s)，3.08(3H，s)，3.75-3.84(2H，m)，4.55-4.65(1H，m)，6.77(1H，s)，6.88(1H，t，J＝2.0Hz)，7.16(2H，d，J＝8.7Hz)，7.28(1H，br)，7.45(1H，br)，7.95(2H，d，J＝8.7Hz)
ESI-MS(m/e)：507[M+H]
+
Preparation example 100
N-(4-cyano group-thiazol-2-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)
The preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-4-cyano thiazole; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 100 with preparation example 89.
1H NMR(CDCl
3)δ：1.32(d，3H，J＝6.2Hz)，2.48(brs，1H)，3.12(s，3H)，3.75-3.85(m，2H)，4.59-4.62(m，1H)，6.88(s，1H)，7.15(d，2H，J＝8.8Hz)，7.22(s，1H)，7.38(s，1H)，7.70(s，1H)，7.94(d，2H，J＝8.8Hz)，10.52(brs，1H)
ESI-MS(m/e)：474[M+H]
+，472[M-H]
-
Preparation example 101
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazoles-
The 3-yl) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 101 of white crystals with preparation example 89.
1H NMR(CDCl
3)δ：1.31(d，3H，J＝6.3Hz)，3.08(s，3H)，3.77(m，2H)，3.81(s，3H)，4.57(m，1H)，6.78(m，1H)，6.82(m，1H)，7.11(m，1H)，7.15(d，2H，J＝8.9H z)，7.30(m，2H)，7.93(d，2H，J＝8.9Hz)，8.45(br，1H)
ESI-MS(m/e)：466[M+H]
+
Preparation example 102
5-(1-hydroxymethyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-(pyridine-2-yl) benzamide
Preparation
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate; in order to replace (2R)-1-(t-butyldimethylsilyloxy the base)-2-hydroxyl butane of (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane; and 2-aminopyridine; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 102 with preparation example 89.
1H NMR(CDCl
3)δ：1.01(t，3H，J＝7.7Hz)，1.76(qd，2H，J＝7.7，6.2Hz)，2.10(brs，1H)，3.09(s，3H)，3.78-3.88(m，2H)，4.38-4.44(m，1H)，6.86(s，1H)，7.10(dd，1H，J＝4.0，8.4Hz)，7.15(d，2H，J＝9.2Hz)，7.17(s，1H)，7.37(s，1H)，7.77(dd，1H，J＝8.4，8.4Hz)，7.93(d，2H，J＝9.2Hz)，8.29(d，1H，J＝4.0Hz)，8.34(d，1H，J＝8.4Hz)，8.62(brs，1H)
ESI-MS(m/e)：457[M+H]
+
Preparation example 103
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(5-methyl-isothiazole-3-
Base) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-5-methyl-isothiazole; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 103 of white with preparation example 89.
1H NMR(CDCl
3)δ：1.30(d，3H，J＝6.2Hz)，2.58(s，3H)，3.07(s，3H)，3.75(m，2H)，4.57(m，1H)，6.82(m，1H)，7.13(d，2H，J＝8.9Hz)，7.15(m，1H)，7.31(m，1H)，7.73(m，1H)，7.92(d，2H，J＝8.9Hz)，9.12(br，1H)
ESI-MS(m/e)：463[M+H]
+
Preparation example 104
5-(3-hydroxyl-cyclopentyloxy)-3-(4-methylsulfonyl phenoxy group)-N-(thiazol-2-yl) benzamide
Preparation
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, in order to replace 3-(tert-butyl diphenyl siloxy-) cyclopentanol and the 2-amino-thiazolyl-of (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 104 with preparation example 89.
1H NMR(CDCl
3)δ：1.92(m，6H)，3.08(s，3H)，4.39(s，1H)，4.82-4.84(s，1H)，6.82(t，1H，J＝1.9Hz)，7.00(d，1H，J＝3.6Hz)，7.13(d，2H，J＝8.6Hz)，7.16(d，1H，J＝1.9Hz)，7.23(d，1H，J＝3.6Hz)，7.34(d，1H，J＝1.9Hz)，7.92(d，2H，J＝8.6Hz)
ESI-MS(m/e)：475[M+H]
+
Preparation example 105
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(5-methoxyl group-thiazole-2-
Base) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-5-methoxy thiazole; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 105 of white solid with preparation example 89.
1H NMR(CDCl
3)δ：1.28(d，3H，J＝6.2Hz)，3.07(s，3H)，3.75(d，2H，J＝5.6Hz)，3.87(s，3H)，4.57(m，1H)，6.52(s，1H)，6.81(m，1H)，7.12(d，2H，J＝8.8Hz)，7.17(m，1H)，7.31(m，1H)，7.90(d，2H，J＝8.8Hz)，11.5(br，1H)
ESI-MS(m/e)：479[M+H]
+
Preparation example 106
5-(1-hydroxymethyl-2-methyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-(thiazol-2-yl) benzene
The preparation of methane amide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, in order to replace 1-(t-butyldimethylsilyloxy the base)-pure and mild 2-amino-thiazolyl-of 3-methyl fourth-2-of (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 106 of white with preparation example 89.
1H NMR(CDCl
3)δ：0.97(m，6H)，2.05(m，1H)，3.07(s，3H)，3.83(m，2H)，4.22(m，1H)，6.84(m，1H)，6.96(d，1H，J＝3.7Hz)，7.11(d，2H，J＝8.9Hz)，7.18(m，1H)，7.23(d，1H，J＝3.7Hz)，7.39(m，1H)，7.91(d，2H，J＝8.8Hz)，12.0(br，1H)
ESI-MS(m/e)：477[M+H]
+
Preparation example 107
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(1H-[1,2,3] triazole-4-
Base) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 4-amino-1H-[1; 2; 3] triazole; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 107 with preparation example 89.
1H NMR(CDCl
3)δ：1.31(d，3H，J＝6.2Hz)，3.11(s，3H)，3.34(s，1H)，3.67-3.68(m，2H)，4.56-4.60(m，2H)，6.93(s，1H)，7.21(d，2H，J＝8.8Hz)，7.25(s，1H)，7.43(s，1H)，7.94(d，2H，J＝8.8Hz)，8.08(brs，1H)
ESI-MS(m/e)：433[M+H]
+，431[M-H]
-
Preparation example 108
N-(1-ethanoyl-1H-pyrazole-3-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl
Phenoxy group) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-ethanoyl-1H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 108 of white with preparation example 89.
1H NMR(CDCl
3)δ：1.36(d，3H，J＝6.3Hz)，2.65(s，3H)，3.12(s，3H)，3.82(m，2H)，4.61(m，1H)，6.89(m，1H)，7.16-7.22(m，4H)，7.35(m，1H)，7.98(d，2H，J＝8.8H z)，8.22(d，1H，J＝3.0Hz)，8.46(br，1H)
ESI-MS(m/e)：474[M+H]
+
Preparation example 109
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(pyrazole-3-yl) benzoyl
The preparation of amine
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 109 of white with preparation example 89.
1HNMR(CDCl
3)δ：1.26(d，3H，J＝6.3Hz)，3.05(s，3H)，3.73(m，2H)，4.52(m，1H)，6.75(m，2H)，7.06(d，2H，J＝8.8Hz)，7.14(m，1H)，7.32(m，1H)，7.46(m，1H)，7.85(d，2H，J＝8.8Hz)，9.72(br，1H)
ESI-MS(m/e)：432[M+H]
+
Preparation example 110
N-(5,6-dihydro-4H-cyclopenta thiazol-2-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-
The methylsulfonyl phenoxy group) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-5; 6-dihydro-4H-cyclopenta thiazole; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 110 with preparation example 89.
1H NMR(CDCl
3)δ：1.28(d，3H，J＝6.2Hz)，2.44(tt，2H，J＝7.0，7.0Hz)，2.61(t，2H，J＝7.0Hz)，2.90(t，2H，J＝7.0Hz)，3.08(s，3H)，3.70-3.76(m，2H)，4.51-4.55(m，1H)，6.76(s，1H)，7.10(d，2H，J＝8.8Hz)，7.12(s，1H)，7.28(s，1H)，7.90(d，2H，J＝9.2Hz)
ESI-MS(m/e)：489[M+H]
+，487[M-H]
-
Preparation example 111
5-(1-hydroxymethyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)
The preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, in order to replace the pure and mild 3-amino of (2R)-1-(the t-butyldimethylsilyloxy base)-Ding-2--1-methyl isophthalic acid H-pyrazoles of (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 111 of white with preparation example 89.
1H NMR(CDCl
3)δ：0.93(t，3H，J＝7.5Hz)，1.69(quintet，1H，J＝7.5Hz)，2.75(t，1H，J＝6.2Hz)，3.06(s，3H)，3.74(s，3H)，3.70-3.80(m，2H)，4.33(m，1H)，6.77(m，2H)，7.09(d，2H，J＝8.8Hz)，7.11(m，1H)，7.27(m，2H)，7.99(d，2H，J＝8.8Hz)，9.03(br，1H)
ESI-MS(m/e)：460[M+H]
+
Preparation example 112
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(thieno-[3,2-d] thiazole
-2-yl) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-thieno-[3; 2-d] thiazole; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 112 with preparation example 89.
1H NMR(CDCl
3)δ：1.30(d，3H，J＝6.2Hz)，2.05(brs，1H)，3.09(s，3H)，3.76-3.78(m，2H)，4.55-4.57(m，1H)，6.84(s，1H)，7.11(d，2H，J＝8.8Hz)，7.11(s，1H)，7.19(s，1H)，7.36(s，1H)，7.38(s，1H)，7.92(d，2H，J＝8.8Hz)，10.42(brs，1H)
ESI-MS(m/e)：505[M+H]
+，503[M-H]
-
Preparation example 113
3-(3-fluoro-4-methylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-
Pyrazole-3-yl) preparation of benzamide
3-(3-fluoro-4-methylsulfonyl phenoxy group)-5-hydroxy-benzoic acid methyl esters, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles that use makes by the method the same with preparation example 42; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 113 of white crystals with preparation example 2.
1H NMR(CDCl
3)δ：1.31(d，3H，J＝6.3Hz)，2.20(t，1H，J＝6.5Hz)，3.23(s，3H)，3.77(m，2H)，3.80(s，3H)，4.57(sextet，1H，J＝4.5Hz)，6.79-6.93(m，4H)，7.14(m，1H)，7.30(m，1H)，7.33(m，1H)，7.92(t，1H，J＝8.4Hz)，8.57(br，1H)
ESI-MS(m/e)：464[M+H]
+
Preparation example 114
3-(4-methylsulfonyl phenoxy group)-5-(2-methoxyl group-1-methyl-oxyethyl group)-N-(pyrazole-3-yl) benzene first
The preparation of acid amides
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-methoxyl group-2-propyl alcohol and 3-amino-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 114 of white with preparation example 89.
1H NMR(CDCl
3)δ：1.32(d，3H，J＝6.2Hz)，3.05(s，3H)，3.39(s，3H)，3.50-3.60(m，2H)，4.60(m，1H)，6.80(t，1H，J＝2.2Hz)，6.85(d，1H，J＝2.2Hz)，7.09(d，2H，J＝8.8Hz)，7.16(t，1H，J＝2.2Hz)，7.39(t，1H，J＝2.2Hz)，7.47(d，1H，J＝2.2Hz)，7.87(d，2H，J＝8.8Hz)，9.80(br，1H)
ESI-MS(m/e)：446[M+H]
+
Preparation example 115
3-(4-cyano group-phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)
The preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate and to cyano-phenyl boric acid, 3-(4-cyano group-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles that use makes by the method the same with preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 115 with preparation example 89.
1H NMR(CDCl
3)δ：1.30(d，3H，J＝6.2Hz)，2.31(brs，1H)，3.76-3.79(m，2H)，3.79(s，3H)，4.54(qt，1H，J＝6.2Hz，4.0Hz)，6.77(d，1H，J＝2.2Hz)，6.78(s，1H)，7.07(d，2H，J＝8.8Hz)，7.09(s，1H)，7.27(s，1H)，7.28(d，1H，J＝2.2Hz)，7.63(d，2H，8.8Hz)，8.64(brs，1H)
ESI-MS(m/e)：393[M+H]
+
Preparation example 116
3-(4-ethylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazoles
-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate and to the ethyl phenyl sulfide ylboronic acid; methoxymethyl to 3-(4-ethylmercapto group-phenoxy group)-5-methoxymethoxy-methyl benzoate of making by the method the same with preparation example 1 carries out deprotection; use 3-(4-ethylmercapto group-phenoxy group)-5-hydroxy-benzoic acid methyl esters that obtains thus; (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same with preparation example 2; based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 116.
1H NMR(CDCl
3)δ：1.32(d，3H，J＝6.2Hz)，1.33(t，3H，J＝7.7Hz)，2.05(brs，1H)，3.14(q，2H，J＝7.7Hz)，3.75-3.79(m，2H)，3.81(s，3H)，4.56(qt，1H，J＝6.2，3.7Hz)，6.78(s，1H)，6.81(d，1H，J＝2.2Hz)，7.11(s，1H)，7.12(d，2H，J＝8.8Hz)，7.28(d，1H，J＝2.2Hz)，7.28(s，1H)，7.87(d，2H，J＝8.8Hz)，8.41(brs，1H)
ESI-MS(m/e)：460[M+H]
+，458[M-H]
-
Preparation example 117
3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(the 1-methyl-
The 1H-pyrazole-3-yl) preparation of benzamide
N to 100mg (0.47mmol) 5-hydroxyl-3-methoxymethoxy methyl benzoate; add 178mg (0.71mmol) 5-bromo-2-b sulfonyl pyridine and 232mg (0.71mmol) cesium carbonate in the dinethylformamide solution (1.0ml), under nitrogen atmosphere, stirred 2.5 hours then in 100 degree.In reaction solution, add ethyl acetate and aqueous ammonium chloride solution, use the ethyl acetate extraction water layer, use saturated common salt solution washing organic layer afterwards, dry back concentrating under reduced pressure.(hexane: ethyl acetate=1: 1) purifying obtains 165mg (yield: 91%) be the 3-of colorless oil (6-ethylsulfonyl-pyridin-3-yl oxygen base)-5-methoxymethoxy methyl benzoate by silica gel column chromatography with the gained resistates.
In the dichloromethane solution (50.0ml) of 11.8g (30.9mmol) gained ester cpds, add the 30.0ml trifluoroacetic acid, reaction solution was at room temperature stirred 5 hours.The concentrating under reduced pressure reaction solution, (hexane: ethyl acetate=2: 1) purifying obtains 8.86g (yield: 85%) be the 3-of colorless oil (6-ethylsulfonyl-pyridin-3-yl oxygen base)-5-methyl hydroxybenzoate by silica gel column chromatography with the gained resistates.
In the tetrahydrofuran solution (30.0ml) of 1.00g (2.97mmol) gained phenolic compound, add 1.02g (5.34mmol) (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 1.40g (5.34mmol) triphenyl phosphine, at ice-cooled 40% toluene solution that adds 2.42ml (5.34mmol) diethyl azodiformate down, at room temperature stirred 1 hour then.The concentrating under reduced pressure reaction solution; (hexane: ethyl acetate=3: 2) purifying obtains 1.31g (yield: 78%) be the 3-of colorless oil ((1S)-2-(t-butyldimethylsilyloxy base)-1-methyl-oxyethyl group)-5-(6-ethylsulfonyl-pyridin-3-yl oxygen base)-methyl benzoate by silica gel column chromatography with the gained resistates.
Use gained 3-((1S)-2-(t-butyldimethylsilyloxy base)-1-methyl-oxyethyl group)-5-(6-ethylsulfonyl-pyridin-3-yl oxygen base)-methyl benzoate and 3-amino-1-methylpyrazole; by the method the same, based on its method or with these methods and ordinary method combination, can make compound into colourless unbodied preparation example 117 with preparation example 2.
1H NMR(CDCl
3)δ：1.32(d，3H，J＝6.2Hz)，1.33(t，3H，J＝7.3Hz)，3.40(q，2H，J＝7.3Hz)，3.75-3.77(m，2H)，3.81(s，3H)，4.54-4.59(m，1H，J＝6.2，-Hz)，6.76(d，1H，J＝2.2Hz)，6.81(dd，1H，J＝2.2，2.2Hz)，7.14(dd，1H，J＝2.2，1.7Hz)，7.28(d，1H，J＝2.2Hz)，7.32(d，1H，J＝2.2，1.7Hz)，7.43(dd，1H，J＝8.8，2.6Hz)，8.05(d，1H，J＝8.8Hz)，8.45(brs，1H)，8.47(d，1H，J＝2.6Hz)
ESI-MS(m/e)：461[M+H]
+，459[M-H]
-
Preparation example 118
5-(3-hydroxyl-1-methyl-propoxy-)-3-(4-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazoles-
The 3-yl) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, the pure and mild 3-amino of 4-(t-butyldimethylsilyloxy base)-Ding-2--1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 118 with preparation example 89.
1H NMR(CDCl
3)δ：1.37(3H，d，J＝6.2Hz)，1.88-1.93(2H，m)，1.96-2.09(1H，m)，3.08(3H，s)，3.78-3.87(2H，m)，3.81(3H，s)，6.78(1H，d，J＝2.0Hz)，6.81(1H，t，J＝2.1Hz)，7.11-7.18(3H，m)，7.29(1H，d，J＝2.2Hz)，7.35(1H，br)，7.92(2H，d，J＝9.0Hz)，8.51(1H，br)
ESI-MS(m/e)：460[M+H]
+
Preparation example 119
3-(4-ethylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(isoxazole-3-base) benzene first
The preparation of acid amides
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate and to the ethyl phenyl sulfide ylboronic acid; methoxymethyl to 3-(4-ethylmercapto group phenoxy group)-5-methoxymethoxy methyl benzoate of making by the method method the same with preparation example 1 carries out deprotection; 3-(4-ethylmercapto group the phenoxy group)-5-methyl hydroxybenzoate that obtains is handled in use through this deprotection; (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-An isoxazole; by the method the same with preparation example 2; based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 119.
1H NMR(CDCl
3)δ：1.32(t，3H，J＝7.4Hz)，1.32(d，3H，J＝6.3Hz)，3.13(q，2H，J＝7.4Hz)，3.76-3.79(m，2H)，4.56-4.62(m，1H)，6.87(t，1H，J＝1.8Hz)，7.14(d，2H，J＝8.7Hz)，7.16(d，1H，J＝1.8H z)，7.26(d，1H，J＝1.8Hz)，7.31(s，1H)，7.93(d，2H，J＝8.7H z)，8.34(s，1H)，
ESI-MS(m/e)：477[M+H]
+
Preparation example 120
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-sec.-propyl alkylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrrole
Azoles-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate and to iprotiazem base phenyl-boron dihydroxide; methoxymethyl to 3-(4-iprotiazem phenoxyl)-5-methoxymethoxy methyl benzoate of making by the method method the same with preparation example 1 carries out deprotection; 3-(4-iprotiazem base-phenoxy group)-5-methyl hydroxybenzoate that obtains is handled in use through this deprotection; (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same with preparation example 2; based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 120.
1H NMR(CDCl
3)δ：1.32(d，3H，J＝6.2Hz)，1.32(d，6H，J＝7.0Hz)，3.20(septet，1H，J＝7.0Hz)，3.76-3.77(m，2H)，3.79(s，3H)，4.55(qt，1H，J＝6.2，4.0Hz)，6.79(d，1H，J＝2.2Hz)，6.80(s，1H)，7.10(d，2H，J＝8.8Hz)，7.13(s，1H)，7.29(d，1H，J＝2.2Hz)，7.29(s，1H)，7.83(d，2H，J＝8.8Hz)，8.61(brs，1H)
ESI-MS(m/e)：474[M+H]
+，472[M-H]
-
Preparation example 121
5-(2-hydroxyl-1-methyl-oxyethyl group)-(4-hydroxy-4-methyl-4,5,6,6a-tetrahydrochysene-3aH-encircles penta 2 to N-
Alkene and thiazol-2-yl)-preparation of 3-(4-methylsulfonyl phenoxy group) benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-amino-4-hydroxy-4-methyl-4; 5; 6; 6a-tetrahydrochysene-3aH-cyclopenta thiazole; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 121 with preparation example 89.
1H NMR(CDCl
3)δ：1.27-1.33(3H，m)，1.60(3H，s)，2.56(2H，m)，2.75-3.07(2H，m)，3.08(3H，s)，3.74-3.82(2H，m)，4.53-4.65(1H，m)，6.75-6.83(1H，m)，7.11-7.20(3H，m)，7.29-7.35(1H，m)，7.93(2H，d，J＝8.9Hz)
ESI-MS(m/e)：519[M+H]
+
Preparation example 122
3-(4-formyl-dimethylamino-phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(the 1-methyl-
The 1H-pyrazole-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate and to the formyl radical phenyl-boron dihydroxide; the formyl radical of 3-(4-formyl radical-phenoxy group)-5-methoxymethoxy-methyl benzoate that will make by the method the same with preparation example 1 converts carboxyl to; make itself and dimethylamine carry out condensation reaction then; the methoxymethyl of 3-(4-formyl-dimethylamino-phenoxy group)-5-methoxymethoxy-methyl benzoate of forming is thus carried out deprotection to be handled; the 3-that use obtains through this processing (4-formyl-dimethylamino-phenoxy group)-5-hydroxy-benzoic acid methyl esters; (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same with preparation example 2; based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 122.
1H NMR(CDCl
3)δ：1.33(d，3H，J＝6.2Hz)，2.11(brs，1H)，3.08(s，3H)，3.13(s，3H)，3.74-3.81(m，2H)，3.83(s，3H)，4.54-4.58(m，1H)，6.77(s，1H)，6.80(s，1H)，7.06(d，2H，J＝7.7Hz)，7.10(s，1H)，7.26(s，1H)，7.30(s，1H)，7.46(d，2H，J＝7.7Hz)，8.49(brs，1H)
ESI-MS(m/e)：439[M+H]
+，437[M-H]
-
Preparation example 123
3-(4-ethanoyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazoles-3-
Base) preparation of benzamide
Make the formyl radical and the Diethylaminoethyl reactive magnesium of 3-(4-formyl radical-phenoxy group)-5-methoxymethoxy-methyl benzoate that makes by the method the same with preparation example 122; the methoxymethyl of 3-(4-ethanoyl-phenoxy group)-5-methoxymethoxy-methyl benzoate of obtaining by oxidizing reaction is subsequently carried out deprotection to be handled; the 3-that use obtains through this processing (4-ethanoyl-phenoxy group)-5-hydroxy-benzoic acid methyl esters; (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane; 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same with preparation example 2; based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 123.
1H NMR(CDCl
3)δ：1.30(d，3H，J＝6.2Hz)，2.59(s，3H)，3.75-3.76(m，2H)，3.79(s，3H)，4.52-4.56(m，1H，J＝6.2，-Hz)，6.78(d，1H，J＝2.2Hz，d d，1H，J＝2.2，1.8Hz)，7.04(d，2H，J＝8.8Hz)，7.07(dd，1H，J＝1.8，1.8Hz)，7.25(dd，1H，J＝2.2，1.8Hz)，7.26(d，1H，J＝2.2Hz)，7.95(d，2H，J＝8.8Hz)，8.52(br，1H)
ESI-MS(m/e)：410[M+H]
+，408[M-H]
-
Preparation example 124
5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-3-(1,3,4-thiadiazoles-2-
The base sulfenyl) preparation of benzamide
Use 3-hydroxyl-5-iodo-benzoic acid methyl esters, uncle's 1-dimethylsilane oxygen base-2-hydroxy propane, 2-sulfydryl-[1,3,4] thiadiazoles and 3-amino-1-methyl isophthalic acid H-pyrazoles, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 124 with preparation example 74 or 82.
1H NMR(CDCl
3)δ：1.31(3H，d，J＝6.2Hz)，3.74-3.79(2H，m)，3.82(3H，s)，4.54-4.63(1H，m)，6.78(1H，d，J＝2.2Hz)，7.30(1H，d，J＝2.3Hz)，7.39(1H，m)，7.54(1H，m)，7.69(1H，m)，8.55(1H，br)，9.05(1H，s)
ESI-MS(m/e)：392[M+H]
+
Preparation example 125
N-(1-ethyl-1H-pyrazole-3-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl benzene
The oxygen base) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-ethyl-1H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 125 of white with preparation example 89.
1H NMR(CDCl
3)δ：1.30(d，3H，J＝6.2Hz)，1.43(t，3H，J＝7.3Hz)，3.07(s，3H)，3.76(m，2H)，4.05(q，2H，J＝7.3Hz)，4.56(m，1H)，6.79(m，2H)，7.12(d，2H，J＝8.8Hz)，7.14(m，1H)，7.30(m，1H)，7.33(m，1H)，7.92(d，2H，J＝8.8Hz)，8.70(br，1H)
ESI-MS(m/e)：460[M+H]
+
Preparation example 126
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(the 1-methyl-
The 1H-pyrazole-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-methylsulfonyl pyridine, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 126 of white with preparation example 117.
1HNMR(CDCl
3)δ：1.29(d，3H，J＝6.3Hz)，3.22(s，3H)，3.75(m，2H)，3.78(s，3H)，4.55(m，1H)，6.75(m，1H)，6.78(m，1H)，7.11(m，1H)，7.26(m，1H)，7.29(m，1H)，7.42(d d，1H，J＝2.9，8.5Hz)，8.03(d，1H，J＝8.5Hz)，8.44(d，1H，J＝2.9Hz)，8.65(br，1H)
ESI-MS(m/e)：447[M+H]
+
Preparation example 127
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methoxycarbonyl amino methyl-phenoxy group)-N-(3-first
Base-1,2,4-thiadiazoles-5-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate to replace 5-hydroxyl-3-isopropoxy methyl benzoate; the methoxymethyl of 3-(4-methoxycarbonyl amino methyl phenoxy group)-5-methoxymethoxy-methyl benzoate of making by the method the same with preparation example 59 is carried out deprotection to be handled; the 3-that use obtains through this processing (4-methoxycarbonyl amino methyl phenoxy group)-5-hydroxy-benzoic acid methyl esters; (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 5-amino-3-methyl-[1; 2; 4]-thiadiazoles; by the method the same with preparation example 2; based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 127.
1H NMR(CDCl
3)δ：1.29(d，3H，J＝6.2Hz)，2.45(s，3H)，3.71(s，3H)，3.73-3.78(m，2H)，4.35(d，2H，J＝6.2Hz)，4.50-4.57(m，1H，J＝6.2Hz，-)，5.08(brs，1H)，6.76(s，1H)，6.97(d，2H，J＝8.3Hz)，7.01(s，1H)，7.16(s，1H)，7.27(d，2H，J＝8.3Hz)，10.8(brs，1H)
ESI-MS(m/e)：495[M+Na]
+，473[M+H]
+，471[M-H]
-
Preparation example 128
5-(1-hydroxymethyl-propoxy-)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(1-methyl isophthalic acid H-pyrrole
Azoles-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-methylsulfonyl pyridine, (2S)-1-(t-butyldimethylsilyloxy base)-2-hydroxyl butane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 128 with preparation example 117.
1HNMR(CDCl
3)δ：0.99(t，3H，J＝7.5Hz)，1.70-1.77(m，2H)，3.24(s，3H)，3.79-3.82(m，5H)，4.36-4.40(m，1H)，6.78(d，1H，J＝1.8Hz)，6.85(d，1H，J＝1.8Hz)，7.13(s，1H)，7.29(d，1H，J＝2.3H z)，7.34(d，1H，J＝2.3Hz)，7.46(dd，1H，J＝2.6，8.9H z)，8.08(d，1H，J＝8.9Hz)，8.48(d，1H，J＝2.6Hz)
ESI-MS(m/e)：461[M+H]
+
Preparation example 129
3-(6-methylsulfonyl pyridin-3-yl oxygen base)-5-(1-methoxymethyl-propoxy-)-N-(1-methyl isophthalic acid H-
Pyrazole-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-methylsulfonyl pyridine, (2S)-1-methoxyl group-2-hydroxyl butane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 129 with preparation example 117.
1HNMR(CDCl
3)δ：0.99(t，3H，J＝7.4Hz)，1.74-1.79(m，2H)，3.24(s，3H)，3.37(s，3H)，3.56-3.57(m，2H)，3.79(s，3H)，4.37-4.40(m，1H)，6.79(s，1H)，6.87(t，1H，J＝1.2Hz)，7.14(s，1H)，7.29(d，1H，J＝1.2Hz)，7.34(d，1H，J＝1.2Hz)，7.45(dd，1H，J＝2.0，8.6Hz)，8.06(d，1H，J＝8.6Hz)，8.48(d，1H，J＝2.0Hz)
ESI-MS(m/e)：475[M+H]
+
Preparation example 130
5-isopropoxy-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzene
The preparation of methane amide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-methylsulfonyl pyridine, 2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 130 of white with preparation example 117.
1H NMR(CDCl
3)δ：1.35(d，6H，J＝6.2Hz)，3.22(s，3H)，3.77(s，3H)，6.75(septe，1H，J＝6.2Hz)，6.74(m，1H)，6.76(m，1H)，7.08(m，1H)，7.24(m，1H)，7.26(m，1H)，7.41(dd，1H，J＝2.9，8.8Hz)，8.03(d，1H，J＝8.8Hz)，8.44(d，1H，J＝2.9Hz)，8.64(br，1H)
ESI-MS(m/e)：431[M+H]
+
Preparation example 131
5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(the 1-methyl-
The 1H-pyrazole-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-methylsulfonyl pyridine, 1; 3-two fluoro-2-propyl alcohol and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 131 of white with preparation example 117.
1H NMR(CDCl
3)δ：3.23(s，3H)，3.75(s，3H)，4.55-4.61(m，2H)，4.61-4.80(m，3H)，6.75(m，1H)，6.88(m，1H)，7.18(m，1H)，7.27(m，1H)，7.34(m，1H)，7.43(d d，1H，J＝2.4，8.4Hz)，8.04(d，1H)，8.44(d，1H，J＝2.4Hz)，8.84(br，1H)
ESI-MS(m/e)：467[M+H]
+
Preparation example 132
3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(isoxazole-3-
Base) preparation of benzamide
Use amino-isoxazoles of 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-b sulfonyl pyridine, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 132 with preparation example 117.
1H NMR(CDCl
3)δ：1.31(d，3H，J＝6.2Hz)，1.32(t，3H，J＝7.3Hz)，2.22(brs，1H)，3.40(q，2H，J＝7.3Hz)，3.75-3.77(m，2H)，4.56-4.61(m，1H，J＝6.2，-Hz)，6.86(d，1H，J＝2.2Hz)，7.17(d，1H，J＝2.2Hz)，7.26(d，1H，0.7Hz)，7.40(d，1H，J＝2.2Hz)，7.43(dd，1H，J＝8.8，2.9Hz)，8.04(d，1H，J＝8.8Hz)，8.26(d，1H，J＝0.7Hz)，8.46(d，1H，J＝2.9Hz)，9.83(brs，1H)
ESI-MS(m/e)：448[M+H]
+，446[M-H]
-
Preparation example 133
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenyl sulfenyl)-N-(1-methyl isophthalic acid H-pyrazoles
-3-yl) preparation of benzamide
Use 3-hydroxyl-5-iodo-benzoic acid methyl esters, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane, 4-methylsulfonyl benzenethiol and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 133 with preparation example 74 or 82.
1H NMR(CDCl
3)δ：1.30(3H，d，J＝6.2Hz)，3.05(3H，s)，3.74-3.79(2H，m)，3.81(3H，s)，4.52-4.63(1H，m)，6.78(1H，d，J＝2.3Hz)，7.21(1H，m)，7.30(1H，d，J＝2.2Hz)，7.34(2H，d，J＝8.6Hz)，7.47-7.50(1H，m)，7.51-7.54(1H，m)，7.82(2H，d，J＝8.6Hz)，8.53(1H，br)
ESI-MS(m/e)：392[M+H]
+
Preparation example 134
5-ring propoxy--3-(4-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide
Preparation
Make 5-hydroxyl-3-methoxymethoxy methyl benzoate, tetrem thiazolinyl tin and venus crystals reaction, gained 5-methoxymethoxy-3-vinyl oxygen base-methyl benzoate is then reacted with zinc ethyl and methylene iodide, use the 3-ring propoxy--5-methoxymethoxy-methyl benzoate obtain thus, to methylthio phenyl ylboronic acid and 3-amino-1-methyl isophthalic acid H-pyrazoles, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 134 of colorless oil with preparation example 1.
1H NMR(CDCl
3)δ：0.70-0.85(m，4H)，3.08(s，3H)，3.78(m，1H)，3.79(s，3H)，6.78(m，1H)，6.91(m，1H)，7.10-7.14(m，3H)，7.27(m，1H)，7.41(m，1H)，7.90(d，2H，J＝8.8Hz)，8.52(br，1H)
ESI-MS(m/e)：428[M+H]
+
Preparation example 135
3-(6-methylsulfonyl pyridin-3-yl oxygen base)-5-(1-methoxymethyl-propoxy-)-N-(pyrazole-3-yl)
The preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-methylsulfonyl pyridine, (2R)-1-methoxyl group-2-hydroxyl butane and 3-amino-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 135 with preparation example 117.
1H NMR(CDCl
3)δ：0.98(t，3H，J＝7.4Hz)，1.69-1.78(m，2H)，3.22(s，3H)，3.38(s，3H)，3.58-3.59(m，2H)，4.37-4.43(m，1H)，6.84-6.85(m，2H)，7.20(s，1H)，7.41-7.49(m，3H)，8.04(d，1H，J＝8.6Hz)，8.45(d，1H，J＝2.6Hz)，9.92(brs，1H)
ESI-MS(m/e)：461[M+H]
+
Preparation example 136
5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazoles-
The 3-yl) preparation of benzamide
Use preparation example 89 gained 3-(4-methylsulfonyl-phenoxy group)-5-methoxymethoxy-methyl benzoate, 1; 3-two fluoro-2-propyl alcohol and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 136 with preparation example 89.
1H NMR(CDCl
3)δ：3.09(s，3H)，3.77(s，3H)，4.59-4.76(m，5H)，6.78(s，1H)，6.89(t，1H，J＝2.0Hz)，7.13(d，2H，J＝8.6Hz)，7.18(s，1H)，7.29(d，1H，J＝2.0Hz)，7.33(d，1H，J＝2.0Hz)，7.93(d，2H，J＝8.6Hz)，8.76(brs，1H)
ESI-MS(m/e)：466[M+H]
+
Preparation example 137
3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(1-hydroxymethyl-propoxy-)-N (1-methyl isophthalic acid H-pyrrole
Azoles-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-b sulfonyl pyridine, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxyl butane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 137 with preparation example 117.
1H NMR(CDCl
3)δ：0.97(t，3H，J＝7.4Hz)，1.32(t，3H，J＝7.4Hz)，1.67-1.84(m，2H)，3.40(q，2H，J＝7.4Hz)，3.74-3.84(m，5H)，4.33-4.40(m，1H)，6.77(s，1H)，6.79(s，1H)，7.15(s，1H)，7.28(s，1H)，7.33(s，1H)，7.43(dd，1H，J＝2.6，8.8Hz)，8.05(d，1H，J＝8.8Hz)，8.47(d，1H，J＝2.6Hz)
ESI-MS(m/e)：475[M+H]
+
Preparation example 138
5-(6-b sulfonyl pyridine-3-base oxygen base)-3-(2-methoxyl group-1-methyl-oxyethyl group)-N-(the 1-first its-
The 1H-pyrazole-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-b sulfonyl pyridine, (2R)-2-hydroxyl-1-methoxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 138 with preparation example 117.
1H NMR(CDCl
3)δ：1.34(t，3H，J＝7.3Hz)，1.34(d，3H，J＝4.0Hz)，3.40(s，3H)，3.41(q，2H，J＝7.3Hz)，3.49-3.60(m，2H)，3.80(s，3H)，4.60(qt，1H，J＝4.0，6.2Hz)，6.78(s，1H)，6.83(d，1H，J＝2.2Hz)，7.14(s，1H)，7.28(d，1H，J＝2.2Hz)，7.31(s，1H)，7.42(dd，1H，J＝8.4，2.6Hz)，8.05(d，1H，J＝8.4Hz)，8.48(d，1H，J＝2.6Hz)，8.49(brs，1H)
ESI-MS(m/e)：475[M+H]
+，473[M-H]
-
Preparation example 139
2-[3-(4-methylsulfonyl phenoxy group)-5-(1-methyl isophthalic acid H-pyrazole-3-yl formamyl)-phenoxy group]
The preparation of propionic acid-tertiary butyl ester
Use gained 5-hydroxyl-3-(4-methylthio group phenoxy group) methyl benzoate, the 2 bromopropionic acid tert-butyl ester and 3-amino-1-methyl isophthalic acid H-pyrazoles in the preparation example 1, by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 139 with preparation example 1.
1H NMR(CDCl
3)δ：1.44(9H，s)，1.60(3H，d，J＝6.8Hz)，3.07(3H，s)，3.81(3H，s)，4.69(1H，q，J＝6.8Hz)，6.77(1H，br)，7.10-7.16(3H，m)，7.24(1H，br)，7.29(1H，d，J＝2.2Hz)，7.92(2H，d，J＝8.9Hz)，8.38(1H，br)
ESI-M S(m/e)：516[M+H]
+
Preparation example 140
3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-methoxyl group-1-methyl-oxyethyl group)-N-(pyrazoles-3-
Base)-preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-b sulfonyl pyridine, (2R)-2-hydroxyl-1-methoxy propane and 3-amino-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 140 with preparation example 117.
1H NMR(CDCl
3)δ：1.33(t，3H，J＝7.3Hz)，1.34(d，3H，J＝6.2Hz)，3.40(q，2H，J＝7.3Hz)，3.41(s，3H)，3.52-3.62(m，2H)，4.60-4.65(m，1H，J＝6.2Hz，-Hz)，6.83(d，1H，J＝2.2Hz)，6.86(s，1H)，7.20(s，1H)，7.42(d，1H，J＝2.2Hz)，7.42(dd，1H，J＝8.8，2.6Hz)，7.49(s，1H)，7.04(d，1H，J＝8.8Hz)，8.47(d，1H，J＝2.6Hz)，9.47(brs，1H)
ESI-MS(m/e)：461[M+H]
+，459[M-H]
-
Preparation example 141
3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-(tetrahydrofuran (THF)-
The 3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-methylsulfonyl pyridine, (S)-(+)-3-hydroxyl tetrahydrofuran and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 141 of colorless oil with preparation example 117.
1H NMR(CDCl
3)δ：2.15-2.26(m，1H)，2.26-2.30(m，1H)，3.24(s，3H)，3.80(s，3H)，3.88-4.03(m，4H)，4.97(m，1H)，6.76(m，2H)，7.11(t，1H，J＝2.2Hz)，7.24(d，1H，J＝2.2Hz)7.28(d，1H，J＝2.2Hz)，7.44(dd，1H，J＝2.9，8.4Hz)，8.05(d，1H，J＝8.4Hz)，8.44(br，1H)，8.45(d，1H，J＝2.9Hz)
ESI-MS(m/e)：459[M+H]
+
Preparation example 142
N-(1-ethyl-1H-pyrazole-3-yl)-5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(6-methylsulfonyl pyrrole
Pyridine-3-base oxygen base) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-methylsulfonyl pyridine, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-ethyl-1H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 142 of white with preparation example 117.
1H NMR(CDCl
3)δ：1.33(d，3H，J＝6.2Hz)，1.47(t，3H，J＝7.3Hz)，1.98(m，1H)，3.24(s，3H)3.77(m，2H)，4.07(q，2H，J＝7.3Hz)，4.58(m，1H)，6.77(d，1H，J＝2.6Hz)，6.82(t，1H，J＝2.6Hz)，7.13(m，1H)，7.32(m，2H)，7.45(dd，1H，J＝2.6，8.4Hz)，8.06(d，1H，J＝8.4Hz)，8.34(br、1H)，8.47(d，1H，J＝2.6Hz)
ESI-MS(m/e)：461[M+H]
+
Preparation example 143
5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(pyrazole-3-yl)
The preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-methylsulfonyl pyridine, 1; 3-two fluoro-2-propyl alcohol and 3-amino-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 143 of white with preparation example 117.
1H NMR(CDCl
3)δ：3.23(s，3H)，4.55-4.70(m，2H)，4.70-4.90(m，3H)，6.79(m，1H)，6.91(m，1H)，7.28(m，1H)，7.42-7.51(m，3H)，8.04(d，1H，J＝8.9Hz)，8.44(d，1H，J＝2.6Hz)，9.60(br，1H)
ESI-MS(m/e)：453[M+H]
+
Preparation example 144
3-(6-methylsulfonyl pyridin-3-yl oxygen base)-5-(2-methoxyl group-1-methyl-oxyethyl group)-N-(the 1-methyl-
The 1H-pyrazole-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-methylsulfonyl pyridine, (2R)-2-hydroxyl-1-methoxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the preparation example 144 of colorless oil with preparation example 117.
1H NMR(CDCl
3)δ：1.32(d，3H，J＝6.4Hz)，3.23(s，3H)，3.40(s，3H)，3.54(m，2H)，3.78(s，3H)，4.59(m，1H)，6.78(m，1H)，6.84(m，1H)，7.14(m，1H)，7.29(m，1H)，7.32(m，1H)，7.44(dd，1H，J＝2.6，8.6Hz)，8.05(d，1H，J＝8.6Hz)，8.47(d，1H，J＝2.6Hz)，8.66(br，1H)
ESI-MS(m/e)：461[M+H]
+
Preparation example 145
3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-fluoro-1-methyl fluoride-oxyethyl group)-N-(the 1-methyl-
The 1H-pyrazole-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-b sulfonyl pyridine, 1; 3-two fluoro-2-propyl alcohol and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 145 with preparation example 117.
1H NMR(CDCl
3)δ：1.33(t，3H，J＝7.42Hz)，3.41(q，2H，J＝7.4Hz)，3.80(s，3H)，4.61-4.65(m，2H)，4.73-4.78(m，3H)，6.78(d d，1H，J＝2.0，1.8Hz)，6.91(d，1H，J＝2.3Hz)，7.23(dd，1H，J＝1.8，1.6Hz)，7.30(d，1H，J＝2.3Hz)，7.38(dd，1H，J＝2.0，1.6Hz)，7.16(dd，1H，J＝8.6，2.7Hz)，8.08(d，1H，J＝8.6Hz)，8.50(d，1H，J＝2.7Hz)，8.63(brs，1H)
ESI-MS(m/e)：481[M+H]
+，479[M-H]
-
Preparation example 146
2-[3-(4-methylsulfonyl phenoxy group)-5-(1-methyl isophthalic acid H-pyrazole-3-yl formamyl)-phenoxy group]
The preparation of propionic acid
With preparation example 139 gained 2-[3-(4-methylsulfonyl phenoxy group)-5-(1-methyl isophthalic acid H-pyrazole-3-yl formamyl)-phenoxy group] the tert-butyl ester that propionic acid-tertiary butyl ester had converts carboxyl to, obtains the compound into the preparation example 146 of white solid.The conversion method that ester is converted to carboxyl can be passed through Comprehensive Organic Transformations, works such as Richard L, VCH Publishers company, makes up based on its method or with these methods and ordinary method and to carry out the method for record in 1988 etc.
1H NMR(CD
3OD)δ：1.60(3H，d，J＝6.8Hz)，3.11(3H，s)，3.82(3H，s)，6.54-6.58(1H，br)，6.84(1H，br)，7.16-7.28(3H，m)，7.34(1H，br)，7.49(1H，d，J＝2.1Hz)，7.95(2H，d，J＝8.9Hz)
ESI-MS(m/e)：460[M+H]
+
Preparation example 147
The system of 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-isopropoxy-N-(pyrazole-3-yl) benzamide
Be equipped with
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-b sulfonyl pyridine, 2-hydroxy propane and 3-amino-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 147 with preparation example 117.
1H NMR(CDCl
3)δ：1.32(t，3H，J＝7.3Hz)，1.37(d，6H，J＝5.9Hz)，3.39(q，2H，J＝7.3Hz)，4.60(septet，1H，J＝5.9Hz)，6.76(dd，1H，J＝2.2，2.2Hz)，6.84(s，1H)，7.16(s，1H)，7.33(s，1H)，7.40(dd，1H，J＝8.8，2.6Hz)，7.51(dd，1H，J＝2.2，2.6Hz)，8.03(dd，1H，J＝8.8，2.6Hz)，8.46(dd，1H，J＝2.6，2.6Hz)，9.03(brs，1H)
ESI-MS(m/e)：431[M+H]
+，429[M-H]
-
Preparation example 148
3-(6-b sulfonyl pyridine-3-base oxygen base)-5-isopropoxy-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzene
The preparation of methane amide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-b sulfonyl pyridine, 2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 148 with preparation example 117.
1H NMR(CDCl
3)δ：1.34(t，3H，J＝7.3Hz)，1.37(d，6H，J＝5.9Hz)，3.41(q，2H，J＝7.3Hz)，3.81(s，3H)，4.60(septet，1H，J＝5.9Hz)，6.75-6.78(m，2H)，7.11(s，1H)，7.26(s，1H)，7.28(d，1H，J＝2.2Hz)，7.42(dd，1H，J＝8.8，2.9Hz)，8.05(d，1H，J＝8.8Hz)，8.36(brs，1H)，8.48(d，1H，J＝2.9Hz)
ESI-MS(m/e)：445[M+H]
+，443[M-H]
-
Preparation example 149
3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(pyrazole-3-yl)
The preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-b sulfonyl pyridine, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 149 with preparation example 117.
1H NMR(CDCl
3(one drop of CD
3OD))δ：1.29(d，3H，J＝6.3Hz)，1.31(t，3H，J＝7.4Hz)，3.39(q，2H，J＝7.4Hz)，3.70-3.76(m，2H)，4.55(septet，1H，J＝6.3Hz)，6.77(s，1H)，6.79(d，1H，J＝2.3Hz)，7.20(s，1H)，7.37(s，1H)，7.41(dd，1H，J＝8.6，2.7Hz)，7.49(d，1H，J＝2.3Hz)，8.02(d，1H，J＝8.6Hz)，8.44(d，1H，J＝2.7Hz)，9.55(brs，1H)
ESI-MS(m/e)：447[M+H]
+，445[M-H]
-
Preparation example 150
3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(pyridine-2-yl)
The preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-b sulfonyl pyridine, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 2-aminopyridine; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 150 with preparation example 117.
1H NMR(CDCl
3)δ：1.33(d，3H，J＝6.1Hz)，1.33(t，3H，J＝7.4Hz)，3.41(q，2H，J＝7.4Hz)，3.78-3.80(m，2H)，4.62(dq，1H，J＝4.5，6.1Hz)，6.84(s，1H)，7.11(dd，1H，J＝6.6，5.1Hz)，7.22(s，1H)，7.38(s，1H)，7.45(dd，1H，J＝8.8，2.5Hz)，7.78(dd，1H，J＝8.4，6.6Hz)，8.08(d，1H，J＝8.8Hz)，8.30(d，1H，J＝5.1Hz)，8.34(d，1H，J＝8.4Hz)，8.50(d，1H，J＝2.5Hz)，8.63(brs，1H)
ESI-MS(m/e)：481[M+H]
+
Preparation example 151
3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-thiazol-2-yl-
The preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-b sulfonyl pyridine, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and thiazolamine; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 151 with preparation example 117.
1H NMR(CDCl
3)δ：1.31(d，3H，J＝6.3Hz)，1.33(t，3H，J＝7.4Hz)，3.41(q，2H，J＝7.4Hz)，3.76-3.78(m，2H)，4.55-4.60(m，1H)，6.86(m，1H)，7.02(d，1H，J＝3.5Hz)，7.26(m，1H)，7.29(d，1H，J＝3.5Hz)，7.42(m，1H)，7.46(dd，1H，J＝8.6，2.7Hz)，8.08(d，1H，J＝8.6Hz)，8.49(d，1H，J＝2.7Hz)
ESI-MS(m/e)：464[M+H]+，462[M-H]-
Preparation example 152
5-(2-fluoro-1-methyl-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(1-methyl isophthalic acid H-
Pyrazole-3-yl) preparation of benzamide
After converting the hydroxyl of preparation example 126 gained 5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide to the methylsulfonyl ester with triethylamine, methylsulfonyl chloride; by with the method for tetrabutylammonium fluoride reaction, obtain compound into colourless unbodied preparation example 152.
1H NMR(CDCl
3)δ：1.35(dd，3H，J＝1.6，6.2Hz)，3.24(s，3H)，3.77(s，3H)，4.45(m，1H)，4.57(m，1H)，4.67(m，1H)，6.79(d，1H，J＝2.3Hz)，6.84(t，1H，J＝2.3Hz)，7.16(t，1H，J＝2.3Hz)，7.30(d，1H，J2.3Hz)，7.32(m，1H)，7.45(d，1H，J＝2.3，8.6Hz)，8.06(d，1H，J＝8.6Hz)，8.47(d，1H，J＝2.3Hz)，8.79(br，1H)
ESI-MS(M/E)：449[M+H]
+
Preparation example 153
5-(2-chloro-1-methyl-oxyethyl group)-3-(6-b sulfonyl pyridine-3-base oxygen base)-N-(1-methyl isophthalic acid H-
Pyrazole-3-yl) preparation of benzamide
After converting the hydroxyl of preparation example 117 gained 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide to the methylsulfonyl ester with triethylamine, methylsulfonyl chloride, obtain compound into colourless unbodied preparation example 153.
1H NMR(CDCl
3)δ：1.33(t，3H，J＝7.4Hz)，1.45(d，3H，J＝6.2Hz)，3.41(q，2H，J＝7.4Hz)，3.63(dd，1H，J＝5.0，11.5hz)，3.69(dd，1H，J＝5.0，11.5Hz)，3.79(s，3H)，4.62(m，1H)，6.79(d，1H，J＝2.2Hz)，6.83(t，1H，J＝2.2Hz)，7.18(m，1H)，7.29-7.35(m，2H)，7.45(dd，1H，J＝2.7，8.6Hz)，8.07(d，1H，J＝8.6Hz)，8.49(d，1H，J＝2.7Hz)，8.67(br，1H)
ESI-MS(M/E)：479[M+H]
+
Preparation example 154
5-(2-fluoro-1-methyl fluoride-oxyethyl group)-N-(isoxazole-3-base)-3-(6-methylsulfonyl pyridin-3-yl oxygen
Base) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-methylsulfonyl pyridine, 1; 3-two fluoro-2-propyl alcohol and 3-ammonia base oxazole; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 154 of white with preparation example 117.
1H NMR(CDCl
3)δ：3.24(s，3H)，4.59-4.70(m，2H)，4.70-4.90(m，3H)，6.96(t，1H，J＝2.3Hz)，7.19(m，1H)，7.32(m，1H)，7.45(m，1H)，7.48(dd，1H，J＝2.7，8.5Hz)，8.09(d，1H，J＝8.5Hz)，8.29(m，1H)，8.49(d，1H，J＝2.7Hz)，9.60(br，1H)
ESI-MS(M/E)：454[M+H]
+
Preparation example 155
5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(pyridine-2-yl)
The preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-methylsulfonyl pyridine, 1; 3-two fluoro-2-propyl alcohol and 2-aminopyridine; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 155 of white with preparation example 117.
1HNMR(CDCl
3)δ：3.24(s，3H)，4.60-4.70(m，2H)，4.70-4.90(m，3H)，6.93(t，1H，J＝2.1Hz)，7.10(m，1H)，7.26(m，1H)，7.42(m 1H)，7.48(dd，1H，J＝2.1，8.2Hz)，7.78(d t，1H，J＝)，8.09(d，1H，J＝8.4Hz)，8.30(m，1H)，8.32(d，1H，J＝8.4Hz)，8.49(d，1H，J＝2.1Hz)，8.59(br，1H)
ESI-MS(M/E)：464[M+H]
+
Preparation example 156
5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(the 3-methyl-
[1,2,4]-thiadiazoles-5-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-methylsulfonyl pyridine, 1; 3-two fluoro-2-propyl alcohol and 5-amino-3-methyl-[1; 2; 4] thiadiazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 156 of white with preparation example 117.
1H NMR(CDCl
3)δ：2.50(s，3H)，3.27(s，3H)，4.57-4.67(m，2H)，4.67-4.90(m，3H)，7.01(t，1H，J＝2.3Hz)，7.29(m，1H)，7.45(m，1H)，7.49(dd，1H，J＝2.3，8.7Hz)，8.09(d，1H，J＝8.7Hz)，8.47(d，1H，J＝2.3Hz)
ESI-MS(M/E)：485[M+H]
+
Preparation example 157
3-(4-dimethylamino alkylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-
Pyrazole-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 4-bromo-dimethylamino alkylsulfonyl benzene, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 157 of white with preparation example 42.
1H NMR(CDCl
3)δ：1.31(d，3H，J＝6.3Hz)，2.19(brs，1H)，2.74(s，6H)，3.76-3.80(m，2H)，3.81(s，3H)，4.54-4.59(m，1H，J＝6.3Hz，-Hz)，6.79(m，1H)，6.81(m，1H)，7.11(d，2H，J＝9.0Hz)，7.13(s，1H)，7.29-7.30(m，2H)，7.77(d，2H，J＝9.0Hz)，8.55(br，1H)
ESI-MS(m/e)：475[M+H]+，473[M-H]-
Preparation example 158
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(3-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazoles-
The 3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 3-methylthio group-phenyl-boron dihydroxide, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 158 of white with preparation example 1 or preparation example 89.
1H NMR(CDCl
3)δ：1.30(d，3H，J＝6.2Hz)，2.08(t，1H，J＝6.5Hz)，3.07(s，3H)，3.73-3.78(m，5H)，4.52-4.57(m，1H)，6.77-6.78(m，2H)，7.08(d，1H，J＝2.1Hz)，7.25-7.31(m，3H)，7.54(t，1H，J＝7.6Hz)，7.59(d，1H，J＝2.1Hz)，7.70(d，1H，J＝7.6Hz)，8.49(brs，1H)
ESI-MS(m/e)：446[M+H]
+
Preparation example 159
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(6-sec.-propyl sulfonyl pyridine-3-base oxygen base)-N-(1-first
Base-1H-pyrazole-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 5-bromo-2-sec.-propyl sulfonyl pyridine, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 159 of white with preparation example 117.
1H NMR(CDCl
3)δ：1.31(d，3H，J＝5.9Hz)，1.35(d，6H，J＝6.7Hz)，2.25(brs，1H)，3.72(septet，1H，J＝6.7Hz)，3.70-3.81(m，2H)，3.81(s，3H)，4.53-4.59(m，1H)，6.78-6.79(m，1H)，6.80-6.82(m，1H)，7.17(m，1H)，7.29-7.31(m，1H)，7.32(m，1H)，7.43(dd，1H，J＝8.6，2.7Hz)，8.06(d，1H，J＝8.6Hz)，8.50(d，1H，J＝2.7Hz)，8.60(brs，1H)
ESI-MS(m/e)：475[M+H]+，473[M-H]-
Preparation example 160
3-(3-chloro-4-methylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-
Pyrazole-3-yl) preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 4-bromo-2-chloro-methylsulfonyl benzene, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 160 of white with preparation example 42.
1H NMR(CDCl
3)δ：1.31(d，3H，J＝6.1Hz)，3.28(s，3H)，3.76-3.80(m，5H)，4.54-4.59(m，1H)，6.80-6.81(m，2H)，7.02(dd，1H，J＝2.3，8.8Hz)，7.14-7.15(m，2H)，7.30(d，1H，J＝2.3Hz)，7.33(s，1H)，8.11(d，1H，J＝8.8Hz)，8.75(brs，1H)
ESI-MS(m/e)：480[M+H]
+
Preparation example 161
5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-3-(pyridin-3-yl oxygen base)
The preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 3-iodine pyridine, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 161 of white with preparation example 117.
1H NMR(CDCl
3)δ：1.30(d，3H，J＝6.3Hz)，2.27(br，1H)，3.72-3.80(m，2H)，3.80(s，3H)，4.55(m，1H)，6.75(t，1H，J＝2.3Hz)，6.79(d，1H，J＝2.3Hz)，7.05(m，1H)，7.22(m，1H)，7.29(d，1H，J＝2.3Hz)，7.31-7.38(m，2H)，8.44(m，2H)，8.62(br，1H)
ESI-MS(M/E)：369[M+H]
+
Preparation example 162
5-(2-fluoro-1-methyl fluoride-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-3-(pyridin-3-yl oxygen base)
The preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 3-iodine pyridine, 1,3-two fluoro-2-propyl alcohol and 3-amino-1-methyl isophthalic acid H-pyrazoles, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 162 of white with preparation example 117.
1H NMR(CDCl
3)δ：3.77(s，3H)，4.55-4.67(m，2H)，4.67(m，3H)，6.79(d，1H，J＝2.3Hz)，6.82(t，1H，J＝2.3H z)，7.11(m，1H)，7.26(m，1H)，7.29(d，1H，J＝2.3Hz)，7.30-7.38(m，2H)，8.45(m，2H)，8.70(br，1H)
ESI-MS(M/E)：389[M+H]
+
Preparation example 163
5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-3-(pyridin-4-yl oxygen base)
The preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 4-chloropyridine hydrochloride, (2R)-1-(t-butyldimethylsilyloxy base)-2-hydroxy propane and 3-amino-1-methyl isophthalic acid H-pyrazoles, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 163 of white with preparation example 117.
1H NMR(CDCl
3)δ：1.31(d，3H，J＝6.3Hz)，2.05(br，1H)，3.77(m，2H)，3.82(s，3H)，4.56(m，1H)，6.79(d，1H，J＝2.3Hz)，6.83(t，1H，J＝2.3Hz)，6.88(dd，2H，J＝1.6，4.7Hz)，7.15(m，1H)，7.30(d，1H，J＝2.2Hz)，7.33(m，1H)，8.42(br，1H)，8.51(dd，2H，J＝1.6，4.7Hz)
ESI-M S(M/E)：369[M+H]
+
Preparation example 164
5-(2-fluoro-1-methyl fluoride-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-3-(pyridin-4-yl oxygen base)
The preparation of benzamide
Use 5-hydroxyl-3-methoxymethoxy methyl benzoate, 4-chloropyridine hydrochloride, 1,3-two fluoro-2-propyl alcohol and 3-amino-1-methyl isophthalic acid H-pyrazoles, by the method the same, based on its method or with these methods and ordinary method combination, make compound into the unbodied preparation example 164 of white with preparation example 117.
1H NMR(CDCl
3)δ：3.81(s，3H)，4.58-4.67(m，2H)，4.67-4.82(m，3H)，6.79(d，1H，J＝2.0Hz)，6.89(dd，2H，J＝1.6，4.7Hz)，6.91(t，1H，J2.3Hz)，7.21(t，1H，J＝2.3Hz)，7.30(d，1H，J＝2.0Hz)，7.38(t，1H，J＝2.3Hz)，8.52(br，1H)，8.52(dd，2H，J＝1.6，4.7Hz)
ESI-MS(M/E)：389[M+H]
+
Preparation example 165
2-[3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(1-methyl isophthalic acid H-pyrazole-3-yl formamyl)-
Phenoxy group] preparation of propionic acid
Use preparation example 117 gained 3-(6-b sulfonyl pyridine-3-base oxygen base)-5-hydroxy-benzoic acid methyl esters, the 2 bromopropionic acid tert-butyl ester and 3-amino-1-methyl isophthalic acid H-pyrazoles; the 2-[3-that will make (6-b sulfonyl pyridine-3-base oxygen base)-5-(1-methyl isophthalic acid H-pyrazole-3-yl formamyl)-phenoxy group by the method the same with preparation example 1] tert-butyl ester of propionic acid-tertiary butyl ester converts carboxyl to, obtains the compound into the preparation example 165 of white solid.The conversion method that ester is converted to carboxyl can be passed through Comprehensive Organic Transformations, works such as Richard L, VCH Publishers company, makes up based on its method or with these methods and ordinary method and to carry out the method for record in 1988 etc.
1H NMR(CDCl
3)δ：1.24(3H，t，J＝7.4Hz)，1.59(3H，d，J＝6.8Hz)，3.39(2H，q，J＝7.4Hz)，3.81(3H，s)，4.69-4.80(1H，m)，6.56(1H，d，J＝2.3Hz)，6.90(1H，t，J＝2.2Hz)，7.25(1H，br)，7.37(1H，br)，7.48(1H，d，J＝2.3Hz)，7.62(1H，dd，J＝8.7Hz，2.7Hz)，8.07(1H，d，J＝6.4Hz)，8.52(1H，d，J＝2.7Hz)
ESI-MS(M/E)：475[M+H]
+
Preparation example 166
5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(3-fluoro-4-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-
Pyrazole-3-yl) preparation of benzamide
3-(3-fluoro-4-methylsulfonyl phenoxy group)-5-hydroxy-benzoic acid methyl esters, 1 that use obtains by the method the same with preparation example 42; 3-two fluoro-2-propyl alcohol and 3-amino-1-methyl isophthalic acid H-pyrazoles; by the method the same, based on its method or with these methods and ordinary method combination, make compound into colourless unbodied preparation example 166 with preparation example 2.
1H NMR(CDCl
3)δ：3.23(3H，s)，3.82(3H，s)，4.61-4.78(5H，m)，6.78(1H，d，J＝2.3Hz)，6.83-6.94(3H，m)，7.19(1-H，t，J＝1.8Hz)，7.30(1H，d，J＝2.3Hz)，7.38(1H，t，J＝1.8Hz)，7.94(1H，t，J＝8.4H z)，8.37(1H，brs)
ESI-MS(M/E)：484[M+H]
+
Industrial applicability
It is active that Heteroarylcarbamoylbderivative derivative of the present invention shown in the formula (I) demonstrates excellent glucokinase, thereby can be used for the treatment of and/or prevent at field of medicaments complication or the obesity of diabetes, diabetes.
Claims (11)
1. compound or its pharmacy acceptable salt shown in the formula (I),
X in the formula
1The expression Sauerstoffatom;
X
2The expression Sauerstoffatom;
A ring expression phenyl or pyridyl;
R
1Be illustrated in 1 or 2 substituting groups existing on the A ring, it is selected from C
1-6Alkyl sulphonyl,
C
1-6Alkyloyl, hydroxyl C
1-6Alkyl and halogen atom;
R
2Expression straight or branched C
1-6Alkyl or C
2-6Thiazolinyl, it has and is selected from following 1 or 2 substituting groups: halogen atom, carboxyl, C
1-6Alkoxy carbonyl, hydroxyl, amino, this amino can be further by one or two C
1-6Alkyloyl or C
1-6Alkyl replaces, C
1-6Alkoxyl group and N-(C
1-6Alkyl) formamyl;
B ring expression thiazolyl, thiadiazolyl group, isoxazolyl, pyrido thiazolyl or pyrazolyl wherein are connected to carbon atom formation C=N key in the B ring of nitrogen-atoms of the amide group of formula (I) on the B ring;
R
3Optional C on the expression B ring
1-6Alkyl or hydroxyl C
1-6Alkyl.
2. the compound of claim 1, wherein-X
2-R
2Be selected from 2-methoxyl group-1-methyl-oxyethyl group, 1-methoxymethyl-propoxy-, 3-hydroxyl-1-methyl-propoxy-, 1-hydroxymethyl-propoxy-, 2-hydroxyl-1-methyl-oxyethyl group, 2-acetylamino-1-methyl-oxyethyl group and 2-fluoro-1-methyl fluoride-oxyethyl group.
3. the compound of claim 2, wherein-X
2-R
2Be selected from 2-hydroxyl-1-methyl-oxyethyl group, 1-methoxymethyl-propoxy-and 2-fluoro-1-methyl fluoride-oxyethyl group.
4. the compound of claim 1, wherein-B ring-R
3Expression 1-methyl isophthalic acid H-pyrazole-3-yl.
5. each compound, wherein R among the claim 1-4
1Expression methylsulfonyl or ethylsulfonyl.
6. the compound of claim 5, wherein A ring expression phenyl.
7. the compound of claim 5, wherein A ring expression pyridyl.
8. the compound of claim 1, it is selected from:
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-thiazol-2-yl-benzamide,
N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methylsulfonyl phenoxy group)-5-(1-methoxymethyl-propoxy-)-benzamide,
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(2-methylthiazol-4-yl)-benzamide,
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-benzamide,
5-(2-hydroxyl-1-methyl-oxyethyl group)-3-(4-methylsulfonyl phenoxy group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
3-(3-fluoro-4-methylsulfonyl phenoxy group)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide,
3-(6-b sulfonyl pyridine-3-base oxygen base)-5-(2-hydroxyl-1-methyl-oxyethyl group)-N-(isoxazole-3-base) benzamide,
5-(2-fluoro-1-methyl fluoride-oxyethyl group)-3-(6-methylsulfonyl pyridin-3-yl oxygen base)-N-(pyrazole-3-yl) benzamide,
With their pharmacy acceptable salt.
9. pharmaceutical composition, it comprises among the claim 1-8 each compound and pharmaceutically acceptable carrier.
10. each compound is used for preparing the purposes for the treatment of or preventing the medicine of type ii diabetes among the claim 1-8.
11. each compound is used for preparing the purposes of the medicine of treatment or the prevention obesity relevant with glucokinase among the claim 1-8.
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| JP049466/2003 | 2003-02-26 | ||
| JP2003049466 | 2003-02-26 | ||
| JP2003400882 | 2003-11-28 | ||
| JP400882/2003 | 2003-11-28 | ||
| JP031298/2004 | 2004-02-06 |
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| CN104230892B (en) * | 2011-11-09 | 2016-12-07 | 福建海西新药创制有限公司 | One group of compound improving kinase activity and application thereof |
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| CN102482267B (en) * | 2009-07-31 | 2014-12-03 | 卡迪拉保健有限公司 | Substituted benzamide derivatives as glucokinase (GK) activators |
| BR112012016025A2 (en) * | 2009-12-11 | 2018-11-06 | Astellas Pharma Inc. | benzamide compound |
| CN102558149A (en) * | 2010-12-29 | 2012-07-11 | 中国医学科学院药物研究所 | Pyrimidine derivative, preparation method thereof, medicinal composition and application thereof |
| CN105837599A (en) * | 2015-01-14 | 2016-08-10 | 中国科学院上海药物研究所 | N-substituted-3,5-disubstituted benzamide compound, preparation method and application thereof |
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| CN104230892B (en) * | 2011-11-09 | 2016-12-07 | 福建海西新药创制有限公司 | One group of compound improving kinase activity and application thereof |
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