CN100378094C - Novel 2-pyridinecarboxamide derivatives - Google Patents

Novel 2-pyridinecarboxamide derivatives Download PDF

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CN100378094C
CN100378094C CNB2004800038501A CN200480003850A CN100378094C CN 100378094 C CN100378094 C CN 100378094C CN B2004800038501 A CNB2004800038501 A CN B2004800038501A CN 200480003850 A CN200480003850 A CN 200480003850A CN 100378094 C CN100378094 C CN 100378094C
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sulfenyl
base
triazole
pyridine carboxamide
methyl
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CN1747951A (en
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三谷守弘
番场诚
坂井富美子
渡边瞳
佐佐木康裕
西村辉之
永木淳一
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MSD KK
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Banyu Phamaceutical Co Ltd
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Abstract

The present invention relates to a compound which has a glucokinase-activating effect and is useful as a therapeutic agent for diabetes mellitus, being represented by a formula (I): wherein X<1> represents a nitrogen atom, sulfur atom, oxygen atom or the like; R<1> represents a 6- to 10-membered aryl group, 5- to 7-membered heteroaryl group or the like; D represents an oxygen atom or sulfur atom; R<2> and R<3> are the same or different, each representing a hydrogen atom, lower alkyl group or the like; a formula (II) represents an optionally substituted 5- to 7-membered heteroaryl group or the like; a formula (III) represents a monocyclic or bicyclic heteroaryl groupu or a pharmaceutically acceptable salt thereof.

Description

The 2-derivative of pyridine carboxamide
Technical field
The present invention relates to contain the activators of glucokinase of pyridine-2-carboxamide derivatives as effective constituent.Also relate to novel 2-derivative of pyridine carboxamide or its salt.
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 glycolytic pathway, the reaction of catalysis from glucose to glucose 6-phosphoric acid.Glucokinase mainly is confined to express in liver and the 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 the character of enzyme 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 mouse promptly dead soon (work such as Grupe A after birth of destructive, " Transgenic knockouts reveal acritical requirement for pancreatic beta cell glucokinase in maintainingglucose homeostasis (transgenosis knocks out and shows the keying action of pancreatic beta cell glucokinase in keeping the glucose homeostasis) ", Cell, the 83rd volume, nineteen ninety-five, P69-78), make the blood glucose value normal and diabetic mice of glucokinase overexpression then reduce (work such as Ferre T, " Correction ofdiabetic alterations by glucokinase (correcting diabetic by glucokinase changes) ", Proceedings of the National Academy of Sciencesofthe 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 (work such as Vionnet N, " Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus (nonsense mutation in the glucokinase gene causes the initial in early days of non-insulin-dependent diabetes mellitus (NIDDM)) ", 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 (work such as Glaser B, " Familialhyperinsulinism caused by an activating glucokinase mutation (the familial hyperinsulinemia that the sudden change of reactivity glucokinase causes) ", New England JournalMedicine, 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 liver discharges sugar, thereby can consider the medicine used as the type ii diabetes patient.
In recent years, known that pancreatic beta cell type glucokinase also is to be confined to feeding center especially (ventromedial hypothalamic Ventromedial hypothalamus VMH) expresses in the brain of rat.About 2 one-tenth neurocyte is called as glucose and replys 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 electrophysiology experiment as can be known, glucose is replied neurone and is changed (5-20mM) with physiological glucose concn and echo 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 also may have role of correcting for the obesity that most type ii diabetes patients is formed puzzlement.
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.
As having compound of the present invention (I) pyridine skeleton that is had and the compound that is incorporated into the amide group on this pyridine skeleton, following structural formula (IV) is disclosed
Figure C20048000385000221
Shown in compound (Japanese kokai publication hei 5-213382 communique).
But, the C=N of the different  azoles base that the compound of putting down in writing on the Japanese kokai publication hei 5-213382 communique (IV) is had and the position of amido linkage relation concern different with the C=N of The compounds of this invention and the position of amido linkage, and the purposes of The compounds of this invention is to be used for diabetes, and the purposes of Japanese kokai publication hei 5-213382 communique is to be used for weedicide, and this point is also different.
Close and also be used for the compound of diebetic use as structure, time formula V is disclosed
Figure C20048000385000231
Or following formula (VI)
Shown in compound (Japanese Unexamined Patent Application Publication 2001-522834 communique).
A purposes of the compound of Japanese Unexamined Patent Application Publication 2001-522834 communique is to be used for diabetes, and is the same with the purposes of compound of the present invention (I).
The compound of putting down in writing on the Japanese Unexamined Patent Application Publication 2001-522834 communique (V) or (VI) and The compounds of this invention (I) all have pyridine skeleton as basic framework, and have amido linkage on this pyridine ring, this point is common.
But The compounds of this invention (I) has substituting group on 6 of pyridine ring, and described compound (V) or (VI) not have substituting group, this point on 6 of pyridine ring be different.
And, The compounds of this invention (I) has amido linkage on the nitrogen-atoms next door that constitutes pyridine ring, and the compound of putting down in writing on the Japanese Unexamined Patent Application Publication 2001-522834 communique (VI) is to have amido linkage on the position of 1 carbon atom being separated by with the nitrogen-atoms that constitutes pyridine ring, partly with regard to the relative position relation of amido linkage, the compound of putting down in writing on The compounds of this invention (I) and the Japanese Unexamined Patent Application Publication 2001-522834 communique (VI) is different with regard to the C=N that constitutes part one pyridine ring corresponding with B ring of the present invention.
As the same with compound of the present invention (I) have pyridine this-compound of 2-methane amide skeleton, following formula (VII) is disclosed
Figure C20048000385000241
Shown in compound (international disclose No. 01/81345 brochure).But, compound (VII) is gone up record and nitrogen-atoms bonded 1H-pyrazolo [3 amido linkage, 4-b] nitrogen-atoms in the pyridin-4-yl and the relative position relation of amido linkage, different with the relative position relation of C=N in the B ring of The compounds of this invention (I) and amido linkage.And, be combined with hydrogen atom on 3 and 6 of the pyridine skeleton of formula (VII), then in conjunction with the group beyond the hydrogen atom, this point is different to The compounds of this invention (I), with regard to one-piece construction, formula (VII) differs from one another with The compounds of this invention (I).
Therefore, The compounds of this invention (I) is though with international to disclose the compound of putting down in writing on No. 01/81345 brochure be common all having on the basic framework pyridine-2-carboxamide this point, but the substituent mode this respect of institute's bonded is then different with The compounds of this invention on pyridine skeleton, has the structure different with The compounds of this invention.
Invent problem to be solved and provide and be incorporated into glucokinase, can improve active Remedies for diabetes of glucokinase and/or prophylactic agent, and the anti-obesity medicine is provided, this medicine plays the stimulation satiety center by making the glucokinase activation.
As mentioned above, The compounds of this invention has and possesses good drug effect to having diabetes now, might send out and leave the existing isometric place of the not available new drug effect of diabetes medicament.
Thus, the inventor be develop by with the different effect of above-mentioned existing medicine, possesses the drug effect that is better than existing diabetes medicament, and possesses the novel diabetes medicament of new drug effect, further investigate, found that compound has the glucokinase activation shown in the formula (I), thereby finished the present invention.
Summary of the invention
That is, the present invention relates to
(1) compound or its pharmacy acceptable salt shown in the formula (I),
Figure C20048000385000251
X in the formula 1Expression N, S or O or expression carbonatoms are the divalent saturated hydrocarbyl (when the carbonatoms of this divalent saturated hydrocarbyl is 2 when above, any one carbon atom in this divalent saturated hydrocarbyl can be replaced by nitrogen-atoms, Sauerstoffatom or sulphur atom) of 1-6, R 1The aryl of expression 6-10 unit, the heteroaryl of 5-10 unit, cycloalkyl or low alkyl group (this R that carbonatoms is 3-7 1Can be at R 1On have 1 or 2 and be selected from following group: amino; (hydrogen atom of low alkyl group can be by hydroxyl for low alkyl group; lower alkoxy; halogen atom; formamyl; one or the two elementary alkyl amido formyl radical; carboxyl; alkoxy carbonyl; alkyloyl; amino or one or two-alkylamino replace); (hydrogen atom that constitutes the methylene radical of this lower alkoxy or methyl can be by hydroxyl for lower alkoxy; halogen atom; formamyl; one or the two elementary alkyl amido formyl radical; carboxyl; alkoxy carbonyl; alkyloyl; amino or one or two elementary alkyl amido replace); formamyl; elementary alkyl amido methanoyl; the two elementary alkyl amido formyl radical; formamyl amino; carbamoyloxy; carboxyl; cyano group; sulfamyl; trifluoromethyl; halogen atom; hydroxyl; formyl radical; the C2-C6 alkyloyl; the N-C2-C6 alkanoylamino; the C1-C6 alkylthio; the N-C1-C6 alkylsulfamoyl group; N; N-two-C1-C6 alkylsulfamoyl group; C1-C6 alkyl sulfinyl; the C1-C6 alkyl sulphonyl; the N-C1-C6 alkyl sulfonyl-amino; the C1-C6 alkoxy carbonyl; the N-C1-C6 alkylamino; N; N-two-C1-C6 alkylamino; 6-10 unit's aryl and 5-10 unit heteroaryl); D represents O or S, R 2And R 3Identical or different, expression hydrogen atom, low alkyl group, lower alkoxy or halogen atom, formula (II)
Figure C20048000385000252
Can in this ring, have 1 or 2 following groups: low alkyl group, lower alkoxy, hydroxyl, hydroxyalkyl (hydrogen atom of the hydroxyl in this hydroxyalkyl can further be replaced by low alkyl group) and halogen atom, expression 5-7 unit's heteroaryl or 6-10 unit aryl, formula (III)
Figure C20048000385000261
This nuclear carbon atom that the nitrogen-atoms of amide group of expression with formula (I) in combines and this ring nitrogen form the monocycle of C=N or the heteroaryl of dicyclo, and (this heteroaryl can have 1 or 2 substituting group that is selected from following groups in B encircles: low alkyl group, lower alkoxy, halogen atom, trifluoromethyl, hydroxyalkyl (hydrogen atom of the hydroxyl in this hydroxyalkyl can further be replaced by low alkyl group), aminoalkyl group (amino in this group can further be replaced by identical or different low alkyl group), alkyloyl, carboxyl, alkoxy carbonyl and cyano group);
(2) compound of aforementioned (1), wherein D is S;
(3) each compound, wherein R in aforementioned (1) or (2) 2And R 3It all is hydrogen atom;
(4) each compound in aforementioned (1)-(3), wherein A ring can have 1 or 2 and is selected from following group in this ring: low alkyl group, lower alkoxy, hydroxyl, hydroxyalkyl (hydrogen atom of the hydroxyl in this hydroxyalkyl can further be replaced by low alkyl group) and halogen atom are phenyl, isothiazolyl, imidazolyl,  azoles base, thiadiazolyl group, thienyl, triazolyl, tetrazyl, pyridyl, pyrimidyl, furyl, thiazolyl, different  azoles base or pyrazolyl;
(5) each compound, wherein X in aforementioned (1)-(4) 1For be selected from nitrogen-atoms, sulphur atom, Sauerstoffatom ,-CH 2-,-N-CH 2-,-S-CH 2-,-O-CH 2-,-CH 2-N-,-CH 2-O-and-CH 2The group of-S-;
(6) each compound in aforementioned (1)-(5), wherein the B ring is 5 or 6 yuan of heteroaryls, this heteroaryl has the heteroatoms of the nitrogen-atoms of at least 1 C=N key that constitutes this ring as this ring, perhaps condenses 9 or 10 yuan of heteroaryls that form for this heteroaryl and phenyl or pyridyl;
(7) each compound, wherein R in aforementioned (1)-(6) 1For the aryl of 6-10 unit, the heteroaryl or the carbonatoms of 5-10 unit are the cycloalkyl of 3-7;
(8) each compound, wherein R in aforementioned (1)-(6) 1Be the aryl of 6-10 unit or the heteroaryl of 5-10 unit;
(9) each compound, wherein R in aforementioned (1)-(6) 1Aryl for 6-10 unit;
(10) each compound, wherein R in aforementioned (1)-(6) 1Heteroaryl for 5-10 unit;
(11) compound of aforementioned (9) or (10), wherein the substituting group of A ring is hydrogen atom, low alkyl group, lower alkoxy, hydroxyl or hydroxyl low-grade alkyl (hydrogen atom in the hydroxyl of hydroxyl low-grade alkyl can further be replaced by low alkyl group);
(12) each compound in aforementioned (9)-(11), wherein the B ring is thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl group, triazolyl,  azoles base, different  azoles base, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl, pyrimidyl, pyrido thiazolyl or benzothiazolyl;
(13) each compound in aforementioned (1)-(10), wherein the substituting group of B ring is hydrogen atom, low alkyl group, halogen atom, hydroxyalkyl, aminoalkyl group or alkyloyl;
(14) each compound, wherein R in aforementioned (9)-(12) 1The substituting group that is had is hydrogen atom, hydroxyalkyl, low alkyl group, lower alkoxy, formamyl, alkyl-carbamoyl, dialkyl amido formyl radical, cyano group, trifluoromethyl, halogen atom, C2-C6 alkyloyl, N-C2-C6 alkanoylamino, C1-C6 alkyl sulphonyl, C1-C6 alkylamino or aminoalkyl group;
(15) compound shown in the above-mentioned formula (I), each mark is represented connotation as hereinbefore in the formula,
Figure C20048000385000271
Described compound is following compounds or its pharmacy acceptable salt:
1) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
2) 3-(4-fluoro-phenyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
3) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
4) 3-(4-fluoro-phenyl sulfenyl)-6-(1-methyl-imidazoles-2-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
5) 3-(4-fluoro-phenyl sulfenyl)-6-(1-methyl isophthalic acid H-tetrazolium-5-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
6) 3-(cyclohexyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
7) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
8) 3-(thiazol-2-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
9) 3-(2-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
10) 3-phenyl sulfenyl-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
11) 3-(4-fluoro-phenoxy group)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
12) 3-(4-methoxyl group-phenyl methyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
13) 3-(3-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
14) 3-(2,4-two fluoro-phenyl-sulfenyls)-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
15) 3-(4-fluoro-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
16) 3-(4-cyano group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
17) 3-(pyridin-4-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
18) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole is [5,4-b] pyridine-2-yl also)-2-pyridine carboxamide,
19) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
20) 3-(4-ethanoyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
21) 3-(thiophene-2-base-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
22) 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
23) 3-(4-fluoro-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole is [5,4-b] pyridine-2-yl also)-2-pyridine carboxamide,
24) 3-(4-methyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
25) 3-(4-chloro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
26) 3-(4-fluoro-phenyl sulfenyl)-6-(3H-[1,2,3] triazole-4-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
27) 3-(4-methyl sulphonyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
28) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-hydroxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
29) 3-(4-fluoro-phenyl sulfenyl)-6-(5-methoxymethyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
30) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
31) 3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
32) 3-(4-trifluoromethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
33) 3-(4-methylamino formyl radical-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
34) 3-(hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
35) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-dimethylaminomethyl-thiazol-2-yl)-2-pyridine carboxamide,
36) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
37) 3-(4-hydroxyethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
38) 3-(4-methyl sulfamyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
39) 3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)-2-pyridine carboxamide,
40) 3-(4-hydroxyl-cyclohexyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
41) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-pyridazine-3-yl)-the 2-pyridine carboxamide,
42) 3-(pyrazine-2-base-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
43) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(pyrazine-2-yl)-2-pyridine carboxamide,
44) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
45) 3-[4-(1-hydroxyethyl-phenyl sulfenyl)]-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
46) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(2-methyl-thiazole-4-yl)-2-pyridine carboxamide,
47) 3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(2-methyl-thiazole-4-yl)-2-pyridine carboxamide,
48) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
49) 3-(1-methyl isophthalic acid H-tetrazolium-5-base-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
50) 3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)-2-pyridine carboxamide,
51) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)-2-pyridine carboxamide,
52) 3-(4-fluoro-phenyl sulfenyl)-6-phenoxy group-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
53) 3-(2-chloro-phenyl methyl-amino)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
54) 3,6-two-(pyridine-2-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
55) 3,6-two-(4-fluoro-phenyl sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
56) 3,6-two-(thiazol-2-yl-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
57) 3,6-two-(5-methyl-[1,3,4] thiadiazoles-2-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
58) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-methyl-thiazol-2-yl)-2-pyridine carboxamide,
59) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)-2-pyridine carboxamide,
60) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-([1,3,4] thiadiazoles-2-yl)-2-pyridine carboxamide,
61) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
62) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl carbonyl-thiazol-2-yl)-2-pyridine carboxamide,
63) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(pyrimidine-4-yl)-2-pyridine carboxamide,
64) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(pyridine-2-yl)-2-pyridine carboxamide,
65) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-ethoxy carbonyl-thiazol-2-yl)-2-pyridine carboxamide,
66) 3-(pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
67) 3-(6-methoxyl group-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
68) 3-(pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
69) 3-phenoxymethyl-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
70) 3-phenyl sulfenyl methyl-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
71) 3-phenyl methyl-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
72) 3-(4-fluoro-phenyl methyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
73) 3-(4-dimethyl aminoethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
74) 3-(4-dimethylaminomethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
75) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole-4-yl)-2-pyridine carboxamide,
76) 3-(4-formyl-dimethylamino methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
77) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(4-hydroxyethyl-thiazol-2-yl)-2-pyridine carboxamide,
78) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-hydroxyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
79) 3-(6-methoxycarbonyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
80) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
81) 3-(pyrimidine-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
82) 3-(6-hydroxymethyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
83) 3-[4-(1-methylpyrrolidin-3-base oxygen base)-phenyl sulfenyl]-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
84) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
85) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
86) 3-(1-oxygen base-6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
87) 3-(4-diethyl amino base oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
88) 3-(4-tetramethyleneimine oxyethyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
89) 3-(6-dimethylamino ethoxy-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
90) 3-(pyrazoles-4-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
91) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
92) 3-(4-carbamyl ylmethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
93) 3-(5-bromo-6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
94) 3-[4-(2-hydroxyethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
95) 3-[4-(2-hydroxyethyl-phenyl sulfenyl)]-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
96) 3-(pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
97) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
98) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole is [5,4-b] pyridine-2-yl also)-2-pyridine carboxamide,
99) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
100) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,5] thiadiazoles-3-yl)-2-pyridine carboxamide,
101) 3-(2,3-Dihydrobenzofuranes-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
102) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methoxyl group-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
103) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-cyclopropyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
104) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
105) 3-(2-fluoro-pyridin-4-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
106) 3-(2-methoxyl group-pyrimidine-5-base sulfenyl)-6-(2H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
107) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
108) 3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
109) 3-(4-diethylamino formyl radical methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
110) 3-(6-cyclopropyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
111) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
112) 3-(6-methyl-pyridin-3-yl sulfenyl]-6-(pyrazoles-4-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
113) 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
114) 3-(4-dimethylamino alkylsulfonyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
115) 3-(5-fluoro-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
116) 3-(2,3-Dihydrobenzofuranes-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
117) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] triazine-3-yl)-2-pyridine carboxamide,
118) 3-(4-carboxyl-phenyl sulfenyl)-6-(5-methyl-[1,2,4]-triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
119) 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(pyrazine-2-yl)-2-pyridine carboxamide,
120) 3-(imidazo [1,2-a] pyridine-6-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
121) 3-(2-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4 triazoles-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
122) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole is [4,5-b] pyridine-2-yl also)-2-pyridine carboxamide,
123) 3-(5-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
124) 3-(4,4-difluoro-methoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(pyrazine-2-yl)-2-pyridine carboxamide,
125) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
126) 3-(6-hydroxyethyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
127) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
128) 3-(2-methyl-imidazo [1,2-a] pyridine-6-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
129) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-hydroxymethyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
130) 3-[4-(2-hydroxyethyl)-phenyl sulfenyl]-6-(4-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
131) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-hydroxyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
132) 3-(1-methyl isophthalic acid H-draws azoles-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
133) 3-(3-methyl-[1,2,4]-triazolo [4,3-a] pyridine-7-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
134) 3-(1-oxygen base-6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
135) 3-(6-hydroxymethyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
136) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
137) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
138) 3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
139) 3-[4-(1H-imidazoles-1-yl)-phenyl sulfenyl]-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
140) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
141) 3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide,
142) 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide,
143) 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide,
144) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4,5-dimethylthiazole-2-yl)-2-pyridine carboxamide,
145) 3-(4-fluoro-phenyl sulfenyl)-6-(4,5-dimethyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
146) 3-(4-(1-methoxy ethyl)-phenyl sulfenyl]-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
147) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
148) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-trifluoromethyl thiazole-2-yl)-2-pyridine carboxamide,
149) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-trifluoromethyl thiazole-2-yl)-2-pyridine carboxamide,
150) 3-(3-fluoro-4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
151) 3-[4-(1,1-dimethyl-1-hydroxymethyl)-phenyl sulfenyl]-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
152) 3-(3,4-two fluoro-phenyl sulfenyls)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
153) 3-(3,5-two fluoro-phenyl sulfenyls)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2] pyrazole-3-yl)-2-pyridine carboxamide,
154) 3-(1-methyl-2-oxo-2,3-dihydro-1H-indoles-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
155) 3-(6-methyl-pyridine-3-sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] Triazolopyridine-2-yl)-2-pyridine carboxamide,
156) 3-(4-ethoxyl methyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2] pyrazole-3-yl)-2-pyridine carboxamide,
157) 3-(6-oxo-1,6-dihydro-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
158) 3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
159) 3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide;
(17) be compound or its pharmacy acceptable salt of 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide;
(18) be compound or its pharmacy acceptable salt of 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide;
(19) be compound or its pharmacy acceptable salt of 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-(thiazol-2-yl)-2-pyridine carboxamide;
(20) be compound or its pharmacy acceptable salt of 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide;
(21) be compound or its pharmacy acceptable salt of 3-(hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide;
(22) be compound or its pharmacy acceptable salt of 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide;
(23) be compound or its pharmacy acceptable salt of 3-(4-hydroxyethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide;
(24) be compound or its pharmacy acceptable salt of 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide;
(25) be compound or its pharmacy acceptable salt of 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide;
(26) be compound or its pharmacy acceptable salt of 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide;
(27) be compound or its pharmacy acceptable salt of 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide;
(28) be compound or its pharmacy acceptable salt of 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-2-yl)-2-pyridine carboxamide;
(29) be 3-[4-(2-hydroxyethyl-phenyl sulfenyl)]-compound or its pharmacy acceptable salt of 6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide;
(30) be compound or its pharmacy acceptable salt of 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide;
(31) be compound or its pharmacy acceptable salt of 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide;
(32) be compound or its pharmacy acceptable salt of 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(pyrazine-2-yl)-2-pyridine carboxamide;
(33) be compound or its pharmacy acceptable salt of 3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide;
(34) be compound or its pharmacy acceptable salt of 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide;
(35) be used for the pharmaceutical composition that contains following (1)-(3) of treatment, prevention and/or the delayed onset of type ii diabetes:
(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) secretion of insulin promotor,
(3) pharmaceutically acceptable carrier;
(36) activators of glucokinase, this activator is an effective constituent with each compound in aforementioned (1)-(34);
(37) treatment of diabetes and/or preventive, this treats and/or prevents agent is effective constituent with each compound in aforementioned (1)-(34);
(38) fatly treat and/or prevent agent, this treats and/or prevents agent is effective constituent with each compound in aforementioned (1)-(34).
The best mode that carries out an invention
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 that preferred carbonatoms is the straight or branched alkyl 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.
" cycloalkyl " is meant that carbonatoms is the monocyclic saturated hydrocarbon group base of 3-7, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.
" lower alkoxy " 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.
" alkylsulfamoyl group " is meant the NH of sulfamyl 2The group of hydrogen atom after being replaced by abovementioned alkyl one, for example methyl sulfamyl, ethyl sulfamyl, sec.-propyl sulfamyl etc.
" dialkyl sulfamine " is meant the NH of abovementioned alkyl sulfamyl 2The group of hydrogen atom after being replaced by identical or different abovementioned alkyl two, for example dimethylamino alkylsulfonyl, diethyl amino alkylsulfonyl, methylethyl sulfamyl etc.
" heteroaryl " is meant that having 1-3 in the heteroaryl is selected from Sauerstoffatom, the first monocycle of the heteroatomic 4-7 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, pyrazolyl, thiazolyl, thiadiazolyl group, isothiazolyl,  azoles base, different  azoles base, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, pyrazinyl, quinolyl, isoquinolyl, quinazolyl, quinolizinyl, quinoxalinyl, the cinnolines base, benzimidazolyl-, imidazopyridyl, benzofuryl, naphthyridinyl, 1,2-benzisoxa  azoles base, the benzoxazol base, benzothiazolyl,  azoles 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.
" elementary alkyl amido methanoyl " 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.
" two elementary alkyl amido formyl radical " is meant that the example of " two elementary alkyl 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.
" low-grade alkyl amino " be meant by the monobasic amino of above-mentioned low alkyl group, methylamino, ethylamino, propyl group amino, sec.-propyl amino, butyl amino, sec-butyl amino for example arranged, or tertiary butyl amino etc.
" two elementary alkyl 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.
" 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.
" 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 sulfinyl " is meant the group that abovementioned alkyl and sulfinyl are formed by connecting, for example methyl sulfinyl, ethylsulfinyl-1 base, sec.-propyl sulfinyl 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.
" carbonatoms is the divalent saturated hydrocarbyl of 1-6 " is meant that the straight or branched carbonatoms is the divalent saturated hydrocarbyl of 1-6, specifically has for example methylene radical, ethylidene, propylidene, isopropylidene, butylidene etc.
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.
Can have 1 or 2 5-7 unit's heteroaryl or 6-10 unit aryl that is selected from the group of low alkyl group, lower alkoxy, hydroxyl, hydroxyalkyl (hydrogen atom of the hydroxyl in this hydroxyalkyl can further be replaced by low alkyl group) and halogen atom in this A ring of the ring of A shown in the formula (II) expression
Figure C20048000385000441
[each mark is represented connotation same as described above in the formula].
As " 5-7 unit's heteroaryl or 6-10 unit aryl " shown in the A ring, have 5 or 6 yuan of heteroaryls of at least one nitrogen-atoms in preferred this ring.
The object lesson of A ring has phenyl, isothiazolyl, imidazolyl,  azoles base, thiadiazolyl group, thienyl, triazolyl, tetrazyl, pyridyl, pyrimidyl, furyl, thiazolyl, different  azoles base or pyrazolyl etc., wherein preferred triazolyl, imidazolyl, thiazolyl, pyridyl, more preferably triazolyl.
Below the substituting group that is had on the A ring is described.
A ring in the above-mentioned formula (I) can have substituting group on this ring.
Substituent example on the A ring has low alkyl group, alkoxyl group, halogen atom, hydroxyl, hydroxyalkyl (hydrogen atom of the hydroxyl in this hydroxyalkyl can be replaced by alkyl).Wherein preferred low alkyl group, lower alkoxy, hydroxyl, hydroxyalkyl, more preferably low alkyl group.
Substituent more specifically example on the A ring has methyl, ethyl, sec.-propyl, methoxyl group, oxyethyl group, hydroxyl, hydroxymethyl, hydroxyethyl, methoxymethyl, fluorine atom, chlorine atom etc., wherein preferable methyl, ethyl, more preferably methyl.
Therefore, more particularly, preferred A ring integral body is for example following formula (VIII)
Figure C20048000385000451
Shown in group, more preferably following formula (IX)
Figure C20048000385000452
Shown in group.
D represents Sauerstoffatom or sulphur atom, but is preferably sulphur atom.
Below the B ring is described.
Above-mentioned formula (III)
Figure C20048000385000453
Shown in the heteroaryl of B ring expression monocycle or dicyclo, the nitrogen-atoms of the amido that is had with following formula (I) in this heteroaryl combines, C=N in this ring and amido have following formula (X)
Figure C20048000385000454
Shown in relative position relation.
" heteroaryl of monocycle or dicyclo " shown in the B ring has synonymous with " heteroaryl " of above-mentioned definition.
The object lesson of B ring has thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl group, triazolyl,  azoles base, different  azoles base, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl, pyrimidyl, pyrido thiazolyl or benzothiazolyl etc.Wherein preferred thiazolyl, thiadiazolyl group, different  azoles base, pyrazinyl, pyrido thiazolyl or pyridyl, more preferably thiazolyl, thiadiazolyl group, pyrido thiazolyl or different  azoles base.
The B ring can have 1 or 2 in this ring, preferred 1 is selected from following substituting group: low alkyl group, lower alkoxy, halogen atom, trifluoromethyl, hydroxyl, hydroxyalkyl (hydrogen atom of the hydroxyl in this hydroxyalkyl can be replaced by low alkyl group), aminoalkyl group, alkyloyl, carboxyl, alkoxy carbonyl and cyano group.
Substituting group on the preferred B ring is low alkyl group, lower alkoxy, halogen atom, hydroxyalkyl (hydrogen atom of the hydroxyl in this hydroxyalkyl can be replaced by low alkyl group), aminoalkyl group or the alkyloyl in the described group, more preferably low alkyl group, hydroxyalkyl (hydrogen atom of the hydroxyl in this hydroxyalkyl can be replaced by low alkyl group), alkyloyl.
Substituting group on the B ring specifically can be a methyl for example, ethyl, propyl group, sec.-propyl, butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, the chlorine atom, fluorine atom, bromine atoms, 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, the chlorine atom, fluorine atom, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxy ethyl, methoxycarbonyl, ethoxy carbonyl, amino methyl, amino-ethyl, the methyl carbonyl, ethyl carbonyl etc., more preferably methyl, hydroxymethyl, methoxymethyl, the methyl carbonyl.
Therefore, preferred B ring integral body is for example thiazol-2-yl, 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-methyl carbonyl-[1,3,4] thiadiazoles-2-base, [1,2,4] thiadiazoles-5-base, 3-methyl-[1,2,4] thiadiazoles-5-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-methyl carbonyl-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-methyl carbonyl-[1,2,4] triazole-3-base, different  azoles-3-base, 4-methoxymethyl-different  azoles-2-base, 5-methyl-different  azoles-3-base, 5-hydroxymethyl-different  azoles-3-base, 5-methoxymethyl-different  azoles-3-base, 5-methyl carbonyl-different  azoles-3-base, the different  azoles of 5-chloro--3-base, 5-amino methyl-different  azoles-3-base, 4-methyl isophthalic acid H-pyrazole-3-yl, 1-methyl-pyrazole-3-yl, 6-methyl-pyridazine-3-base, thiazole-4-base, 2-methyl-thiazole-4-base, different  azoles-3-base, pyrido thiazolyl etc.
X 1Expression nitrogen-atoms, sulphur atom or Sauerstoffatom represent that perhaps carbonatoms is the divalent saturated hydrocarbyl of 1-6.
Here, " carbonatoms is the divalent saturated hydrocarbyl of 1-6 " is meant that the carbonatoms in the above-mentioned definition is the alkylidene group of 1-6, for example methylene radical, sec.-propyl, isopropylidene, butylidene etc.When the carbonatoms of this divalent saturated hydrocarbyl was 2-6, any 1 carbon atom in this divalent saturated hydrocarbyl can be by nitrogen-atoms, sulphur atom or Sauerstoffatom displacement.
X 1More specifically example have nitrogen-atoms, Sauerstoffatom, sulphur atom ,-CH 2-,-N-CH 2-,-S-CH 2-,-O-CH 2-,-CH 2-N-,-CH 2-S-or-CH 2-O-etc., wherein preferred X 1For nitrogen-atoms, sulphur atom, Sauerstoffatom ,-N-CH 2-or-CH 2-, sulphur atom more preferably.
R 2And R 3Identical or different, expression hydrogen atom, low alkyl group, alkoxyl group, halogen atom.
Preferred R 2And R 3Shown in " low alkyl group " identical or different, be methyl or ethyl, more preferably R 2And R 3It all is methyl.
Preferred R 2And R 3Shown in " lower alkoxy " identical or different, be methoxy or ethoxy, more preferably R 2And R 3It all is methoxyl group.
Preferred R 2And R 3Shown in " halogen atom " be fluorine atom, chlorine atom or bromine atoms, more preferably fluorine atom or chlorine atom.
Preferred R 2And R 3It all is hydrogen atom.
R 1The aryl of expression 6-10 unit, the heteroaryl of 5-10 unit, cycloalkyl or the low alkyl group that carbonatoms is 3-7.
R 1Shown in " aryl of 6-10 unit " expression carbonatoms be the hydrocarbon cyclophane base of 6-10, perhaps have the bicyclic radicals that 1 or 2 heteroatomic 5-6 aliphatic heterocycle of unit (this aliphatic series heterocycle can be replaced by the oxygen base) that is selected from nitrogen-atoms, sulphur atom and Sauerstoffatom and phenyl ring condense the 9-10 unit that forms in the ring.
The more specifically example of this 6-10 membered hydrocarbon ring aryl has phenyl, naphthyl, xenyl etc., wherein preferred phenyl.
The more specifically example of this 9-10 unit bicyclic aryl has ethylenedioxy phenyl, methylenedioxyphenyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, 2,3-dihydro benzo furyl, 1,3-dihydroisobenzofuran base, oxygen base indyl or pseudoindoyl etc., wherein preferred ethylenedioxy phenyl or tetrahydro isoquinolyl.
R 1Shown in " heteroaryl of 5-10 unit " be meant that having 1-3 in this ring is selected from the bicyclic heteroaryl of heteroatomic 5-7 unit of Sauerstoffatom, nitrogen-atoms and sulphur atom or the bicyclic heteroaryl of 9-10 unit.
The more specifically example of this 5-7 unit bicyclic heteroaryl has different  azoles base, isothiazolyl, imidazolyl,  azoles base, thiazolyl, thiadiazolyl group, thienyl, triazolyl, tetrazyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, pyrazolyl, pyrryl, pyranyl, furyl, furazan base, imidazolidyl etc.
The more specifically example of this 9-10 unit bicyclic heteroaryl has isoquinolyl, pseudoindoyl, indyl, quinolyl, pyrido thiazolyl, benzimidazolyl-, benzoxazol base, benzothiazolyl, benzotriazole base, benzofuryl, imidazopyridyl, Triazolopyridine base etc.
In this 5-10 unit heteroaryl, the bicyclic heteroaryl of preferred 5-7 unit, more preferably pyridyl, imidazolyl, thiazolyl, thienyl.
R 1Shown in " carbonatoms is the cycloalkyl of 3-7 " group identical with above-mentioned definition for example arranged, wherein preferred cyclopentyl or cyclohexyl.
R 1Shown in " low alkyl group " group identical with above-mentioned definition for example arranged, wherein preferred propyl group, butyl.
R 1Be preferably the aryl of 6-10 unit, the heteroaryl of 5-10 unit, the cycloalkyl of 3-7 unit, the more preferably heteroaryl of the aryl of 6-10 unit, 5-10 unit.
Object lesson has phenyl, naphthyl, xenyl, different  azoles base, isothiazolyl, imidazolyl,  azoles base, thiazolyl, thiadiazolyl group, thienyl, triazolyl, tetrazyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, pyrazolyl, pyrryl, pyranyl, furyl, the furazan base, imidazolidyl, isoquinolyl, pseudoindoyl, indyl, the ethylenedioxy phenyl, methylenedioxyphenyl, quinolyl, the pyrido thiazolyl, indolinyl, tetrahydric quinoline group, tetrahydro isoquinolyl, benzimidazolyl-, the benzoxazol base, benzothiazolyl, the benzotriazole base, benzofuryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, methyl, ethyl, propyl group, sec.-propyl, butyl, amyl group etc., wherein preferred phenyl, naphthyl, pyridyl, imidazolyl, thiazolyl, thienyl, cyclopentyl, cyclohexyl etc., more preferably phenyl, pyridyl, imidazolyl, thiazolyl, thienyl, further preferred phenyl or pyridyl.
Below to R 1The substituting group that is had describes.
R 1The substituent example that is had has hydrogen atom; amino; hydroxyl; hydroxyalkyl (hydrogen atom of this hydroxyl can be replaced by low alkyl group); (hydrogen atom in this low alkyl group can be by hydroxyl for low alkyl group; alkoxyl group; amino; alkylamino; dialkyl amido; halogen atom; formamyl; mono-or dialkylcarbamoyl group; carboxyl; alkoxy carbonyl or alkyloyl replace); (methylene radical or the hydrogen atom in the methyl that constitute this lower alkoxy can be by hydroxyls for lower alkoxy; alkoxyl group; amino; alkylamino; dialkyl amido; halogen atom; formamyl; one or the two elementary alkyl amido formyl radical; carboxyl; alkoxy carbonyl or alkyloyl replace); formamyl; alkyl-carbamoyl; the dialkyl amido formyl radical; carbamoyloxy; formamyl amino; cyano group; sulfamyl; trifluoromethyl; halogen atom; formyl radical; the C2-C6 alkyloyl; the N-C2-C6 alkanoylamino; the C1-C6 alkylthio; the N-C1-C6 alkylsulfamoyl group; N; N-two-C1-C6 alkylsulfamoyl group; C1-C6 alkyl sulfinyl; the C1-C6 alkyl sulphonyl; the N-C1-C6 alkyl sulfonyl-amino; the C1-C6 alkoxy carbonyl; C1-C6 alkylamino or N, N-C1-C6-two-alkylamino.
R 1Can have hydroxyalkyl as substituting group.This hydroxyalkyl is preferably for example hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyl sec.-propyl, hydroxybutyl, hydroxyl amyl group etc., more preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyl sec.-propyl.
The hydrogen atom that this hydroxyl had can be the low alkyl group replacement of 1-6 by carbonatoms, the example of described substituted hydroxyalkyl has methoxymethyl, 1-methoxy ethyl, ethoxyl methyl, methoxy ethyl, propoxy-methyl etc., wherein preferred methoxymethyl, methoxy ethyl, more preferably methoxymethyl.
R 1Can have low alkyl group as substituting group.The example of this low alkyl group is the same with the low alkyl group of above-mentioned definition, wherein preferable methyl, ethyl, propyl group, butyl, sec.-propyl etc., more preferably methyl, ethyl etc.
R 1When having low alkyl group as substituting group, the hydrogen atom in this low alkyl group can be replaced by hydroxyl, lower alkoxy, amino, an alkylamino or dialkyl amido.The example of described low alkyl group has hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxyl methyl, methoxy ethyl, amino methyl, amino-ethyl, aminopropyl, the methylamino methyl, the ethylamino methyl, dimethylaminomethyl, ethyl-methylamino methyl, amino methyl, the 2-amino-ethyl, the 1-amino-ethyl, 3-amino-propyl group, 2-amino-1-methyl-ethyl, 2-amino-propyl group, 4-amino-butyl, 2-amino-1-methyl-propyl group, 2-amino-butyl, 5-amino-amyl group, 3-amino-1,2-dimethyl-propyl group, 6-amino-hexyl etc., wherein preferred amino methyl, the 2-amino-ethyl, the 1-amino-ethyl, 3-amino-propyl group, 3-amino-1-methyl-ethyl, 2-amino-propyl group, more preferably 2-amino-ethyl or 3-aminopropyl.
R 1Can have lower alkoxy (hydrogen atom in this lower alkoxy can be replaced by 1 hydroxyl or amino) as substituting group.
The example of this alkoxyl group is the same with the group of the alkoxyl group of above-mentioned definition, wherein preferred methoxyl group, oxyethyl group, propoxy-, isopropoxy etc., more preferably methoxy or ethoxy.When the hydrogen atom in this alkoxyl group is replaced by hydroxyl, its example has 2-hydroxyl-oxyethyl group, 3-hydroxyl-propoxy-, 4-hydroxyl-butoxy, 2-hydroxyl-1-methyl-oxyethyl group, 2-hydroxyl-propoxy-, 3-hydroxy-2-methyl-propoxy-, 3-hydroxyl-butoxy etc., wherein preference such as 2-hydroxyl-oxyethyl group, 3-hydroxyl-propoxy-, 2-hydroxyl-1-methyl-oxyethyl group etc., more preferably 2-hydroxyl-oxyethyl group.
When the hydrogen atom in this alkoxyl group was replaced by amino, this amino can further be replaced by 1 or 2 low alkyl group.When this amino was replaced by 2 low alkyl groups, described low alkyl group can be identical or different, is preferably alkylamino alkoxyl group or dialkyl amido alkoxyl group, more preferably the dialkyl amino base oxethyl.
Example has amino ethoxy, methyl amino ethoxy, dimethylamino ethoxy, dimethylamino propoxy etc., wherein preferable methyl amino ethoxy or dimethylamino ethoxy, more preferably dimethylamino ethoxy more specifically.
R 1Can have elementary alkyl amido methanoyl as substituting group.The example of described elementary alkyl amido methanoyl is the same with the group of the elementary alkyl amido methanoyl of above-mentioned definition, and preferred carbonatoms is the elementary alkyl amido methanoyl of 1-5, and more preferably carbonatoms is the elementary alkyl amido methanoyl of 1-3.The more specifically example of this elementary alkyl amido methanoyl is methylamino formyl radical, ethylamino formyl radical, propyl group formamyl etc., more preferably methylamino formyl radical.
R 1Can have the two elementary alkyl amido formyl radical as substituting group.The example of described two elementary alkyl amido formyl radical is the same with the group of the two elementary alkyl amido formyl radical of above-mentioned definition; for example preferred formyl-dimethylamino, diethylamino formyl radical, ethylmethylamino formyl radical etc., more preferably formyl-dimethylamino.
R 1Can have halogen atom as substituting group.Described halogen atom is the same with the example of the halogen atom of above-mentioned definition, for example is fluorine atom, chlorine atom, bromine atoms etc., wherein more preferably fluorine atom or chlorine atom.
R 1Can have the C2-C6 alkyloyl as substituting group.The example of described C2-C6 alkyloyl is the same with the group of the C2-C6 alkyloyl of above-mentioned definition, more particularly, and preference such as methyl carbonyl, ethyl carbonyl, propyl group carbonyl or sec.-propyl carbonyl, more preferably for example methyl carbonyl or ethyl carbonyl.
R 1Can have the N-C2-C6 alkanoylamino as substituting group.The more specifically example of this N-C2-C6 alkyloyl has ethyl carbonylamino, propyl group carbonylamino, sec.-propyl carbonylamino etc., more preferably methyl carbonylamino, ethyl carbonylamino.
R 1Can have the C1-C6 alkylthio as substituting group.The example of this alkylthio is the same with the example of the alkylthio of above-mentioned definition.More particularly, preferred described alkylthio is for example methylthio group, ethylmercapto group, rosickyite base, iprotiazem base etc., more preferably methylthio group, ethylmercapto group.
R 1Can have alkylsulfamoyl group as substituting group.The example of this alkylsulfamoyl group is the same with the group of above-mentioned definition.Described alkylsulfamoyl group for example is preferably methyl sulfamyl, ethyl sulfamyl, propyl group sulfamyl etc., more preferably methyl sulfamyl, ethyl sulfamyl.
R 1Can have dialkyl sulfamine as substituting group.The example of this dialkyl sulfamine is the same with the group of above-mentioned definition.More particularly, described dialkyl sulfamine is preferably for example dimethylamino alkylsulfonyl, diethyl amino alkylsulfonyl etc., more preferably dimethylamino alkylsulfonyl.
R 1Can have the alkyl sulfinyl as substituting group.The example of this alkyl sulfinyl is the same with the group of above-mentioned definition.More particularly, described alkyl sulfinyl preference such as methyl sulfinyl, ethylsulfinyl-1 base, propyl group sulfinyl, sec.-propyl sulfinyl etc., more preferably methyl sulfinyl, ethylsulfinyl-1 base.
R 1Can have alkyl sulphonyl as substituting group.The example of this alkyl sulphonyl is the same with the group of above-mentioned definition.More particularly, described alkyl sulphonyl preference such as methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, sec.-propyl alkylsulfonyl etc., more preferably methyl sulphonyl, ethylsulfonyl.
R 1Can have alkyl sulfonyl-amino as substituting group.The example of this alkyl sulfonyl-amino is the same with the group of above-mentioned definition.More particularly, described alkyl sulfonyl-amino preference such as methyl sulphonyl amino, ethylsulfonyl amino, sulfonyl propyl base amino, sec.-propyl sulfuryl amino etc., more preferably methyl sulphonyl amino, ethylsulfonyl amino.
R 1Can have alkoxy carbonyl as substituting group.The example of this alkoxy carbonyl is the same with the group of above-mentioned definition.More particularly, described alkoxy carbonyl is preferably for example methoxycarbonyl, ethoxy carbonyl, isopropoxy carbonyl, propoxycarbonyl etc., more preferably methoxycarbonyl, ethoxy carbonyl.
R 1Can have alkylamino as substituting group.The example of this alkylamino is the same with the group of above-mentioned definition.More particularly, described alkylamino is preferably for example methylamino, ethylamino etc., more preferably methylamino.
R 1Can have N, N-two-C1-C6 alkylamino is as substituting group.N, N-two-C1-C6 alkylamino are preferably for example dimethylamino, diethylamino, ethyl-methyl-amino, more preferably dimethylamino.
R 1Can have 5 or 6 yuan of cyclic aminos as substituting group.The example of these 5 or 6 yuan of cyclic aminos is the same with the example of " cyclic amino " of above-mentioned definition." R 1The substituting group that is had " preference such as pyrrolidyl, piperazinyl or morpholinyl etc., more preferably piperidyl or morpholinyl.
As R 1The substituting group that is had, the hydrogen atom in the preferred above-mentioned substituting group, hydroxyalkyl, low alkyl group, lower alkoxy, formamyl, alkyl-carbamoyl, cyano group, trifluoromethyl, halogen atom, C2-C6 alkyloyl, N-C2-C6 alkanoylamino, C1-C6 alkyl sulphonyl, C 1-C 6Alkylamino or aminoalkyl group, more preferably low alkyl group, lower alkoxy, alkyl-carbamoyl, halogen atom, C1-C6 alkyl sulphonyl or aminoalkyl group.
According to foregoing, more particularly, formula involved in the present invention (I)
Figure C20048000385000611
Compound is preferably for example following compound shown in [each mark is represented connotation same as described above in the formula]:
1) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
2) 3-(4-fluoro-phenyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
3) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
4) 3-(4-fluoro-phenyl sulfenyl)-6-(1-methyl-imidazoles-2-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
5) 3-(4-fluoro-phenyl sulfenyl)-6-(1-methyl isophthalic acid H-tetrazolium-5-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
6) 3-(cyclohexyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
7) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
8) 3-(thiazol-2-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
9) 3-(2-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-pyridine carboxamide,
10) 3-phenyl sulfenyl-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
11) 3-(4-fluoro-phenoxy group)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
12) 3-(4-methoxyl group-phenyl methyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
13) 3-(3-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
14) 3-(2,4-two fluoro-phenyl sulfenyls)-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
15) 3-(4-fluoro-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
16) 3-(4-cyano group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl) 2-pyridine carboxamide,
17) 3-(pyridin-4-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
18) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole is [5,4-b] pyridine-2-yl also)-2-pyridine carboxamide,
19) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
20) 3-(4-ethanoyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
21) 3-(thiophene-2-base-sulfenyl)-6-(4H[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
22) 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
23) 3-(4-fluoro-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole is [5,4-b] pyridine-2-yl also)-2-pyridine carboxamide,
24) 3-(4-methyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
25) 3-(4-chloro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
26) 3-(4-fluoro-phenyl sulfenyl)-6-(3H-[1,2,3] triazole-4-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
27) 3-(4-methyl sulphonyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
28) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-hydroxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
29) 3-(4-fluoro-phenyl sulfenyl)-6-(5-methoxymethyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
30) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
31) 3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
32) 3-(4-trifluoromethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
33) 3-(4-methylamino formyl radical-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
34) 3-(hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
35) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-dimethylaminomethyl-thiazol-2-yl)-2-pyridine carboxamide,
36) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
37) 3-(4-hydroxyethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
38) 3-(4-methyl sulfamyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
39) 3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)-2-pyridine carboxamide,
40) 3-(4-hydroxyl-cyclohexyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
41) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-pyridazine-3-yl)-the 2-pyridine carboxamide,
42) 3-(pyrazine-2-base-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
43) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(pyrazine-2-yl)-2-pyridine carboxamide,
44) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
45) 3-[4-(1-hydroxyethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
46) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(2-methyl-thiazole-4-yl)-2-pyridine carboxamide,
47) 3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(2-methyl-thiazole-4-yl)-2-pyridine carboxamide,
48) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
49) 3-(1-methyl isophthalic acid H-tetrazolium-5-base-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
50) 3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)-2-pyridine carboxamide,
51) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)-2-pyridine carboxamide,
52) 3-(4-fluoro-phenyl sulfenyl)-6-phenoxy group-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
53) 3-(2-chloro-phenyl methyl-amino)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
54) 3,6-two-(pyridine-2-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
55) 3,6-two-(4-fluoro-phenyl sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
56) 3,6-two-(thiazol-2-yl-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
57) 3,6-two-(5-methyl-[1,3,4] thiadiazoles-2-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
58) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-methyl-thiazol-2-yl)-2-pyridine carboxamide,
59) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)-2-pyridine carboxamide,
60) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-([1,3,4] thiadiazoles-2-yl)-2-pyridine carboxamide,
61) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
62) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl carbonyl-thiazol-2-yl)-2-pyridine carboxamide,
63) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(pyrimidine-4-yl)-2-pyridine carboxamide,
64) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(pyridine-2-yl)-2-pyridine carboxamide,
65) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-ethoxy carbonyl-thiazol-2-yl)-2-pyridine carboxamide,
66) 3-(pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
67) 3-(6-methoxyl group-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
68) 3-(pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
69) 3-phenoxymethyl-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
70) 3-phenyl sulfenyl methyl-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
71) 3-phenyl methyl-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
72) 3-(4-fluoro-phenyl methyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
73) 3-(4-dimethyl aminoethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
74) 3-(4-dimethylaminomethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
75) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole-4-yl)-2-pyridine carboxamide,
76) 3-(4-formyl-dimethylamino methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
77) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(4-hydroxyethyl-thiazol-2-yl)-2-pyridine carboxamide,
78) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-hydroxyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
79) 3-(6-methoxycarbonyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
80) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
81) 3-(pyrimidine-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
82) 3-(6-hydroxymethyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
83) 3-[4-(1-methylpyrrolidin-3-base oxygen base)-phenyl sulfenyl]-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
84) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
85) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
86) 3-(1-oxygen base-6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
87) 3-(4-diethyl amino base oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
88) 3-(4-tetramethyleneimine oxyethyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
89) 3-(6-dimethylamino ethoxy-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
90) 3-(pyrazoles-4-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
91) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
92) 3-(4-carbamyl ylmethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
93) 3-(5-bromo-6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
94) 3-[4-(2-hydroxyethyl)-phenyl sulfenyl]-6-(4H-[1,2,4]-triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
95) 3-[4-(2-hydroxyethyl-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
96) 3-(pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
97) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
98) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole is [5,4-b] pyridine-2-yl also)-2-pyridine carboxamide,
99) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
100) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,5] thiadiazoles-3-yl)-2-pyridine carboxamide,
101) 3-(2,3-Dihydrobenzofuranes-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
102) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methoxyl group-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
103) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-cyclopropyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
104) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
105) 3-(2-fluoro-pyridin-4-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
106) 3-(2-methoxyl group-pyrimidine-5-base sulfenyl)-6-(2H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
107) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
108) 3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
109) 3-(4-diethylamino formyl radical methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
110) 3-(6-cyclopropyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
111) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
112) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(pyrazoles-4-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
113) 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
114) 3-(4-dimethylamino alkylsulfonyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
115) 3-(5-fluoro-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4]-triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
116) 3-(2,3-Dihydrobenzofuranes-5-base sulfenyl)-6-(4H-[1,2,4]-triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
117) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] triazine-3-yl)-2-pyridine carboxamide,
118) 3-(4-carboxyl-phenyl sulfenyl)-6-(5-methyl-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
119) 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(pyrazine-2-yl)-2-pyridine carboxamide,
120) 3-(imidazo-[1,2-a]-pyridine-6-base sulfenyl)-6-(4H-[1,2,4]-triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
121) 3-(2-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
122)-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole is [4,5-b] pyridine-2-yl also)-2-pyridine carboxamide,
123) 3-(5-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
124) 3-(4,4-difluoro-methoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(pyrazine-2-yl)-2-pyridine carboxamide,
125) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
126) 3-(6-hydroxyethyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
127) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
128) 3-(2-methyl-imidazo-[1,2-a]-pyridine-6-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
129) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-hydroxymethyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
130) 3-[4-(2-hydroxyethyl-phenyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
131) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-hydroxyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
132) 3-(1-methyl isophthalic acid H-indazole-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
133) 3-(3-methyl-[1,2,4]-triazolo-[4,3-a]-pyridine-7-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
134) 3-(1-oxygen base-6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
135) 3-(6-hydroxymethyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
136) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
137) 3 ((4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1H-[1,2]-pyrazole-3-yl)-the 2-pyridine carboxamide,
138) 3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
139) 3-[4-(1H-imidazoles-1-yl)-phenyl sulfenyl]-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
140) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
141) 3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide,
142) 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide,
143) 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide,
144) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4,5-dimethyl-thiazol-2-yl)-2-pyridine carboxamide,
145) 3-(4-fluoro-phenyl sulfenyl)-6-(4,5-dimethyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
146) 3-(4-(1-methoxy ethyl)-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
147) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
148) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(5-trifluoromethyl thiazole-2-yl)-2-pyridine carboxamide,
149) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-trifluoromethyl thiazole-2-yl)-2-pyridine carboxamide,
150) 3-(3-fluoro-4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
151) 3-[4-(1,1-dimethyl-1-hydroxymethyl)-phenyl sulfenyl]-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
152) 3-(3,4-two fluoro-phenyl sulfenyls)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
153) 3-(3,5-two fluoro-phenyl sulfenyls)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
154) 3-(1-methyl-2-oxo-2,3-dihydro-1H-indoles-5-base sulfenyl]-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
155) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] Triazolopyridine-2-yl)-2-pyridine carboxamide,
156) 3-(4-ethoxyl methyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
157) 3-(6-oxo-1,6-dihydro-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
158) 3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
159) 3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide etc.;
More preferably following compound:
1) 3-(4-fluoro-phenyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
2) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
3) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
4) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl) 2-pyridine carboxamide,
5) 3-(4-fluoro-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl) 2-pyridine carboxamide,
6) 3-(pyridin-4-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl) 2-pyridine carboxamide,
7) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
8) 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
9) 3-(4-chloro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
10) 3-(4-fluoro-phenyl sulfenyl)-6-(3H-[1,2,3] triazole-4-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
11) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)-2-pyridine carboxamide,
12) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-([1,3,4] thiadiazoles-2-yl)-2-pyridine carboxamide,
13) 3-(4-methyl sulphonyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
14) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-hydroxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
15) 3-(4-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
16) 3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
17) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
18) 3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3 bases-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
19) 3-(4-N, N-dimethylamino-oxyethyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
20) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
21) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
22) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
23) 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-thiazol-2-yl)-the 2-pyridine carboxamide,
24) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
25) 3-(hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
26) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
27) 3-(4-hydroxyethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
28) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
29) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
30) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
31) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
32) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-2-yl)-2-pyridine carboxamide,
33) 3-[4-(2-hydroxyethyl-phenyl sulfenyl)] 6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
34) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
35) 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
36) 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(pyrazine-2-yl)-2-pyridine carboxamide,
37) 3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide or
38) 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide etc.;
More preferably following compound:
1) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
2) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl) 2-pyridine carboxamide,
3) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
4) 3-(4-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
5) 3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
6) 3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
7) 3-(4-N, N-dimethylamino-oxyethyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
8) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
9) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
10) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
11) 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-(thiazol-2-yl)-2-pyridine carboxamide,
12) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
13) 3-(hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
14) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
15) 3-(4-hydroxyethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
16) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
17) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
18) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
19) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
20) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-2-yl)-2-pyridine carboxamide,
21) 3-[4-(2-hydroxyethyl-phenyl sulfenyl)]-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
22) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
23) 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
24) 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(pyrazine-2-yl)-2-pyridine carboxamide,
25) 3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide or
26) 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide etc.
Pyridine-2-carboxamide derivatives 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 reduces and the factors such as insulin resistance of skeletal muscle, add the insulin resistance that obesity causes and cause morbidity, being mainly seen in the adult and falling ill.Someone proposes described insulin-dependent diabetes is divided into I type and II type according to its different in kind.
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.
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.Preferably be prepared by for example following method.
Figure C20048000385000791
[in the formula, each mark is identical with above-mentioned definition]
(step 1)
This step is to make lontrel derivative or its reactive derivatives and amine compound (2) reaction, prepares the method for compound (3).
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)  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)  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 (2) is different and different with compound used therefor and solvent types, other reaction conditions, with respect to 1 when quantity carboxylic acid (1) 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 (1) 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 (1) 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-two  alkane, 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 ℃ of boiling temperatures to solvent, is preferably 0-30 ℃.
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.
When the B substitution in ring base of the compound (3) of this step preparation has 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 etc., the 2nd edition, the JohnWiley ﹠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 that makes thus (3) 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 2)
This step is in the presence of alkali, makes the compound (3) and the R that make in the above-mentioned steps 1 1X 1H (X 1Expression Sauerstoffatom, nitrogen-atoms or sulphur atom, R 1Represent the connotation identical with above-mentioned definition) shown in compound (4) or formula (II)
Figure C20048000385000821
[each mark is represented the connotation identical with above-mentioned definition in the formula]
Shown in compound reaction, the method for compound shown in preparation formula (5) or (6) or the formula (I-1).
Compound used therefor among the present invention (4) can be amphyl, thiol derivative or sulfonamide derivatives.Here, amphyl not only comprises the situation that connects hydroxyl on the aryl, also is included in the situation that connects hydroxyl on the 5-7 unit heteroaryl.
In this step, when using compound (4), can prepare compound (5).
Formula (II-1) is amphyl or the thiol derivative of connection-DH (D represents Sauerstoffatom or sulphur atom) on the A ring of above-claimed cpd (II).
(here, amphyl is represented connotation same as described above.)
In this step, when using compound (II), can prepare compound (6) or (I-1).
Compound (I-1) is the compound that is included in the The compounds of this invention (I).
In this step, compound used therefor (4) or amount (II) are generally the 0.2-10 equivalent with respect to 1 equivalent compound (3), are preferably the 1-3 equivalent.
Available alkali for example has Trimethylamine 99, triethylamine, N in this step, 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; Basic metal such as potassium metal, sodium Metal 99.5, metallic lithium for example; Alkalimetal hydride such as sodium hydride, potassium hydride KH for example; Alkali metal alkyl compound such as butyllithium for example; Alkali metal alcoholates such as potassium tert.-butoxide, sodium ethylate or sodium methylate for example; Alkali metal hydroxide such as potassium hydroxide, sodium hydroxide for example; Alkaline carbonates such as salt of wormwood, yellow soda ash, cesium carbonate etc. for example, wherein preference such as aliphatic tertiary amine, alkalimetal hydride, alkaline carbonate or alkali metal alcoholates, particularly preferred example such as triethylamine, N, alkali metal alcoholates such as N-diisopropylethylamine, sodium hydride or salt of wormwood, potassium tert.-butoxide, sodium ethylate or sodium methylate.
In this step, used alkali different with solvent types and different with compound used therefor with respect to 1 equivalent compound (3), are generally the 0.2-10 equivalent, are preferably the 1-5 equivalent.
Used reaction solvent only otherwise hinder reaction, then there is no particular limitation as to it, for example preferred inert organic solvents.More particularly, methylene dichloride is for example arranged, chloroform, 1, the 2-ethylene dichloride, trichloroethane, N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, acetone, ethanol, Virahol, the trimethyl carbinol, tertiary amyl alcohol, ethyl acetate, methyl acetate, acetonitrile, benzene, dimethylbenzene, toluene, 1,4-two  alkane, tetrahydrofuran (THF), glycol dimethyl ether or their mixed solvent, preferred N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, acetonitrile, Virahol, tertiary amyl alcohol etc., more preferably N, dinethylformamide, acetonitrile, Virahol etc.
Reaction times is generally 0.2-100 hour, is preferably 1-40 hour.
Temperature of reaction is generally-20 ℃ to the solvent boiling point temperature, is preferably 0 ℃ of boiling temperature to solvent.
In this step, can be as required, the method by the document record (Organic Letters, 2002, the 4th volume, No. 20,3517-3520 page or leaf), based on its method or with these methods and ordinary method combination, in reaction system, add catalyzer and additive.
This step catalyst system therefor then can be any material so long as can promote the material of the reaction in this step, for example can be cupric chloride, cupric bromide, cupric iodide, cupric oxide, venus crystals etc., wherein, and more preferably cupric iodide.
As long as additive therefor can promote the material of the reaction of this step, then can be any material, for example can be ethylene glycol, glycol dimethyl ether etc., wherein, more preferably ethylene glycol.
Known separation purification method can be passed through in the compound that makes thus (5) or (6), for example concentrates, 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.
Compound of the present invention (I-1) can pass through known separation purification method, for example concentrates, concentrating under reduced pressure, redeposition, solvent extraction, crystallization, chromatography etc. carry out separation and purification.
Figure C20048000385000841
[each mark is identical with above-mentioned definition in the formula]
(step 3-1)
This step is in the presence of alkali, makes in the above-mentioned steps 2 gained compound (5) and has above-mentioned formula (II)
Figure C20048000385000842
The amphyl or the thiol derivative of the ring of A shown in [each mark is represented connotation same as described above in the formula] react, and prepare the method for The compounds of this invention (I-2).
Reaction conditionss such as the equivalents of compound used therefor, reaction solvent, reaction times, temperature of reaction can be undertaken by the method the same with above-mentioned steps 2 in this step.
The compound that makes thus (I-1) can pass through known separation purification method, for example concentrates, 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 3-2)
This step is to make gained compound (6) and R in the above-mentioned steps 2 1X 1Each mark is represented the connotation identical with above-mentioned definition in the H[formula] shown in compound (4) reaction, prepare the method for compound (I-3).
Reaction conditionss such as the equivalents of compound used therefor, alkali, reaction solvent, reaction times, temperature of reaction are the same with the condition of above-mentioned steps 2 in this step, can carry out the reaction of this step by the method the same with above-mentioned steps 2.
The compound that makes thus (I-3) can pass through known separation purification method, for example concentrates, 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.
Compound of the present invention (I-4) also can be by following method preparation.
Figure C20048000385000851
[in the formula, W represents the protecting group of carboxyl, and other mark is identical with above-mentioned definition]
(step 4)
This step is by importing protecting group on the carboxyl of dichloropyridine-2-carboxylic acid derivative (1), preparing the method for compound (11).Compound (11) can be prepared by known method or based on its method.Compound (11) if the protecting group W of carboxyl can be that the protecting group as carboxyl works in step 5 and step 6, and the group of deprotection gets final product easily in step 7, there is no particular limitation as to it, can use any group, for example straight or branched low alkyl groups such as methyl, ethyl, the tertiary butyl; 2-iodate ethyl, 2,2, junior alkyl halides such as 2-three chloroethyls; Allyl group, 2-propenyl, 2-methyl-low-grade alkenyls such as 2-propenyl; Aralkyl such as benzyl, PMB base etc.
The importing of such carboxyl-protecting group W and remove method, method that can be by the document record (Protective Groups in Organic Synthesis for example, T.W.Green work, the 2nd edition, John Wiley ﹠amp; Sons society, 1991, etc.), combine with ordinary method based on its method or with these methods and to carry out.
The compound that makes thus (11) can pass through known separation purification method, for example concentrates, 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.
(step 5)
This step is to make gained compound (11) and R in the above-mentioned steps 4 1X 1Each mark is represented the connotation identical with above-mentioned definition in the H[formula] shown in compound (12) reaction, prepare the method for compound (13).
Conditions such as the equivalents of compound used therefor, alkali, temperature of reaction, reaction times, reaction solvent are the same with the condition of above-mentioned steps 2 in this step.
The compound that makes thus (13) can pass through known separation purification method, for example concentrates, 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 6)
This step is to make gained compound (13) and following formula (II) in the above-mentioned steps 5
Figure C20048000385000861
The reaction of amphyl or thiol derivative shown in [each mark is represented the connotation identical with above-mentioned definition in the formula] prepares the method for compound (15).Here, amphyl is represented the connotation identical with above-mentioned definition.
Conditions such as the amount of the equivalents of compound, used alkali, reaction times, temperature of reaction, reaction solvent are the same with the condition of above-mentioned steps 2 in this step.
The compound that makes thus (15) can pass through known separation purification method, for example concentrates, 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.
(step 7)
This step is by removing the carboxyl-protecting group W of gained compound (15) in the above-mentioned steps 6, preparing the method for compound (16).
The dereaction of removing of carboxyl-protecting group W in this step can be by method (Protective Groups in Organic Synthesis, T.W.Green work, the 2nd edition, the JohnWiley of document record; Sons society, 1991, etc.), combine with ordinary method based on its method or with these methods and to carry out.
The compound that makes thus (16) can pass through known separation purification method, for example concentrates, 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 8)
This step is to make gained carboxylic acid derivative (16) and above-claimed cpd (2) reaction in the above-mentioned steps 7, prepares the method for The compounds of this invention (I-4).
The reaction that this step adopted is so-called one-tenth amido linkage reaction, and reaction conditionss such as the equivalents of compound used therefor, temperature of reaction, reaction times, condensing agent and reaction promoter are the same with above-mentioned steps 1.
The compound that makes thus (I-4) can pass through known separation purification method, for example concentrates, 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.
Compound of the present invention (I-5) can be by following method preparation.
Figure C20048000385000881
[in the formula, W1 represents the protecting group of thiol, X 2The expression leavings group, other mark is represented the connotation identical with above-mentioned definition]
(step 9)
This step is by the protecting group of the thiol of removing compound (19), prepares the method for compound (20).
Removing of the protecting group of the thiol in this step can be by method (Protective Groups in Organic Synthesis, T.W.Green work, the 2nd edition, the JohnWiley ﹠amp of document record; Sons society, 1991, etc.), combine with ordinary method based on its method or with these methods and to carry out.
The protecting group W1 of thiol can be any group of easy in this step deprotection, generation SH base.The protecting group W1 of this thiol can be an acyl group such as acetyl or benzoyl base for example, or substituted aralkyls such as trityl or 4-methoxy-benzyl.
The compound that makes thus (20) can pass through known separation purification method, for example concentrates, 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 10)
This step is in the presence of alkali, makes gained compound (20) and compound (21) reaction in the above-mentioned steps 9, prepares the method for compound (22).
The X of compound used therefor in this step (21) 2So long as can in step 21, play the group that leavings group is used for preparing compound (22), it then can be any group, for example halogen atom, sulfonate group, phosphonate groups etc. such as fluorine atom, chlorine atom bromine atoms, iodine atom, wherein preferred fluorine atom, chlorine atom, iodine atom, trifluoromethanesulfonic acid ester group, more preferably fluorine atom, bromine atoms or iodine atom etc.
Reaction conditionss such as the amount of compound used therefor and alkali, reaction times, temperature of reaction, reaction solvent can be undertaken by the method the same with above-mentioned steps 2 etc. in this step.
The compound that makes thus (22) can pass through known separation purification method, for example concentrates, 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 11)
This step is in the presence of alkali, makes compound (8) reaction of gained compound (22) and above-mentioned record in the above-mentioned steps 10, prepares the method for compound (I-5).
Reaction conditionss such as the amount of compound used therefor and alkali, reaction times, temperature of reaction, reaction solvent can be undertaken by the method the same with above-mentioned steps 2 etc. in this step.
The compound that makes thus (I-5) can pass through known separation purification method, for example concentrates, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatography etc. carry out separation and purification.
In the compound of the present invention, the X in the above-mentioned formula (I) 1-R 1Be CH 2-O-R 1Or-CH 2-S-R 1The time, can prepare compound of the present invention (I-6) by following method.
[in the formula, each mark is represented connotation same as described above]
(step 12)
This step is to make cyanopyridine derivative (25) and mCPBA reaction, prepares the method for compound (26).The oxidizing reaction that is adopted in this step can be by document record method (for example Tetrahedron, the 42nd volume, the 5th phase, 1475-1485 page or leaf), combine with ordinary method based on its method or with these methods and to carry out.The amount of used mCPBA is generally the 0.5-1 equivalent with respect to 1 equivalent compound (25), is preferably the 1-3 equivalent.
Reaction times is 10 minutes to 24 hours, is preferably 30 minutes to 12 hours.
Temperature of reaction is generally-20 ℃ of boiling temperatures to solvent, is preferably 0 ℃ of boiling temperature to solvent.
Used reaction solvent only otherwise hinder reaction can use any solvent, for example preferred chloroform, methylene dichloride, 1,2-ethylene dichloride etc.
The compound that makes thus (26) can pass through known separation purification method, for example concentrates, 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 13)
This step is to make gained compound (26) and POCl in the above-mentioned steps (12) 3Reaction prepares the method for compound (27).
Used POCl 3Amount with respect to 1 equivalent compound (26), be generally the 0.5-100 equivalent, be preferably the 1-20 equivalent.
Temperature of reaction is generally-20 ℃ to solvent boiling point, is preferably 20 ℃ to solvent boiling point.
Reaction times is generally 0.5-50 hour, is preferably 1-24 hour.
Solvent for use only otherwise hinder reaction then can use any solvent, preference such as methylene dichloride, chloroform, ethylene dichloride, acetonitrile, N, dinethylformamide etc.
The compound that makes thus (27) can pass through known separation purification method, for example concentrates, 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.
(step 14)
This step is in the presence of alkali, makes gained compound (27) and middle compound used therefor (12) reaction of above-mentioned steps (5) in the above-mentioned steps 13, prepares the method for compound (28).The reaction that this step adopted can be carried out according to the reaction the same with the step 5 of above-mentioned record, the amount of compound used therefor (12) is different and different with reaction conditionss such as the amount of used alkali, temperature of reaction, reaction times, temperature of reaction, can carry out according to the method the same with above-mentioned steps 2 grades.
The compound that makes thus (28) can pass through known separation purification method, for example concentrates, 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 15)
This step is to make above-mentioned steps 14 gained compounds (28) and above-claimed cpd (14) reaction, prepares the method for compound (29).
The amount of this step compound used therefor is different and different with reaction conditionss such as the amount of alkali, temperature of reaction, reaction times, reaction solvents, can carry out according to the method the same with above-mentioned steps 2 grades.
The compound that makes thus (29) can pass through known separation purification method, for example concentrates, 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 by with gained compound (29) hydrolysis in the above-mentioned steps 15, prepares the method for carboxylic acid cpd (30).Be hydrolyzed with alkali in this step.
Used alkali is so long as can be transformed into the cyano group of above-claimed cpd (29) alkali of carboxyl, then can be any alkali, wherein, preferred aqueous sodium hydroxide solution, potassium hydroxide, hydrated barta, lithium hydroxide etc., more preferably aqueous sodium hydroxide solution, potassium hydroxide aqueous solution etc.
The amount of used alkali is different and different with compound used therefor and solvent types, other reaction conditions, with respect to 1 equivalent compound (29), is generally the 1-100 equivalent, is preferably the 1-30 equivalent.
Temperature of reaction is generally 0 ℃ to solvent boiling point, is preferably 50-100 ℃.
Reaction times is generally 0.5-50 hour, is preferably 1-24 hour.
Used reaction solvent is preferably methyl alcohol, ethanol, Virahol, two  alkane, glycol dimethyl ether, ethylene glycol etc., more preferably ethanol, Virahol, two  alkane etc.
The compound that makes thus (30) can pass through known separation purification method, for example concentrates, 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 to make gained carboxylic acid cpd (30) and compound (2) reaction in the above-mentioned steps 16, prepares the method for compound (31).This step can adopt the one-tenth amido linkage reaction the same with above-mentioned steps 1,8 etc. to carry out, can be by method (for example peptide synthetic basis and the experiment of document record, spring room letter husband etc., ball is kind, nineteen eighty-three, Comprehensive OrganicSynthesis, the 6th volume, Pergamon Press society, 1991, etc.), combine with ordinary method based on its method or with these methods and to carry out.
One-tenth amido linkage reaction in the step 1 of reaction conditionss such as the amount of compound used therefor (2), reaction solvent, temperature of reaction and above-mentioned record, 8 etc. is the same.The compound that makes thus (30) can pass through known separation purification method, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification.
In the compound of the present invention (I)-X 1-R 1For-CH 2-Cm-R 1Compound (I-7) can be by the preparation of following method.(here, Cm is that carbonatoms is the divalent saturated hydrocarbyl of 2-5, and 1 carbon atom in this divalent saturated hydrocarbyl can be by nitrogen-atoms, Sauerstoffatom or sulphur atom displacement, R 1Identical with above-mentioned definition)
Figure C20048000385000941
[each mark is identical with above-mentioned definition in the formula]
Step (18)
This step is by importing protecting group on the carboxyl of compound (32), preparing the method for compound (33).The introduction method of carboxyl-protecting group can be by for example carrying out with the same method of above-mentioned steps 4, also can be according to the method for document record (Protective Groups in OrganicSynthesis for example, T.W.Green work, the 2nd edition, John Wiley ﹠amp; Sons society, 1991, etc.), combine with ordinary method based on its method or with these methods and to carry out.
The compound that makes thus (33) can pass through known separation purification method, for example concentrates, 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 19)
This step is to make gained compound (33) and mCPBA reaction in the above-mentioned steps 1, prepares the method for compound (34).The amount of used mCPBA in this step, temperature of reaction, reaction solvent, other reaction conditions get final product according to the condition the same with above-mentioned steps 12.The compound that makes thus (34) can pass through known separation purification method, for example concentrates, 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.
(step 20)
This step is to make gained compound (34) and POCl in the above-mentioned steps 19 3Reaction prepares the method for compound (35).
With respect to the compound (34) in 1 this step of equivalent, POCl 3Other reaction conditionss such as amount, temperature of reaction, reaction times the same with above-mentioned steps 13.
The compound that makes thus (35) can pass through known separation purification method, for example concentrates, 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.
(step 21)
This step is by removing the protecting group of the carboxyl of gained compound (35) in the above-mentioned steps 20, preparing the method for compound (36).
The protecting group W's of used carboxyl removes dereaction and can carry out under the reaction conditions the same with above-mentioned steps 7 in this step, can be according to the method for document record (ProtectiveGroups in Organic Synthesis for example, the T.W.Green work, the 2nd edition, John Wiley ﹠amp; Sons society, 1991, etc.), combine with ordinary method based on its method or with these methods and to carry out.The compound that makes thus (36) can pass through known separation purification method, for example concentrates, 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 compound (2) reaction that makes gained compound (36) and above-mentioned record in the above-mentioned steps 21, prepares the method for compound (37).
The reaction of being adopted in this step can be reacted the same carrying out with the one-tenth amido linkage of above-mentioned steps 1 or 8 etc.The compound that makes thus (37) can pass through known separation purification method, for example concentrates, 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 23)
This step is in the presence of alkali, makes gained compound (37) and above-claimed cpd (14) reaction in the above-mentioned steps 22, prepares the method for compound (38).The reaction of being adopted in this step can be undertaken by the method the same with above-mentioned steps 2 grades.The compound that makes thus (38) can pass through known separation purification method, for example concentrates, 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.
(step 24)
This step is to make gained compound (38) and NaBH in the above-mentioned steps 23 4Reaction prepares the method for compound (39).Reaction in this step can combine with ordinary method by the method (for example Comprehensive Organic Synthesis) of document record, based on its method or with these methods to be carried out.Used NaBH 4Amount with compound used therefor (38), solvent types, other reaction conditions is different and different, with respect to 1 equivalent compound (38), is generally the 0.2-30 equivalent, is preferably the 1-10 equivalent.
Temperature of reaction is generally-78 ℃ of boiling points to solvent, is preferably-10 ℃ to 40 ℃.
Reaction times is generally 0.1-24 hour, is preferably 0.2-5 hour.
Used reaction solvent only otherwise hinder reaction then can be used any solvent, for example particular methanol, ethanol, Virahol, tetrahydrofuran (THF) etc., more preferably methyl alcohol, ethanol etc.The compound that makes thus (39) can pass through known separation purification method, for example concentrates, 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.
(step 25)
This step is to make gained compound (39) and HSiEt in the above-mentioned steps 24 3React, prepare the method for compound (I-7).Used reduction reaction can combine with ordinary method by the method (for example J.O.C. the 53rd rolls up the 22nd phase, 5301-5304 page or leaf (1988)) of document record, based on its method or with these methods and carry out in this step.
Used HSiEt 3Amount different and different with the kind of compound (39) and solvent types, other reaction conditions, with respect to 1 equivalent compound (39), be generally the 0.5-100 equivalent, be preferably the 1-10 equivalent.
Reaction times is generally 0.2-30 hour, is preferably 0.5-10 hour.
Temperature of reaction is generally-10 ℃ to solvent boiling point, is preferably 0 ℃ to solvent boiling point.
Used reaction solvent then can be any solvent only otherwise hinder the reaction of this step, for example preferred trifluoroacetic acid.The compound of the present invention (I-7) that makes thus can pass through known separation purification method, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, redeposition, chromatography etc. carry out separation and purification.
Work as R 2Or R 3During for lower alkoxy, the hydrogen atom that constitutes the alkyl of alkoxyl group can be by hydroxyl or amino the replacement, when by this hydroxyl or amino the replacement, in any step of above-mentioned steps 1-25, carries out the importing of this hydroxyl or amino protecting group as required or removes.
Import or when removing this protecting group, method that can be by the document record (for example method of record such as Protective Groups in Organic Synthesis), combine with ordinary method based on its method or with these methods and to carry out.
In addition, as A ring, R 1Or when having substituting group on the B ring, can be according to substituent form, on each substituting group, import as required or remove protecting group, the reaction of each step is carried out smoothly.
The importing of described protecting group and remove the method that dereaction can be by the document record (Protective Groups in Organic Synthesis for example, T.W.Green work, the 2nd edition, JohnWiley; Sons society, 1991, etc.), combine with ordinary method based on its method or with these methods and to carry out.
Can exist with the form of pharmacy acceptable salt by pyridine-2-carboxamide derivatives provided by the invention, can use following formula (I-1) that The compounds of this invention (I) comprised, (I-2), (I-3), (I-4), (I-5), (I-6) and (I-7), prepare according to ordinary method.
Specifically, above-mentioned (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) and compound (I-7) are when its intramolecularly has the basic group that for example is derived from amino, pyridyl etc., 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 relative disease or symptom, formula of the present invention (I) compound can be used in combination formula (I) compound and carrier substance.
Formula of the present invention (I) compound is used to prevent or the dosage when treating changes with the character of treatment symptom, selected specific compound and route of administration certainly.
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, contain lozenge, 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 when the glucose-6-phosphate dehydrogenase as the report enzyme generates phosphogluconolactone by Robison ester, study the activation degree of glucokinase by the amount of measuring the Thio-NADH that is generated.
In this test used recombinant human liver GK as the FLAG fusion rotein at expression in escherichia coli, by ANTIFLAG M2AFFINITY GEL (Sigma) purifying.
Test uses flat 96 orifice plates to carry out at 30 ℃.Dispensing 69 μ l test damping fluid (25mMHepes Buffer: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 l 25mM glucose as substrate then, begin to react (final glucose concn=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, compound is estimated every 30 seconds.Add FLAG-GK, make that 1%DMSO exists down, the absorbancy increasing amount after 5 minutes reaches 0.05-0.1.
OD value with the DMSO contrast is 100%, measures the OD value of compound to be evaluated under each concentration.By the OD value of each concentration, calculate Emax (%) and EC50 (μ M), 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)
Compound number Emax(％) EC50(μM)
Preparation example 1 997 0.05
Preparation example 7 1067 0.06
Preparation example 30 818 0.12
As above shown in the table 1, as index, The compounds of this invention has enough GK activation energy with the value of Emax and EC50.
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.
The thin-layer chromatography of embodiment adopts Silicagel 60 F 245(Merck), use the U detector in the detection method as pole plate.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
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2- The preparation of pyridine carboxamide
To 14.1g (73.0mmol) 3, add 9.00g (89.9mmol) aminothiazole, 12.1g (89.7mmol) N-hydroxy benzotriazole hydrate and 19.0g (99.2mmol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride in the chloroformic solution (400ml) of 6-two chloro-2-pyridine carboxylic acids successively, at room temperature stirred then 24 hours.Concentration of reaction solution adds ethyl acetate afterwards in resistates, with 0.2N-aqueous hydrochloric acid, water, saturated sodium bicarbonate aqueous solution and saturated common salt solution washing.Dry, concentrated, then with of mixed solvent (5: the 1) crystallization of gained resistates, obtain 12.8g (yield: 64%) be 3 of white solid, 6-two chloro-N-(thiazol-2-yl)-2-pyridine carboxamides with hexane/ethyl acetate.
To the N of 1.27g (4.64mmol) gained dichloro body, add 1.25g (9.04mmol) salt of wormwood and 605 μ l (4.87mmol) 4-methoxybenzenethiols in the dinethylformamide solution (10ml), at room temperature stirred then 24 hours.In reaction solution, add entry, use ethyl acetate extraction, use the saturated common salt solution washing then.After dry and concentrated, (hexane: ethyl acetate=4: 1-1: 1) purifying obtains 1.70g (yield: 97%) be the 6-chloro-3-of white solid (4-methoxyl group-phenyl sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide with silica gel column chromatography with the gained resistates.
To the N of 705mg (1.87mmol) gained 6-chlorine derivative, add 350mg (2.53mmol) salt of wormwood and 285mg (2.82mmol) 3-sulfydryl-1,2 in the dinethylformamide solution (10ml), the 4-triazole, reflux is 35 hours then.In reaction solution, add entry, use chloroform extraction 3 times, dry then organic layer, concentrating under reduced pressure.By silica gel column chromatography (chloroform: methyl alcohol=100: 1), and, the gained resistates is carried out purifying, obtain 410mg (yield: 50%) be the title compound of white solid with mixed solvent (1: the 1) crystallization of hexane/ethyl acetate.
1H NMR(CDCl 3)δ：3.87(3H，s)，6.07-7.07(4H，m)，7.22(1H，d，J＝8.7Hz)，7.45(1H，d，J＝3.6Hz)，7.49(2H，d，J＝9.0Hz)，8.35(1H，s)
ESI-MS(m/e)：443[M+H] +
By the method the same, make the compound of preparation example 2-51 with above-mentioned preparation example 1.Provide the analytical data of these compounds below.
Preparation example 2
Figure C20048000385001071
3-(4-fluoro-phenyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4 methyl-thiophene Azoles-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methylthiazol, 4-fluoro-thiophenol and 3-sulfydryl-4-methyl isophthalic acid, 2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 2 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.42(3H，s)，3.74(3H，s)，6.62(1H，s)，7.00(1H，d，J＝9.0Hz)，7.10(1H，d，J＝9.0Hz)，7.17(2H，m)，7.53(2H，m)，8.40(1H，s)
ESI-MS(m/e)：459[M+H] +
Preparation example 3
3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)- The preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methylthiazol, 4-fluoro-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 3 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.40(3H，s)，6.61(1H，s)，7.01(1H，d，J＝9.3Hz)，7.17-7.25(3H，m)，7.58(2H，m)，8.35(1H，s)
ESI-MS(m/e)：445[M+H] +
Preparation example 4
3-(4-fluoro-phenyl sulfenyl)-6-(1-methyl-imidazoles-2-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2- The preparation of pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methylthiazol, 4-fluoro thiophenol and 3-sulfydryl-4-methyl isophthalic acid, 2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 4 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.41(3H，s)，3.73(3H，s)，6.60(1H，s)，6.77(1H，d，J＝8.7Hz)，6.92(1H，d，J＝8.7Hz)，7.10-7.22(4H，m)，7.52(2H，m)
ESI-MS(m/e)：458[M+H] +
Preparation example 5
Figure C20048000385001091
3-(4-fluoro-phenyl sulfenyl)-6-(1-methyl isophthalic acid H-tetrazolium-5-base sulfenyl)-N-(4-methylthiazol-2- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methylthiazol, 4-fluoro thiophenol and 5-sulfydryl-1-methyl-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 5 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.43(3H，s)，4.12(3H，s)，6.65(1H，s)，7.12(1H，d，J＝9.0Hz)，7.21(2H，m)，7.45(1H，d，J＝9.0Hz)，7.58(2H，m)
ESI-MS(m/e)：460[M+H] +
Preparation example 6
Figure C20048000385001101
3-(cyclohexyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2- The preparation of pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methylthiazol, cyclohexylmercaptan and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 6 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：1.20-1.75(6H，m)，1.84(2H，m)，2.06(2H，m)，2.36(3H，s)，3.25(1H，m)，6.56(1H，s)，7.43(1H，d，J＝8.7Hz)，7.64(1H，d，J＝8.7Hz)，8.33(1H，s)
ESI-MS(m/e)：433[M+H] +
Preparation example 7
Figure C20048000385001102
3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine The preparation of methane amide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 4-fluoro thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 7 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：7.01(1H，d，J＝8.7Hz)，7.09(1H，d，J＝3.6Hz)，7.19(2H，m)，7.25(1H，d，J＝8.7Hz)，7.50(1H，d，J＝3.6Hz)，7.50(2H，m)，8.35(1H，s)
ESI-MS(m/e)：431[M+H] +
Preparation example 8
3-(thiazol-2-yl-sulfenyl)-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-(4-methyl-thiazole-2- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methylthiazol, 2-sulfydryl-thiazole and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 8 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.40(3H，s)，6.60(1H，m)，7.30-7.36(2H，m)，7.59(1H，d，J＝3.6Hz)，8.02(1H，d，J＝3.6Hz)，8.34(1H，s)
ESI-MS(m/e)：434[M+H] +
Preparation example 9
Figure C20048000385001112
3-(2-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine The preparation of methane amide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 2-fluoro thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 9 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：7.01-7.04(2H，m)，7.20-7.28(3H，m)，7.46(1H，d，J＝3.6Hz)，7.51-7.64(2H，m)，8.36(1H，s)
ESI-MS(m/e)：431[M+H] +
Preparation example 10
Figure C20048000385001121
3-phenyl sulfenyl-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine formyl The preparation of amine
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, thiophenol and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 10.
1H NMR(CDCl 3)δ：7.02-7.09(2H，m)，7.24(1H，d，J＝8.7Hz)，7.47-7.53(4H，m)，7.57-7.63(2H，m)，8.38(1H，s)
ESI-MS(m/e)：413[M+H] +
Preparation example 11
Figure C20048000385001131
3-(4-fluoro-phenoxy group)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine first The preparation of acid amides
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 4-fluorophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 11 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：7.04(1H，d，J＝3.6Hz)，7.05-7.13(4H，m)，7.24(1H，d，J＝8.7Hz)，7.46-7.51(2H，m)，8.32(1H，s)
ESI-MS(m/e)：415[M+H] +
Preparation example 12
Figure C20048000385001132
3-(4-methoxyl group-phenyl methyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N- The preparation of (thiazol-2-yl)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 4-methoxy-benzyl mercaptan and 3-sulfydryl-4-methyl isophthalic acid, 2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 12 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.76(3H，s)，3.79(3H，s)，4.11(2H，s)，6.84(2H，d，J＝8.8Hz)，7.01(1H，d，J＝3.2Hz)，7.30(1H，d，J＝8.8Hz)，7.32(2H，d，J＝8.8Hz)，7.51(1H，d，J＝3.2Hz)，7.65(1H，d，J＝8.8Hz)，8.44(1H，s)
ESI-MS(m/e)：471[M+H] +
Preparation example 13
Figure C20048000385001141
3-(3-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine The preparation of methane amide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 3-fluoro thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 13 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：7.02(1H，d，J＝3.6Hz)，7.05(1H，d，J＝8.4Hz)，7.18(1H，td，J＝8.4Hz，3.2Hz)，7.24(1H，d，J＝8.4Hz)，7.29(1H，ddd，J＝8.4Hz，2.8Hz，2.8Hz)，7.36(1H，d，J＝7.6Hz)，7.42-7.48(2H，m)，8.35(1H，s)
ESI-MS(m/e)：431[M+H] +
Preparation example 14
Figure C20048000385001151
3-(2,4-two fluoro-phenyl sulfenyls)-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2- The preparation of pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 2,4 difluorobenzene thiophenol and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 14.
1H NMR(CDCl 3)δ：6.98-7.05(4H，m)，7.28(1H，d，J＝8.8Hz)，7.46(1H，d，J＝3.6Hz)，7.58-7.64(1H，m)，8.36(1H，s)
ESI-MS(m/e)：449[M+H] +
Preparation example 15
Figure C20048000385001152
3-(4-fluoro-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4]-triazole-3-base-sulfenyl)-N-(thiazole-2- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 4-fluoro thiophenol and 3-sulfydryl-5-methyl isophthalic acid, 2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 15 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.58(3H，s)，6.97(1H，d，J＝8.4Hz)，7.04(1H，d，J＝3.6Hz)，7.15-7.23(3H，m)，7.48(1H，d，J＝3.6Hz)，7.54-7.58(2H，m)
ESI-MS(m/e)：445[M+H] +
Preparation example 16
Figure C20048000385001161
3-(4-cyano group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyrrole The preparation of pyridine methane amide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 4-cyano group thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 16 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：7.06(1H，d，J＝3.6Hz)，7.11(1H，d，J＝8.8Hz)，7.30(1H，d，J＝8.8Hz)，7.49(1H，d，J＝3.6Hz)，7.65(2H，d，J＝8.8Hz)，7.73(2H，d，J＝8.8Hz)，8.40(1H，s)
ESI-MS(m/e)：438[M+H] +
Preparation example 17
Figure C20048000385001171
3-(pyridin-4-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine The preparation of methane amide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 4-sulfydryl-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 17 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：7.09(1H，d，J＝3.6Hz)，7.28-7.35(2H，m)，7.43(2H，d，J＝6.0Hz)，7.51(1H，d，J＝3.6Hz)，8.39(1H，s)，8.62(2H，d，J＝6.0Hz)
ESI-MS(m/e)：414[M+H] +
Preparation example 18
Figure C20048000385001172
3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole also [5,4-b] pyridine- The 2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-be [5,4-b] pyridine, 4-fluoro thiophenol and 3-sulfydryl-1 also, 2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 18.
1H NMR(CDCl 3)δ：7.00(1H，d，J＝8.8Hz)，7.16-7.20(2H，m)，7.25(1H，d，J＝8.8Hz)，7.37-7.41(1H，m)，7.55-7.58(2H，m)，8.02(1H，d，J＝8.4Hz)，8.42(1H，s)，8.51(1H，d，J＝4.4Hz)
ESI-MS(m/e)：482[M+H] +
Preparation example 19
Figure C20048000385001181
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 4-methoxymethyl- The preparation of thiazole-2-)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methoxymethyl-thiazole, 4-methoxyl group-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 19 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.43(3H，s)，3.86(3H，s)，4.51(2H，s)，6.92(1H，s)，6.96-7.02(3H，m)，7.22(1H，d，J＝8.7Hz)，7.49(2H，d，J＝8.7Hz)，8.35(1H，s)
ESI-MS(m/e)：487[M+H] +
Preparation example 20
Figure C20048000385001191
3-(4-ethanoyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2- The preparation of pyridine carboxamide
Use 3; 6-two chloro-2-pyridine carboxylic acids, thiazolamine, 4-acetylbenzene thiophenol and 3-sulfydryl-1,2, the 4-triazole; by the method the same, combine with ordinary method, can make the compound of preparation example 20 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.65(3H，s)，7.05(1H，d，J＝3.6Hz)，7.10(1H，d，J＝8.4Hz)，7.25(1H，d，J＝8.4Hz)，7.47(1H，d，J＝3.6Hz)，7.65(2H，d，J＝8.6Hz)，8.01(2H，d，J＝8.6Hz)，8.36(1H，s)
ESI-MS(m/e)：455[M+H] +
Preparation example 21
Figure C20048000385001192
3-(thiophene-2-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine The preparation of methane amide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 2-sulfydryl-thiophene and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 21 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：7.01(1H，d，J＝3.2Hz)，7.06(1H，d，J＝8.8Hz)，7.16(1H，dd，J＝3.6，5.2Hz)，7.26(1H，d，J＝8.8Hz)，7.35(1H，dd，J＝1.2，3.6Hz)，7.43(1H，d，J＝3.2Hz)，7.60(1H，dd，J＝1.2，5.2Hz)，8.35(1H，s)
ESI-MS(m/e)：419[M+H] +
Preparation example 22
Figure C20048000385001201
3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-(thiazol-2-yl)- The preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 4-methoxymethyl-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 22 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.46(3H，s)，4.50(2H，s)，7.00(1H，d，J＝3.2Hz)，7.02(1H，d，J＝8.8Hz)，7.17(1H，d，J＝8.8Hz)，7.42(1H，d，J＝3.2Hz)，7.43(2H，d，J＝8.0Hz)，7.54(2H，d，J＝8.0Hz)，8.33(1H，s)
ESI-MS(m/e)：457[M+H] +
Preparation example 23
Figure C20048000385001211
3-(4-fluoro-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-(thiazole is also for N- [5,4-b] pyridine-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-also [5,4-b] pyridine, 4-fluoro thiophenol and 3-sulfydryl-5-methyl isophthalic acid, 2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 23 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.54(3H，s)，6.96(1H，d，J＝8.8Hz)，7.11-7.16(2H，m)，7.17(1H，d，J＝8.8Hz)，7.37(1H，dd，J＝4.8，8.0Hz)，7.50-7.54(2H，m)，8.00(1H，d，J＝8.0Hz)，8.45(1H，d，J＝4.8Hz)
ESI-MS(m/e)：496[M+H] +
Preparation example 24
Figure C20048000385001221
3-(4-methyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(the 4-methoxymethyl- Thiazol-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methoxymethyl-thiazole, 4-methylbenzene thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 24 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.42(3H，s)，3.43(3H，s)，4.51(2H，s)，6.91(1H，s)，7.00(1H，d，J＝8.8Hz)，7.19(1H，d，J＝8.8Hz)，7.26(2H，d，J＝8.4Hz)，7.44(2H，d，J＝8.4Hz)，8.34(1H，s)
ESI-MS(m/e)：471[M+H] +
Preparation example 25
Figure C20048000385001222
3-(4-chloro-phenyl sulfenyl)-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiophene Azoles-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methoxymethyl-thiazole, 4-chlorothio-phenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 25 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.43(3H，s)，4.50(2H，s)，6.91(1H，s)，6.97(1H，d，J＝8.8Hz)，7.20(1H，d，J＝8.8Hz)，7.42(2H，d，J＝8.4Hz)，7.49(2H，d，J＝8.4Hz)，8.33(1H，s)
ESI-MS(m/e)：491[M+H] +
Preparation example 26
Figure C20048000385001231
3-(4-fluoro-phenyl sulfenyl)-6-(3H-[1,2,3] triazole-4-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine The preparation of methane amide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methoxymethyl-thiazole, 4-fluoro thiophenol and 4-sulfydryl-1,2,3-triazoles, by the method the same, combine with ordinary method, can make the compound of preparation example 26 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：6.66(1H，d，J＝8.8Hz)，6.72(1H，d，J＝8.8Hz)，6.86(1H，d，J＝4.0Hz)，6.89-6.94(2H，m)，7.25(1H，d，J＝4.0Hz)，7.27-7.30(2H，m)，7.72(1H，s)，
ESI-MS(m/e)：431[M+H] +
Preparation example 27
3-(4-methyl sulphonyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole-2- Base)-preparation of 2-pyridine carboxamide
Use 3; 6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-methyl sulphonyl thiophenol and 3-sulfydryl-1,2, the 4-triazole; by the method the same, combine with ordinary method, can make the compound of preparation example 27 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.12(3H，s)，7.05(1H，d，J＝3.6Hz)，7.11(1H，d，J＝8.8Hz)，7.28(1H，d，J＝8.8Hz)，7.48(1H，d，J＝3.6Hz)，7.74(2H，d，J＝8.0Hz)，8.00(2H，d，J＝8.0Hz)8.39(1H，s)
ESI-MS(m/e)：491[M+H] +
Preparation example 28
Figure C20048000385001242
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(the 5-hydroxymethyl- Thiazol-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-hydroxy methyl-thiazole, 4-methoxybenzenethiol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 28 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.86(3H，s)，4.78(2H，s)，6.99(2H，d，J＝8.8Hz)，7.02(1H，d，J＝8.8Hz)，7，18(1H，d，J＝8.8Hz)，7.35(1H，s)，7.46(2H，d，J＝8.8Hz)，8.39(1H，s)
ESI-MS(m/e)：473[M+H] +
Preparation example 29
Figure C20048000385001251
3-(4-fluoro-phenyl sulfenyl)-6-(5-methoxymethyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiophene Azoles-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-fluoro thiophenol and 3-sulfydryl-5-methoxymethyl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 29 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.50(3H，s)，4.76(2H，s)，6.98(1H，d，J＝8.8Hz)，7.03(1H，d，J＝3.2Hz)，7.14-7.22(3H，m)，7.48(1H，d，J＝3.2Hz)，7.54-7.57(2H，m)
ESI-MS(m/e)：475[M+H] +
Preparation example 30
Figure C20048000385001261
3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole-2- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 30 based on its method or with these methods with preparation example 1.
1H NMR(DMSO-d 6)δ：2.51(3H，s)，7.17(1H，d，J＝8.8Hz)，7.21(1H，d，J＝8.8Hz)，7.35(1H，d，J＝3.6Hz)，7.36(1H，d，J＝8.8Hz)，7.57(1H，d，J＝3.6Hz)，7.83(1H，dd，J＝2.4，8.8Hz)，8.53(1H，d，J＝2.4Hz)，8.72(1H，s)，
ESI-MS(m/e)：428[M+H]
Preparation example 31
Figure C20048000385001262
3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiophene Azoles-2-yl)-preparation of 2-pyridine carboxamide
Use 3; 6-two chloro-2-pyridine carboxylic acids, thiazolamine, 4-formyl-dimethylamino thiophenol and 3-sulfydryl-1,2, the 4-triazole; by the method the same, combine with ordinary method, can make the compound of preparation example 31 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.02(3H，s)3.15(3H，s)，7.04(1H，d，J＝3.6Hz)，7.06(1H，d，J＝8.8Hz)，7.23(1H，d，J＝8.8Hz)，7.49(1H，d，J＝3.6Hz)，7.50(2H，d，J＝8.4Hz)，7.61(2H，d，J＝8.4Hz)，8.39(1H，s)
ESI-M S(m/e)：484[M+H] +
Preparation example 32
Figure C20048000385001271
3-(4-trifluoromethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)- The preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-trifluoromethyl thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 32 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：7.04(1H，d，J＝3.6Hz)7.06(1H，d，J＝8.8Hz)，7.26(1H，d，J＝8.8Hz)，7.47(1H，d，J＝3.6Hz)，7.66-7.74(4H，m)，8.38(1H，s)，
ESI-MS(m/e)：481[M+H] +
Preparation example 33
Figure C20048000385001281
3-(4-methylamino formyl radical-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole -2-yl)-preparation of 2-pyridine carboxamide
Use 3; 6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-methylamino formyl radical thiophenol and 3-sulfydryl-1,2, the 4-triazole; by the method the same, combine with ordinary method, can make the compound of preparation example 33 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.00(3H，d，J＝4.8Hz)，7.02(1H，d，J＝8.8Hz)，7.05(1H，d，J＝3.6Hz)，7.20(1H，d，J＝8.8Hz)，7.47(1H，d，J＝3.6Hz)，7.59(2H，d，J＝8.4Hz)，7.81(2H，d，J＝8.4Hz)，8.32(1H，s)，
ESI-MS(m/e)：470[M+H] +
Preparation example 34
Figure C20048000385001291
3-(hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)- The preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-hydroxyl-oxethyl-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 34 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.97(2H，m)，4.13(2H，m)，7.00-7.11(4H，m)，7.23(1H，d，J＝9.0Hz)，7.46-7.54(3H，m)，8.36(1H，s)
ESI-MS(m/e)：473[M+H] +
Preparation example 35
Figure C20048000385001292
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-dimethylamino Methyl-thiazol-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-5-dimethylaminomethyl thiazole, 4-methoxybenzenethiol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 35 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.32(6H，s)，3.70(2H，s)，3.85(3H，s)，6.97(2H，d，J＝8.8Hz)，7.00(1H，d，J＝8.5Hz)，7.19(1H，d，J＝8.5Hz)，7.26(1H，s)，7.46(2H，d，J＝8.8Hz)，8.31(1H，s)
ESI-MS(m/e)：500[M+H] +
Preparation example 36
Figure C20048000385001301
3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiophene Azoles-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-dimethyl aminoethyl thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 36 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.40(6H，s)，2.82(2H，t，J＝5.6Hz)，4.13(2H，t，J＝5.6Hz)，6.95-7.05(4H，m)，7.21(1H，d，J＝8.7Hz)，7.42-7.50(3H，m)，8.36(1H，s)
ESI-MS(m/e)：500[M+H] +
Preparation example 37
Figure C20048000385001311
3-(4-hydroxyethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)- The preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 4-hydroxyethyl thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 37 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.93(2H，m)，3.90(2H，m)，7.04-7.10(2H，m)，7.23(1H，d，J＝9.0Hz)，7.36(2H，d，J＝7.8Hz)，7.48-7.56(3H，m)，8.34(1H，s)
ESI-MS(m/e)：457[M+H] +
Preparation example 38
Figure C20048000385001321
3-(4-methyl sulfamyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole- The 2-yl)-preparation of 2-pyridine carboxamide
Use 3; 6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-methyl sulfamyl thiophenol and 3-sulfydryl-1,2, the 4-triazole; by the method the same, combine with ordinary method, can make the compound of preparation example 38 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.97(3H，s)，6.98(1H，d，J＝3.6Hz)，7.21-7.25(3H，m)，7.30-7.50(4H，m)，8.28(1H，s)
ESI-MS(m/e)：505[M] +
Preparation example 39
Figure C20048000385001322
3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-is (different  azoles-3-yl)-preparation of 2-pyridine carboxamide
Use 3; 6-two chloro-2-pyridine carboxylic acids, 3-amino- azoles, 4-formyl-dimethylamino-thiophenol and 3-sulfydryl-1,2, the 4-triazole; by the method the same, combine with ordinary method, can make the compound of preparation example 39 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.01(3H，s)，3.15(3H，s)，6.99(1H，d，J＝8.8Hz)，7.19(1H，d，J＝8.8Hz)，7.25(1H，d，J＝1.6Hz)，7.48(2H，d，J＝8.1Hz)，7.56(2H，d，J＝8.1Hz)，8.31(1H，d，J＝1.6Hz)，8.41(1H，s)
ESI-MS(m/e)：468[M+H] +
Preparation example 40
3-(4-hydroxyl-cyclohexyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2- The preparation of pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-sulfydryl-hexalin and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 40 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：1.30-1.60(4H，m)，1.90-2.15(4H，m)，3.10-3.22(1H，m)，3.60-3.70(1H，m)，6.99(1H，d，J＝3.6Hz)，7.40(1H，d，J＝8.8Hz)，7.43(1H，d，J＝3.6Hz)，7.61(1H，d，J＝8.8Hz)，8.32(1H，s)
ESI-MS(m/e)：435[M+H] +
Preparation example 41
Figure C20048000385001341
3-(4-fluoro-phenyl sulfenyl)-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(pyridazine-3-yl)-2-pyridine first The preparation of acid amides
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-pyridazine, 4-fluoro thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 41 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：6.96(1H，d，J＝9.2Hz)，7.12-7.16(2H，m)，7.19(1H，d，J＝9.2Hz)，7.50-7.55(3H，m)，8.41(1H，s)，8.65(1H，d，J＝9.2Hz)，8.85(1H，d，J＝4.8Hz)
ESI-MS(m/e)：426[M+H] +
Preparation example 42
3-(pyrazine-2-base-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine The preparation of methane amide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 2-sulfydryl-pyrazine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 42 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：7.02(1H，d，J＝3.6Hz)，7.39(1H，d，J＝8.8Hz)，7.45(1H，d，J＝3.6Hz)，7.68(1H，d，J＝8.8Hz)，8.38(1H，s)，8.44-8.46(2H，m)，8.70(1H，d，J＝1.6Hz)
ESI-MS(m/e)：415[M+H] +
Preparation example 43
Figure C20048000385001351
3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(pyrazine-2- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-pyrazino, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 43 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.64(3H，s)，6.96(1H，d，J＝8.8Hz)，7.17(1H，d，J＝8.8Hz)，7.28(1H，d，J＝8.1Hz)，7.77(1H，dd，J＝8.1，2.2Hz)，8.29(1H，dd，J＝2.6，1.5Hz)，8.35(1H，d，J＝2.6Hz)，8.41(1H，s)，8.61(1H，d，J＝2.2Hz)，9.68(1H，d，J＝1.5Hz)
ESI-MS(m/e)：423[M+H] +
Preparation example 44
Figure C20048000385001361
3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiophene Azoles-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methyl-thiazole, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 44 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.39(3H，s)，2.63(3H，s)，6.58(1H，s)，6.99(1H，d，J＝8.8Hz)，7.20-7.80(2H，m)，7.74(1H，d，J＝8.0Hz)，8.32(1H，s)，8.62(1H，s)
ESI-MS(m/e)：442[M+H] +
Preparation example 45
Figure C20048000385001362
3-[4-(1-hydroxyethyl-phenyl sulfenyl)]-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole-2- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 4-(1-hydroxyethyl) thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 45 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：1.52(3H，d，J＝6.4Hz)，4.97(1H，q，J＝6.4Hz)，7.03(1H，d，J＝8.4Hz)，7.06(1H，d，J＝3.6Hz)，7.18(1H，d，J＝8.4Hz)，7.47(2H，d，J＝8.0Hz)，7.48(1H，d，J＝3.6Hz)，7.52(2H，d，J＝8.0Hz)，8.34(1H，s)
ESI-MS(m/e)：457[M+H]
Preparation example 46
Figure C20048000385001371
3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(2-methyl-thiophene Azoles-4-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methylthiazol, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 46 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.63(3H，s)，2.72(3H，s)，6.96(1H，d，J＝8.4Hz)，7.19(1H，d，J＝8.1Hz)，7.27(1H，d，J＝8.4Hz)，7.68(1H，s)，7.76(1H，dd，J＝8.4，2.2Hz)，8.26(1H，s)，8.59(1H，d，J＝2.2Hz)
ESI-MS(m/e)：442[M+H] +
Preparation example 47
3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(2- Methyl-thiazole-4-yl)-preparation of 2-pyridine carboxamide
Use 3; 6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methylthiazol, 4-formyl-dimethylamino thiophenol and 3-sulfydryl-1; 2; the 4-triazole; by the method the same, combine with ordinary method, can make the compound of preparation example 47 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.69(3H，s)，3.00(3H，s)，3.14(3H，s)，6.95(1H，d，J＝8.8Hz)，7.11(1H，d，J＝8.8Hz)，7.45(2H，d，J＝8.1Hz)，7.56(2H，d，J＝8.1Hz)，7.64(1H，s)，8.29(1H，s)
ESI-MS(m/e)：498[M+H] +
Preparation example 48
3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxyl group Methyl-thiazol-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methoxymethyl-thiazole, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 48 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.62(3H，s)，3.44(3H，s)，4.51(2H，s)，6.91(1H，s)，6.93(1H，d，J＝8.4Hz)，7.19(1H，d，J＝8.4Hz)，7.26(1H，d，J＝8.0Hz)，7.77(1H，dd，J＝8.0Hz，2.4Hz)，8.35(1H，s)，8.61(1H，d，J＝2.4Hz)
ESI-MS(m/e)：472[M+H]
Preparation example 49
Figure C20048000385001392
3-(1-methyl isophthalic acid H-tetrazolium-5-base-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole- The 2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 5-sulfydryl-1-methyl isophthalic acid, 2,4-triazole and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 49 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：4.11(3H，s)，7.11(1H，d，J＝3.2Hz)，7.32(1H，d，J＝8.8Hz)，7.36(1H，d，J＝8.8Hz)，7.52(1H，d，J＝3.2Hz)，8.42(1H，s)
ESI-MS(m/e)：419[M+H]
Preparation example 50
Figure C20048000385001401
3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(different  azoles- The 3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, the amino  azoles of 3-, 4-hydroxyethyl thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 50 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.91(2H，t，J＝4.6Hz)，4.05(2H，t，J＝4.6Hz)，6.91(1H，d，J＝8.8Hz)，6.92(2H，d，J＝8.4Hz)，7.11(1H，d，J＝8.8Hz)，7.22(1H，d，J＝1.5Hz)，7.39(2H，d，J＝8.4Hz)，8.25(1H，d，J＝1.5Hz)，8.29(1H，s)
ESI-MS(m/e)：457[M+H] +
Preparation example 51
3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-is (different  azoles-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino- azoles, 4-dimethylamino ethoxy-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 51 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.43(6H，s)，2.85(2H，t，J＝5.5Hz)，4.12.(2H，t，J＝5.5Hz)，6.90(2H，d，J＝8.8Hz)，6.93(1H，d，J＝8.8Hz)，7.15(1H，d，J＝8.8Hz)，7.24(1H，s)，7.38(2H，d，J＝8.8Hz)，8.30(1H，s)，8.38(1H，s)
ESI-MS(m/e)：484[M+H] +
Preparation example 52
Figure C20048000385001421
The system of 3-(4-fluoro-phenyl sulfenyl)-6-phenoxy group-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide Be equipped with
To 84mg (0.292mmol) by the method the same with preparation example 1 make 3, the N of 6-two chloro-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide, add 135mg (1.43mmol) phenol and 540mg (1.66mmol) cesium carbonate in the dinethylformamide solution (3ml), stirred 24 hours at 120 ℃ then.In reaction solution, add the 1N aqueous sodium hydroxide solution, use ethyl acetate extraction then.Water, saturated common salt solution washing organic layer, drying, concentrating under reduced pressure.With the gained resistates by thin layer silica gel column chromatography (hexane: ethyl acetate=4: 1) purify, obtain 61mg (yield: 61%) be 3-chloro-6-phenoxy group-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide of white solid.
To the N of 23mg (0.0799mmol) gained 3-chlorinated derivative, add 80mg (0.579mmol) salt of wormwood and 20 μ l (0.188mmol) 4-fluorobenzene thiophenols in the dinethylformamide solution (2ml), stirred 16 hours at 100 ℃ then.In reaction solution, add entry, use ethyl acetate extraction, use the saturated common salt solution washing afterwards.Dry and and concentrate after, with the gained resistates by thin layer silica gel column chromatography (hexane: ethyl acetate=4: 1) carry out purifying, obtain 11mg (yield: 32%) be the title compound of white solid.
1H NMR(CDCl 3)δ：2.37(3H，s)，6.58(1H，s)，6.90(1H，d，J＝9.0Hz)，7.10-7.23(6H，m)，7.46(1H，dd，J＝7.8，7.8Hz)，7.62(2H，m)
ESI-MS(m/e)：438[M+H] +
By the method the same, obtain the compound of preparation example 53 with above-mentioned preparation example 52.The analytical data of compound is as follows.
Preparation example 53
Figure C20048000385001431
3-(2-chloro-phenyl methyl-amino)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-first Base-thiazol-2-yl)-preparation of 2-pyridine carboxamide
Use by the method the same with preparation example 1 make 3,6-two chloro-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide, 2-chloro-benzylamine and 3-sulfydryl-4-methyl isophthalic acid, 2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 53 based on its method or with these methods with preparation example 52.
1H NMR(CDCl 3)δ：2.41(3H，s)，3.73(3H，s)，4.55(2H，d，J＝6.0Hz)，6.58(1H，s)，6.92(1H，d，J＝9.3Hz)，7.20-7.45(5H，m)，8.32(1H，s)，8.72(1H，m)
ESI-MS(m/e)：472，474[M+H] +
Preparation example 54
Figure C20048000385001432
3, the preparation of 6-two-(pyridine-2-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide
To 43mg (0.149mmol) by the method the same with preparation example 1 make 3, the N of 6-two chloro-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide, add 24mg (0.205mmol) 2-mercaptopyridine and 68mg (0.492mmol) salt of wormwood in the dinethylformamide solution (2ml), stirred 15 hours at 100 ℃ then.In reaction solution, add entry, use ethyl acetate extraction, use the saturated common salt solution washing afterwards.Dry and concentrate after, with the gained resistates by thin layer silica gel column chromatography (chloroform: methyl alcohol=20: 1) carry out purifying, obtain 15mg (yield: 23%) be the title compound of yellow solid.
1H NMR(CDCl 3)δ：2.39(3H，s)，6.58(1H，s)，7.20-7.30(2H，m)，7.40(1H，d，J＝8.6Hz)，7.46(1H，br.d，J＝8.1Hz)，7.52-7.75(4H，m)，8.55-8.65(2H，m)
ESI-MS(m/e)：438[M+H] +
By the method the same, obtain the compound of preparation example 55-57 with above-mentioned preparation example 54.The analytical data of these compounds is as follows.
Preparation example 55
Figure C20048000385001441
3, the preparation of 6-two-(4-fluoro-phenyl sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide
Use by the method the same with preparation example 1 make 3,6-two chloro-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide and 4-fluoro thiophenol, by the method the same, combine with ordinary method, can make the compound of preparation example 55 based on its method or with these methods with preparation example 54.
1H NMR(CDCl 3)δ：2.41(3H，s)，6.59(1H，s)，6.77(1H，d，J＝9.0Hz)，6.88(1H，d，J＝9.0Hz)，7.09-7.20(4H，m)，7.49-7.60(4H，m)
ESI-MS(m/e)：472[M+H] +
Preparation example 56
Figure C20048000385001451
3, the preparation of 6-two-(thiazol-2-yl-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide
Use by the method the same with preparation example 1 make 3,6-two chloro-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide and 2-sulfydryl-thiazole, by the method the same, combine with ordinary method, can make the compound of preparation example 56 based on its method or with these methods with preparation example 54.
1H NMR(CDCl 3)δ：7.06(1H，d，J＝3.6Hz)，7.27(1H，d，J＝8.8Hz)，7.37(1H，d，J＝8.8Hz)，7.54(1H，d，J＝3.6Hz)，7.59(1H，d，J＝3.6Hz)，7.61(1H，d，J＝3.6Hz)，7.98(1H，d，J＝3.6Hz)，8.02(1H，d，J＝3.6Hz)
ESI-MS(m/e)：436[M+H] +
Preparation example 57
3,6-two-(5-methyl-[1,3,4] thiadiazoles-2-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide Preparation
Use by the method the same with preparation example 1 make 3,6-two chloro-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide and 2-sulfydryl-5-methyl isophthalic acid, 3, the 4-thiazole, by the method the same, combine with ordinary method, can make the compound of preparation example 57 based on its method or with these methods with preparation example 54.
1H NMR(CDCl 3)δ：2.86(3H，s)，2.91(3H，s)，7.07(1H，d，J＝3.6Hz)，7.44(1H，d，J＝8.8Hz)，7.52(1H，d，J＝3.6Hz)，7.64(1H，d，J＝8.8Hz)
ESI-MS(m/e)：466[M+H] +
Preparation example 58
Figure C20048000385001462
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-methyl-thiazole- The 2-yl)-preparation of 2-pyridine carboxamide
At room temperature, drip 0.441ml (8.27mmol) vitriol oil in the methylene dichloride suspension (35ml) of 3.86g (32.2mmol) sal epsom, dropping was at room temperature stirred 20 minutes after finishing.At room temperature, in this reaction solution, add 750mg (3.91mmol) 3, methylene dichloride (10ml) solution of the 6-two chloro-2-pyridine carboxylic acids and 3.84ml (40.2mmol) trimethyl carbinol, vigorous stirring 15 hours at room temperature then.Drip the aqueous solution (40ml) of 3.0g yellow soda ash down in reaction solution ice-cooled, being stirred to reaction solution becomes uniform solution.Use the chloroform extraction reaction solution, dry then with saturated common salt solution washing organic layer, concentrating under reduced pressure.With the gained resistates by silica gel column chromatography (hexane: ethyl acetate=97: 3) carry out purifying, obtain 644mg (yield: 66%) for white solid 3, the 6-two chloro-2-pyridine carboxylic acid tert-butyl esters.
At room temperature,, add 0.927ml (7.55mmol) 4-methoxybenzenethiol and 1.14g (8.26mmol) salt of wormwood in the dinethylformamide solution (70ml), stirred 1 hour to the N of gained 1.70g (6.86mmol) ester cpds.In reaction solution, add chloroform, behind saturated sodium bicarbonate aqueous solution saturated common salt solution washing, drying, concentrating under reduced pressure.(hexane: ethyl acetate=9: 1) purifying obtains 743mg (yield: 31%) be the 6-chloro-3-of colorless oil (4-methoxyl group-phenyl sulfenyl)-2-pyridine carboxylic acid tert-butyl ester by silica gel column chromatography with the gained resistates.
At room temperature, to the N of 451mg (1.28mmol) gained chlorinated compound, add 258mg (2.55mmol) 3-sulfydryl-1,2 in the dinethylformamide solution (30ml), 4-triazole and 353mg (2.56mmol) salt of wormwood stirs reaction solution 10 hours at 130 ℃.In reaction solution, add chloroform, dry then with saturated sodium bicarbonate aqueous solution and saturated common salt solution washing, concentrating under reduced pressure.The gained resistates is passed through silica gel column chromatography (hexane: ethyl acetate=2: 1) purifying, obtain 264mg (yield: 49%) be the 3-of colorless oil (4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-the 2-pyridine carboxylic acid tert-butyl ester.
At room temperature, in the dichloromethane solution (5.0ml) of gained 264mg (0.633mmol) ester cpds, add the 2.0ml trifluoroacetic acid, reaction solution was at room temperature stirred 1.5 hours.The concentrating under reduced pressure reaction solution obtains the 3-that 228mg is a faint yellow solid (4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-2-pyridine carboxylic acid.
At room temperature, in the dichloromethane solution (1.0ml) of 5.9mg (16 μ mol) gained carboxylic acid cpd, add 3.2mg (29 μ mol) 5-methylamino thiazole, 3.8mg (27 μ mol) N-hydroxy benzotriazole hydrate, 5.4mg (28 μ mol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride successively, reaction solution was at room temperature stirred 3 hours.In reaction solution, add saturated sodium bicarbonate aqueous solution, use chloroform extraction.With saturated common salt solution washing organic layer, dry then, concentrating under reduced pressure.(chloroform: purifying methyl alcohol=95: 5) obtains 2.0mg (yield: 15%) be the title compound of faint yellow solid by silica gel column chromatography with the gained resistates.
1H NMR(CDCl 3)δ：2.43(3H，s)，3.86(3H，s)，6.98(2H，d，J＝8.4Hz)，6.99(1H，d，J＝8.4Hz)，7.09(1H，s)，7.19(1H，d，J＝8.4Hz)，7.47(2H，d，J＝8.4Hz)，8.32(1H，s)
ESI-MS(m/e)：457[M+H] +
By the method the same, obtain the compound of preparation example 59-65 with above-mentioned preparation example 58.The analytical data of these compounds is as follows.
Preparation example 59
Figure C20048000385001481
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)- The preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 4-methoxybenzenethiol, 3-sulfydryl-1,2,4-triazole and 3-amino-different  azoles, by the method the same, combine with ordinary method, can make the compound of preparation example 59 based on its method or with these methods with preparation example 58.
1H NMR(CDCl 3)δ：3.86(3H，s)，6.98(2H，d，J＝8.4Hz)，6.99(1H，d，J＝8.4Hz)，7.19(1H，d，J＝8.4Hz)，7.30(1H，s)，7.47(2H，d，J＝8.4Hz)，8.31(1H，s)，8.41(1H，s)
ESI-MS(m/e)：427[M+H] +
Preparation example 60
Figure C20048000385001491
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-([1,3,4] thiadiazoles- The 2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 4-methoxybenzenethiol, 3-sulfydryl-1,2,4-triazole and 2-amino-1,3, the 4-thiadiazoles, by the method the same, combine with ordinary method, can make the compound of preparation example 60 based on its method or with these methods with preparation example 58.
1H NMR(CDCl 3)δ：3.86(3H，s)，6.99(2H，d，J＝8.5Hz)，7.03(1H，d，J＝8.4Hz)，7.23(1H，d，J＝8.4Hz)，7.47(2H，d，J＝8.5Hz)，8.45(1H，s)，8.85(1H，s)
ESI-MS(m/e)：444[M+H] +
Preparation example 61
Figure C20048000385001501
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-([1,2,4]-thiadiazoles -5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 4-methoxybenzenethiol, 3-sulfydryl-1,2,4-triazole and 5-amino-1,2, the 4-thiadiazoles, by the method the same, combine with ordinary method, can make the compound of preparation example 61 based on its method or with these methods with preparation example 58.
1H NMR(CDCl 3)δ：3.87(3H，s)，7.00(2H，d，J＝8.4Hz)，7.01(1H，d，J＝8.4Hz)，7.20(1H，d，J＝8.4Hz)，7.48(2H，d，J＝8.5Hz)，7.80(1H，s)，8.36(1H，s)
ESI-MS(m/e)：444[M+H] +
Preparation example 62
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl carbonyl- Thiazol-2-yl)-preparation of 2-pyridine carboxamide
Use 3; 6-two chloro-2-pyridine carboxylic acids, 4-methoxybenzenethiol, 3-sulfydryl-1,2,4-triazole and 4-ethanoyl-2-amino-thiazolyl-; by the method the same, combine with ordinary method, can make the compound of preparation example 62 based on its method or with these methods with preparation example 58.
1H NMR(CDCl 3)δ：2.63(3H，s)，3.86(3H，s)，6.98(1H，d，J＝8.8Hz)，7.01(2H，d，J＝8.8Hz)，7.22(1H，d，J＝8.8Hz)，7.46(2H，d，J＝8.8Hz)，7.86(1H，s)，8.33(1H，s)
ESI-MS(m/e)：485[M+H] +
Preparation example 63
Figure C20048000385001511
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(pyrimidine-4-yl)-2- The preparation of pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 4-methoxybenzenethiol, 3-sulfydryl-1,2,4-triazole and 4-amino-pyrimidine, by the method the same, combine with ordinary method, can make the compound of preparation example 63 based on its method or with these methods with preparation example 58.
1H NMR(CDCl 3)δ：3.86(3H，s)，6.98(2H，d，J＝8.8Hz)，7.02(1H，d，J＝8.4Hz)，7.22(1H，d，J＝8.4Hz)，7.46(2H，d，J＝8.8Hz)，8.38(1H，dd，J＝5.9，0.8Hz)，8.41(1H，s)，8.65(1H，d，J＝5.9Hz)，8.93(1H，d，J＝0.8Hz)
ESI-MS(m/e)：438[M+H] +
Preparation example 64
Figure C20048000385001521
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(pyridine-2-yl)-2- The preparation of pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 4-methoxybenzenethiol, 3-sulfydryl-1,2,4-triazole and 2-amino-pyridine, by the method the same, combine with ordinary method, can make the compound of preparation example 64 based on its method or with these methods with preparation example 58.
1H NMR(CDCl 3)δ：3.85(3H，s)，6.97(2H，d，J＝8.8Hz)，6.99(1H，d，J＝8.8Hz)，7.05(1H，dd，J＝8.5，4.5Hz)，7.18(1H，d，J＝8.8Hz)，7.46(2H，d，J＝8.8Hz)，7.73(1H，ddd，J＝8.5，8.5，1.5Hz)，8.29(1H，dd，J＝4.5，1.5Hz)，8.31(1H，s)，8.41(1H，d，J＝8.5Hz)
ESI-MS(m/e)：437[M+H] +
Preparation example 65
Figure C20048000385001531
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-ethoxy carbonyl -thiazol-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 4-methoxybenzenethiol, 3-sulfydryl-1,2,4-triazole and 2-amino-5-ethoxy carbonyl-thiazole, by the method the same, combine with ordinary method, can make the compound of preparation example 65 based on its method or with these methods with preparation example 58.
1H NMR(CDCl 3)δ：1.37(3H，t，J＝7.0Hz)，3.86(3H，s)，4.34(2H，q，J＝7.0Hz)，6.98(2H，d，J＝8.8Hz)，7.00(1H，d，J＝8.5Hz)，7.20(1H，d，J＝8.5Hz)，7.46(2H，d，J＝8.8Hz)，8.11(1H，s)，8.36(1H，s)
ESI-MS(m/e)：515[M+H] +
Preparation example 66
3-(pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine The preparation of methane amide
In 6-chloro-3-(4-methoxyl group-phenyl methyl sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide that 152mg (0.390mmol) makes by the method the same with preparation example 1, add 0.40ml (0.390mmol) phenylmethylether and 5ml trifluoroacetic acid, reaction solution was stirred 5 hours at 60 ℃, at room temperature stir afterwards and spend the night.The concentrating under reduced pressure reaction solution obtains the 3-thiol derivative into orange.
In the 2-propanol solution (3ml) of previous gained 3-thiol derivative, add 62 μ l (1.10mmol) ethylene glycol, 141mg (1.02mmol) salt of wormwood, 114mg (0.560mmol) 3-iodine pyridine and 5.3mg (0.030mmol) cupric iodide, reaction solution is stirred a night at 80 ℃.With the reaction solution diatomite filtration, filtrate is distributed between chloroform and water.Wash organic layer with water, drying, concentrating under reduced pressure then.(hexane: ethyl acetate=1: 1) purifying obtains 28mg (yield: 21%) be the 6-chlorinated derivative of faint yellow solid by the thin layer silica gel column chromatography with the gained resistates.
N to 25mg (0.22mmol) potassium tert.-butoxide, add 22mg (0.22mol) 3-sulfydryl-1 in the dinethylformamide solution (1ml), 2, the 4-triazole, drip the N of 28mg (0.080mmol) the 6-chlorinated derivative that had before made then, dinethylformamide solution (3ml) after dropping finishes, stirs reaction solution 2 hours at 120 ℃.In reaction solution, add entry, use chloroform extraction.Wash organic layer with water, dry and concentrated.(chloroform: purifying methyl alcohol=9: 1) obtains 12mg (yield: 37%) be the title compound of faint yellow solid by the thin layer silica gel column chromatography with the gained resistates.
1H NMR(CDCl 3)δ：6.96(1H，d，J＝8.8Hz)，7.05(1H，d，J＝3.6Hz)，7.22(1H，d，J＝8.8Hz)，7.40-7.43(1H，m)，7.47(1H，d，J＝3.6Hz)，7.87-7.90(1H，m)，8.32(1H，s)，8.64-8.66(1H，m)，8.70-8.71(1H，m)
ESI-MS(m/e)：414[M+H] +
By the method the same, obtain the compound of preparation example 67-68 with above-mentioned preparation example 66.The analytical data of these compounds is as follows.
Preparation example 67
Figure C20048000385001551
3-(6-methoxyl group-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole-2- Base)-preparation of 2-pyridine carboxamide
6-chloro-3-(4-methoxyl group-phenyl methyl sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide, 6-methoxyl group-3-iodine pyridine and 3-sulfydryl-1 that use makes by the method the same with preparation example 1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 67 based on its method or with these methods with preparation example 66.
1H NMR(CDCl 3)δ：4.00(3H，s)，6.87(1H，d，J＝8.7Hz)，7.00-7.11(2H，m)，7.26(1H，d，J＝8.4Hz)，7.46(1H，d，J＝3.3Hz)，7.77(1H，dd，J＝2.4，8.7Hz)，8.35(1H，d，J＝2.4Hz)，8.38(1H，s)
ESI-MS(m/e)：444[M+H] +
Preparation example 68
Figure C20048000385001552
3-(pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiophene Azoles-2-yl)-preparation of 2-pyridine carboxamide
6-chloro-3-(4-methoxyl group-phenyl methyl sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide, 3-iodine pyridine and 3-sulfydryl-1 that use makes by the method the same with preparation example 1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 68 based on its method or with these methods with preparation example 66.
1H NMR(CDCl 3)δ：3.49(3H，s)，4.56(2H，s)，6.94(1H，s)，6.97(1H，d，J＝8.8Hz)，7.27(1H，d，J＝8.8Hz)，7.43(1H，dd，J＝7.6Hz，3.3Hz)，7.93(1H，d，J＝7.6Hz)，8.38(1H，s)，8.71(1H，d，J＝4.8Hz)，8.77(1H，s)
ESI-MS(m/e)：458[M+H] +
Preparation example 69
3-phenoxymethyl-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyrrole The preparation of pyridine methane amide
In the chloroformic solution (50ml) of 3.50g (14.0mmol) 2-cyano group-3-t-butyldimethylsilyloxy ylmethyl pyridine, add 6.30g (21.0mmol) 3-chloroperoxybenzoic acid, one night of reflux.In reaction solution, add saturated sodium bicarbonate aqueous solution, use chloroform extraction then, water, saturated sodium bicarbonate aqueous solution, saturated common salt solution washing organic layer.After dry and concentrated, (hexane: ethyl acetate=2: 1) purifying obtains 1.50g (yield: 41%) be the N-oxide compound of white solid by silica gel column chromatography with the gained resistates.
The phosphoryl chloride solution (10ml) of gained 1.50g (5.70mmol) N-oxide compound was stirred 1 hour at 80 ℃.Behind the concentrating under reduced pressure reaction solution, in the gained resistates, add saturated sodium bicarbonate aqueous solution, use chloroform extraction, with saturated sodium bicarbonate aqueous solution, saturated common salt solution washing organic layer.After dry and concentrated, (hexane: ethyl acetate=2: 1) purifying obtains 625mg (yield: 58%) be the 2-chloro-5-chloromethyl-6-cyanopyridine of white solid by silica gel column chromatography with the gained resistates.
In the acetonitrile solution (5ml) of 50mg (0.27mmol) 2-chloro-5-chloromethyl-6-cyanopyridine, add 30mg (0.32mmol) phenol and 44mg (0.32mmol) salt of wormwood, at room temperature stirred then 8 hours 30 minutes.In reaction solution, add entry, use ethyl acetate extraction, with saturated common salt solution washing organic layer.After dry and concentrated, (hexane: ethyl acetate=6: 1) purifying obtains 61mg (yield: 93%) be the 2-chloro-6-cyano group-5-phenoxymethyl pyridine of white solid by the thin layer column chromatography with the gained resistates.
N to gained 61mg (0.249mmol) 2-chloro-6-cyano group-5-phenoxymethyl pyridine, add 44mg (0.380mmol) 3-sulfydryl-4-methyl-4H-1 in the dinethylformamide solution (5ml), 2,4-triazole and 52mg (0.380mmol) salt of wormwood spends the night 100 ℃ of stirrings then.In reaction solution, add entry, use ethyl acetate extraction, water, saturated sodium bicarbonate aqueous solution, saturated common salt solution washing organic layer.After dry and concentrated, (chloroform: purifying methyl alcohol=10: 1) obtains 4.4mg (yield: 5%) be the sulfo-triazole derivative of white solid by the thin layer column chromatography with the gained resistates.
In the ethanolic soln (5ml) of gained 4.4mg (0.014mmol) sulfo-triazole derivative, add 0.5ml 1N-aqueous sodium hydroxide solution, one night of reflux.In reaction solution, add the 1N aqueous hydrochloric acid and make it be acid, use ethyl acetate extraction, with saturated common salt solution washing organic layer.After dry and concentrated, in the dichloromethane solution (3ml) of gained resistates, add 3mg (0.028mmol) thiazolamine, 4mg (0.030mmol) N-hydroxy benzotriazole hydrate and 6mg (0.030mmol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride successively, at room temperature stir then and spend the night.In reaction solution, add saturated sodium bicarbonate aqueous solution, use chloroform extraction, water, saturated sodium bicarbonate aqueous solution, saturated common salt water washing organic layer.After dry and concentrated, (chloroform: purifying methyl alcohol=10: 1) obtains 2.8mg (yield: 47%) be the title compound of white solid by the thin layer silica gel column chromatography with the gained resistates.
1H NMR(CDCl 3)δ：3.79(3H，s)，5.71(2H，s)，6.97-7.02(3H，m)，7.05(1H，d，J＝3.6Hz)，7.30(2H，t，J＝7.6Hz)，7.40(1H，d，J＝8.4Hz)，7.54(1H，d，J＝3.6Hz)，8.22(1H，d，J＝8.4Hz)，8.50(1H，s)
ESI-MS(m/e)：425[M+H]
By the method the same, obtain the compound of preparation example 70 with above-mentioned preparation example 69.The analytical data of this compound is as follows.
Preparation example 70
Figure C20048000385001581
3-phenyl sulfenyl methyl-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2- The preparation of pyridine carboxamide
Use 2-cyano group-3-t-butyldimethylsilyloxy ylmethyl pyridine, thiophenol, 3-sulfydryl-4-methyl-4H-1,2,4-triazole and thiazolamine, by the method the same, combine with ordinary method, can make the compound of preparation example 70 based on its method or with these methods with preparation example 69.
1H NMR(CDCl 3)δ：3.77(3H，s)，4.74(2H，s)，7.04(1H，d，J＝3.2Hz)，7.20(1H，d，J＝8.4Hz)，7.24-7.28(5H，m)，7.53(1H，d，J＝3.2Hz)，7.58(1H，d，J＝8.4Hz)，8.48(1H，s)
ESI-MS(m/e)：441[M+H]
Preparation example 71
Figure C20048000385001591
3-phenyl methyl-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide Preparation
2.0g (8.8mmol) 3-benzoyl-2-pyridine carboxylic acid is dissolved in the methyl alcohol (10ml), at room temperature, to wherein dripping 10 vitriol oils, reflux diel.After the cooling, heat up in a steamer methyl alcohol, neutralize with saturated sodium bicarbonate aqueous solution.Use chloroform extraction, use dried over sodium sulfate then, concentrate, obtain the crude product of 2.0g 3-benzoyl-2-pyridine carboxylic acid methyl esters.
The 2.0g ester cpds is dissolved in the chloroform (10ml), adds 3.57g (20.7mmol) mCPBA, the reflux diel.After the cooling, in reaction solution, add saturated sodium bicarbonate aqueous solution, make its alkalize, use chloroform extraction.Use dried over sodium sulfate, decompression is heated up in a steamer, and obtains the crude product of N-oxide compound.In this crude product, add phosphoryl chloride (10ml), stirred 2 hours at 80 ℃.After the cooling,, use ethyl acetate extraction with the saturated sodium bicarbonate aqueous solution neutralization.Use dried over sodium sulfate, decompression is heated up in a steamer, and (ethyl acetate: purifying hexane=1: 2) obtains 600mg (yield of three steps is 26%) 3-benzoyl-6-chloro-2-pyridine carboxylic acid methyl esters by silica gel column chromatography then.
300mg (1.10mmol) chlorinated compound is dissolved in the methyl alcohol (15ml), adds 1N sodium hydroxide (5ml), at room temperature stirred 2 hours.After heating up in a steamer methyl alcohol,, use chloroform extraction then with the neutralization of 1N hydrochloric acid.Use dried over sodium sulfate, decompression is heated up in a steamer then, obtains the crude product of 285mg (yield 100%) 3-benzoyl-6-chloro-2-pyridine carboxylic acid.
With 285mg (1.1mmol) as above the carboxylic acid of gained be dissolved in the chloroform (10ml), add 109mg (1.1mmol) thiazolamine, 221mg (1.64mmol) N-hydroxy benzotriazole hydrate, 229mg (1.2mmol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, at room temperature stir diel.Add distilled water, use chloroform extraction then, use dried over sodium sulfate.Decompression is heated up in a steamer and is desolvated, and (ethyl acetate: purifying hexane=1: 2) obtains 25mg (yield of two steps is 60%) 3-benzoyl-6-chloro-N-(thiazol-2-yl)-2-pyridine carboxamide by column chromatography with the gained resistates.
The above-mentioned chlorinated compound that makes of 170mg (0.495mmol) is dissolved among the DMF (3ml), adds 55mg (0.544mmol) 3-sulfydryl-1,2,4-triazole, 171mg (1.24mmol) salt of wormwood stir diel at 100 ℃.With after the reaction solution cooling, DMF is heated up in a steamer in decompression, adds distilled water, with in the 1N hydrochloric acid and after, use chloroform extraction.Use dried over sodium sulfate; decompression is heated up in a steamer then, and (methyl alcohol: purifying chloroform=1: 10) obtains 101mg (yield 50%) 3-benzoyl-6-(4H-[1 by silica gel column chromatography with the gained resistates; 2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide.
The above-mentioned ketone compound that makes of 70mg (0.172mmol) is suspended in the methyl alcohol (5ml), adds 12.7mg (0.343mmol) sodium borohydride, at room temperature stirred 30 minutes, heat up in a steamer and desolvate.In the gained resistates, add 99mg (0.853mmol) triethyl silicane, trifluoroacetic acid (5ml), stirred 1 hour at 60 ℃.After concentrating, distribute, use the dried over sodium sulfate chloroform layer with chloroform and saturated sodium bicarbonate aqueous solution.Behind the concentrated solvent, the gained resistates is passed through twice thin layer silica gel column chromatography (methyl alcohol: chloroform=1: 8, ethyl acetate: acetone=2: 1) carry out purifying, obtain 13.5mg (yield 20%) title compound.
1H NMR(CDCl 3)δ：4.63(2H，s)，6.99(1H，d，J＝3.6Hz)，7.18-7.29(5H，m)，7.38(1H，d，J＝8.4Hz)，7.41(1H，dd，J＝3.6Hz)，7.45(1H，d，J＝8.4Hz)，8.33(1H，s)
ESI-MS(m/e)：395[M+H] +
Preparation example 72
Figure C20048000385001611
3-(4-fluoro-phenyl methyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine The preparation of methane amide
1H NMR(CDCl 3)δ：4.60(2H，s)，6.94-6.98(2H，m)，7.01(1H，d，J＝3.6Hz)，7.14-7.17(2H，m)，7.40-7.46(3H，m)，8.35(1H，s)
ESI-MS(m/e)：413[M+H] +
Use 3-(4-fluoro benzoyl)-2-pyridine carboxylic acid, thiazolamine and 3-sulfydryl-1; 2; the 4-triazole by the method the same with preparation example 71, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 72.
Preparation example 73
Figure C20048000385001612
3-(4-dimethyl aminoethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole- The 2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-dimethyl aminoethyl-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 73 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.39(6H，s)，2.68(2H，m)，2.84(2H，m)，7.00-7.05(2H，m)，7.18(1H，d，J＝8.7Hz)，7.28(2H，d，J＝8.4Hz)，7.41-7.58(3H，m)，8.32(1H，s)
ESI-MS(m/e)：484[M+H] +
Preparation example 74
Figure C20048000385001621
3-(4-dimethylaminomethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole- The 2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 4-dimethylaminomethyl-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 74 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.23(6H，s)，6.96(1H，d，J＝8.8Hz)，7.00(1H，d，J＝3.6Hz)，7.11(1H，d，J＝8.8Hz)，7.34(2H，d，J＝8.0Hz)，7.43(1H，d，J＝3.6Hz)，7.46(2H，d，J＝8.0Hz)，8.29(1H，s)
ESI-MS(m/e)：470[M+H] +
Preparation example 75
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole-4-yl)-2- The preparation of pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 4-amino-thiazolyl-, 4-methoxyl group-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 75 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.85(3H，s)，6.96(2H，d，J＝8.8Hz)，6.98(1H，d，J＝8.8Hz)，7.15(1H，d，J＝8.8Hz)，7.46(2H，d，J＝8.8Hz)，7.90(1H，d，J＝2.4Hz)，8.34(1H，s)，8.61(1H，d，J＝2.4Hz)，
ESI-MS(m/e)：443[M+H] +
Preparation example 76
Figure C20048000385001641
3-(4-formyl-dimethylamino methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulphur Base)-preparation of N-(thiazol-2-yl)-2-pyridine carboxamide
Use 3; 6-two chloro-2-pyridine carboxylic acids, thiazolamine, 4-formyl-dimethylamino methoxyl group-thiophenol and 3-sulfydryl-1; 2; the 4-triazole; by the method the same, combine with ordinary method, can make the compound of preparation example 76 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.99(3H，s)，3.09(3H，s)，4.73(2H，s)，6.99(2H，d，J＝8.8Hz)，7.01-7.03(1H，m)，7.03(1H，d，J＝3.6Hz)，7.19(2H，d，J＝8.4Hz)，7.45(2H，d，J＝8.8Hz)，7.46(2H，d，J＝3.6Hz)，8.30(1H，s)
ESI-MS(m/e)：514[M+H] +
Preparation example 77
Figure C20048000385001651
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(4-hydroxyethyl-thiophene Azoles-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-hydroxy ethyl-thiazole, 4-methoxyl group-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 77 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.90(2H，t，J＝4.8Hz)，3.83(3H，s)，3.90(2H，t，J＝4.8Hz)，6.65(1H，s)，6.95(2H，d，J＝8.0Hz)，6.97(1H，d，J＝8.8Hz)，7.17(1H，d，J＝8.8Hz)，7.43(2H，d，J＝8.0Hz)，8.34(1H，s)
ESI-MS(m/e)：487[M+H] +
Preparation example 78
Figure C20048000385001661
3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-hydroxyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole -2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-hydroxyl-thiophenol and 5-hydroxyl-3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 78 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.65(3H，s)，6.98-7.50(5H，m)，7.82(1H，m)，8.64(1H，brs)，
ESI-MS(m/e)：444[M+H] +
Preparation example 79
3-(6-methoxycarbonyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole -2-yl)-preparation of 2-pyridine carboxamide
6-chloro-3-(4-methoxyl group-phenyl methyl sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide, 5-iodo-3-methoxycarbonyl-pyridine and 3-sulfydryl-1 that use makes by the method the same with preparation example 1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 79 based on its method or with these methods with preparation example 66.
1H NMR(CDCl 3)δ：4.01(3H，s)，7.03(1H，d，J＝7.6Hz)，7.05(1H，d，J＝3.6Hz)，7.24(1H，d，J＝7.6Hz)，7.47(1H，d，J＝3.6Hz)，8.00(1H，m)，8.16(1H，d，J＝8.0Hz)，8.33(1H，s)，8.79(1H，m)
ESI-MS(m/e)：472[M+H] +
Preparation example 80
Figure C20048000385001671
3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N- The preparation of ([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-1,2,4-thiadiazoles, 4-dimethylamino ethoxy-thiophenol and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 80.
1H NMR(CDCl 3)δ：2.42(6H，s)，2.84(2H，t，J＝5.1Hz)，4.13(2H，t，J＝5.1Hz)，6.96(2H，d，J＝8.4Hz)，7.00(1H，d，J＝8.8Hz)，7.21(1H，d，J＝8.8Hz)，7.43(2H，d、J＝8.4Hz)，8.35(1H，s)
ESI-MS(m/e)：501[M+H] +
Preparation example 81
Figure C20048000385001681
3-(pyrimidine-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine The preparation of methane amide
6-chloro-3-(4-methoxyl group-phenyl methyl sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide, 5-iodo-pyrimidine and 3-sulfydryl-1 that use makes by the method the same with preparation example 1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 81 based on its method or with these methods with preparation example 66.
1H NMR(CDCl 3)δ：6.95(1H，d，J＝8.4Hz)，7.03(1H，d，J＝3.6Hz)，7.22(1H，d，J＝8.4Hz)，7.44(1H，d，J＝3.6Hz)，8.33(1H，s)，8.82(2H，s)，9.20(1H，s)
ESI-MS(m/e)：415[M+H] +
Preparation example 82
Figure C20048000385001691
3-(6-hydroxymethyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole-2- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-hydroxymethyl-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 82 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：4.86(2H，s)，7.01(1H，d，J＝9.2Hz)，7.07(1H，d，J＝3.2Hz)，7.28(1H，d，J＝9.2Hz)，7.41(1H，d，J＝7.6Hz)，7.52(1H，d，J＝3.2Hz)，7.90(1H，m)，8.42(1H，s)，8.74(1H，m)
ESI-MS(m/e)：444[M+H] +
Preparation example 83
3-[4-(1-methyl-tetramethyleneimine-3-base oxygen base)-phenyl sulfenyl]-6-(4H-[1,2,4] triazole-3-base sulphur Base)-preparation of N-(thiazol-2-yl)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-(1-methyl-tetramethyleneimine-3-yl)-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 83 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：1.90-1.98(1H，m)，2.35(3H，s)，2.25-2.35(2H，m)，2.43-2.47(1H，m)，2.80-2.83(2H，m)，4.78-4.85(1H，m)，6.85(2H，d，J＝8.4Hz)，6.95(1H，d，J＝8.8Hz)，7.00(1H，d，J＝3.6Hz)，7.12(1H，d，J＝8.8Hz)，7.38(2H，d，J＝8.4Hz)，7.42(1H，d，J＝3.6Hz)，8.29(1H，s)
ESI-MS(m/e)：512[M+H] +
Preparation example 84
Figure C20048000385001711
3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiophene two Azoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-1,2,4-thiadiazoles, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 84.
1H NMR(CDCl 3)δ：2.65(3H，s)，7.01(1H，d，J＝8.6Hz)，7.26(1H，d，J＝8.6Hz)，7.30(1H，d，J＝8.0Hz)，7.78(1H，dd，J＝8.0，2.2Hz)，8.35(1H，s)，8.42(1H，s)，8.64(1H，d，J＝2.2Hz)
ESI-MS(m/e)：429[M+H] +
Preparation example 85
Figure C20048000385001721
3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulphur Base)-preparation of N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-1,2,4-thiadiazoles, 4-dimethylamino ethoxy-thiophenol and 3-sulfydryl-5-methyl isophthalic acid, 2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 85.
1H NMR(CDCl 3)δ：2.40(6H，s)，2.62(6H，s)，2.81(2H，t，J＝5.5Hz)，4.12(2H，t，J＝5.1Hz)，6.96(2H，d，J＝8.5Hz)，6.98(1H，d，J＝8.5Hz)，7.20(1H，d，J＝8.5Hz)，7.42(2H，d、J＝8.5Hz)，8.34(1H，s)
ESI-MS(m/e)：515[M+H] +
Preparation example 86
Figure C20048000385001731
3-(1-oxygen base-6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-the N-thiazole- The 2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 3-sulfydryl-6-methyl isophthalic acid-oxygen base-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 86 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.60(3H，s)，7.06(1H，d，J＝3.2Hz)，7.12(1H，d，J＝8.4Hz)，7.32(1H，d，J＝8.4Hz)，7.39-7.39(2H，m)，7.51(1H，d，J＝3.2Hz)，8.44(1H，s)，8.51(1H，brs)
ESI-MS(m/e)：446[M+H]
Preparation example 87
Figure C20048000385001741
3-(4-diethyl amino base oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiophene Azoles-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-diethyl amino base oxethyl-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 87 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：1.14(6H，t，J＝7.6Hz)，2.73(4H，q，J＝7.6Hz)，2.99(2H，t，J＝6.0Hz)，4.14(2H，t，J＝6.0Hz)，6.99(2H，d，J＝8.8Hz)，7.01(1H，d，J＝8.4Hz)，7.07(1H，d，J＝4.0Hz)，7.18(1H，d，J＝8.4Hz)，7.46(2H，d，J＝8.8Hz)，7.49(1H，d，J＝4.0Hz)，8.36(1H，s)
ESI-MS(m/e)：528[M+H] +
Preparation example 88
3-(4-tetramethyleneimine oxyethyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole-2- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-tetramethyleneimine oxyethyl group-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 88 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：1.80-1.90(4H，m)，2.70-2.80(4H，m)，3.02(2H，t，J＝5.2Hz)，4.18(2H，t，J＝5.2Hz)，6.95(2H，d，J＝8.8Hz)，6.97(1H，d，J＝8.4Hz)，7.02(1H，d，J＝3.6Hz)，7.17(1H，d，J＝8.4Hz)，7.42(2H，d，J＝8.8Hz)，7.45(1H，d，J＝3.6Hz)，8.29(1H，s)
ESI-MS(m/e)：526[M+H] +
Preparation example 89
Figure C20048000385001761
3-(6-dimethylamino ethoxy-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)- The preparation of N-(thiazol-2-yl)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 3-sulfydryl-6-dimethylamino ethoxy-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 89 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.41(6H，s)，2.82(2H，t，J＝5.6Hz)，4.48(2H，t，J＝5.6Hz)，6.80(1H，d，J＝8.4Hz)，6.98(1H，d，J＝8.4Hz)，7.03(1H，d，J＝3.6Hz)，7.23(1H，d，J＝8.4Hz)，7.47(1H，d，J＝3.6Hz)，7.63(1H，dd，J＝2.4，8.4Hz)，7.27(1H，d，J＝2.4Hz)，8.36(1H，s)
ESI-MS(m/e)：501[M+H] +
Preparation example 90
Figure C20048000385001771
3-(pyrazoles-4-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine The preparation of methane amide
6-chloro-3-(4-methoxyl group-phenyl methyl sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide, 4-iodine pyrazoles and 3-sulfydryl-1 that use makes by the method the same with preparation example 1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 90 based on its method or with these methods with preparation example 66.
1H NMR(CDCl 3)δ：7.07(1H，d，J＝3.6Hz)，7.18(1H，d，J＝8.4Hz)，7.25(1H，d，J＝8.4Hz)，7.49(1H，d，J＝3.6Hz)，7.70(2H，s)，8.35(1H，s)
ESI-MS(m/e)：403[M+H] +
Preparation example 91
Figure C20048000385001772
3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3- Methyl-[1,2,4] thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3-6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 4-dimethylamino ethoxy-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 91 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.37(6H，s)，2.61(3H，s)，2.80(2H，t，J＝5.6Hz)，4.12(2H，t，J＝5.6Hz)，7.00(2H，d，J＝8.4Hz)，7.02(1H，d，J＝8.8Hz)，7.22(1H，d，J＝8.8Hz)，7.45(2H，d、J＝8.4Hz)，8.34(1H，s)
ESI-MS(m/e)：515[M+H] +
Preparation example 92
3-(4-carbamyl ylmethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiophene Azoles-2-yl)-preparation of 2-pyridine carboxamide
Use 3; 6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-carbamyl ylmethoxy-thiophenol and 3-sulfydryl-1,2, the 4-triazole; by the method the same, combine with ordinary method, can make the compound of preparation example 92 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：4.48(2H，s)，6.95(1H，d，J＝8.4Hz)，6.98(2H，d，J＝8.8Hz)，7.02(1H，d，J＝3.6Hz)，7.13(1H，d，J＝8.4Hz)，7.44(1H，d，J＝3.6Hz)，7.45(2H，d，J＝8.8Hz)，8.33(1H，s)
ESI-MS(m/e)：486[M+H] +
Preparation example 93
Figure C20048000385001791
3-(5-bromo-6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole- The 2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 5-bromo-3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 93 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.72(3H，s)，7.00(1H，d，J＝8.4Hz)，7.05(1H，d，J＝3.6Hz)，7.22-7，24(1H，m)，7.48(1H，d，J＝3.6Hz)，8.01(1H，d，J＝2.0Hz)，8.38(1H，s)，8.52(1H，d，J＝2.0Hz)
ESI-MS(m/e)：505，507[M+H] +
Preparation example 94
3-[4-(2-hydroxyethyl-phenyl sulfenyl)]-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 3-methyl- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 4-(2-hydroxyethyl)-thiophenol and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 94.
1H NMR(CDCl 3)δ：2.61(3H，s)，2.91(2H，t，J＝6.8Hz)，3.84(2H，t，J＝6.8Hz)，7.07(1H，d，J＝8.4Hz)，7.21(1H，d，J＝8.4Hz)，7.35(2H，d，J＝8.0Hz)，7.48(2H，d，J＝8.0Hz)，8.36(1H，s)
ESI-MS(m/e)：472[M+H] +
Preparation example 95
3-[4-(2-hydroxyethyl-phenyl sulfenyl)]-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N- The preparation of (3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 4-(2-hydroxyethyl)-thiophenol and 3-sulfydryl-5-methyl isophthalic acid, 2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 95.
1H NMR(CDCl 3)δ：2.59(3H，s)，2.59(3H，s)，2.94(2H，t，J＝6.4Hz)，3.94(2H，t，J＝6.4Hz)，7.03(1H，d，J＝8.8Hz)，7.21(1H，d，J＝8.8Hz)，7.34(2H，d，J＝8.0Hz)，7.49(2H，d，J＝8.0Hz)ESI-MS(m/e)：486[M+H] +
Preparation example 96
Figure C20048000385001821
3-(pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[[1,2,4]-thiophene Diazole-5-yl]-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 3-sulfydryl-pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 96.
1H NMR(CDCl 3)δ：2.61(3H，s)，7.00(1H，d，J＝8.8Hz)，7.29(1H，d，J＝8.8Hz)，7.41-7.44(1H，m)，7.88-7.91(1H，m)，8.41(1H，s)，8.71-8.73(1H，m)，8.76-8.77(1H，m)
ESI-MS(m/e)：429[M+H] +
Preparation example 97
3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 3-methyl- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 97.
1H NMR(CDCl 3)δ：2.62(3H，s)，2.64(3H，s)，7.02(1H，d，J＝8.0Hz)，7.25(1H，d，J＝8.0Hz)，7.31(1H，d，J＝8.0H)，7.78(1H，dd，J＝1.6Hz，8.0Hz)，8.35(1H，s)，8.60(1H，d，J＝1.6Hz)
ESI-MS(m/e)：443[M+H] +
Preparation example 98
Figure C20048000385001831
3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiophene Azoles is [5,4-b] pyridine-2-yl also)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine also [5,4-b] pyridine, 4-dimethylamino ethoxy-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 98 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.43(6H，s)，2.70-2.88(2H，m)，4.08-4.14(2H，m)，6.88(2H，d，J＝8.4Hz)，6.89-6.93(1H，m)，7.13(1H，d，J＝8.8Hz)，7.31-7.35(1H，m)，7.38(2H，d，J＝8.8Hz)，7.96(1H，d，J＝8.4Hz)，8.37(1H，s)，8.44(1H，d，J＝4.0Hz)
ESI-MS(m/e)：551[M+H] +
Preparation example 99
Figure C20048000385001841
3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-first Base-[1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-5-methyl isophthalic acid, 2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 99.
1H NMR(CDCl 3)δ：2.60(3H，s)，2.61(3H，s)，3.64(3H，s)，7.00(1H，d，J＝8.8Hz)，7.20-7，36(1H，m)，7.29(1H，d，J＝8.0Hz)，7.77(1H，dd，J＝2.4，8.0Hz)，8.63(1H，d，J＝2.4Hz)
ESI-MS(m/e)：457[M+H] +
Preparation example 100
Figure C20048000385001851
3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,5] thiophene two Azoles-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1,2,5-thiadiazoles, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 100.
1H NMR(CDCl 3)δ：2.63(3H，s)，6.99(1H，d，J＝8.8Hz)，7.21(1H，d，J＝8.8Hz)，7.29(1H，d，J＝8.1Hz)，7.78(1H，dd，J＝8.1，2.2Hz)，8.37(1H，s)，8.60(1H，d，J＝2.2Hz)，9.38(1H，s)
ESI-MS(m/e)：429[M+H] +
Preparation example 101
3-2-, 3-Dihydrobenzofuranes-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl sulfenyl)-N-(thiazole- The 2-yl)-preparation of 2-pyridine carboxamide
6-chloro-3-(4-methoxyl group-phenyl methyl sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide, 5-iodo-2 that use makes by the method the same with preparation example 1,3-Dihydrobenzofuranes and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 101 based on its method or with these methods with preparation example 66.
1H NMR(CDCl 3)δ：3.26(2H，t，J＝8.8Hz)，4.66(2H，t，J＝8.8Hz)，6.86(1H，d，J＝8.0Hz)，7.02(1H，d，J＝3.2Hz)，7.06(1H，d，J＝8.8Hz)，7.22(1H，d，J＝8.8Hz)，7.31(1H，d，J＝8.0Hz)，7.35(1H，brs)，7.45(1H，d，J＝3.2Hz)，8.34(1H，s)
ESI-MS(m/e)：455[M+H] +
Preparation example 102
Figure C20048000385001871
3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 3-methoxyl group- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methoxyl group-1,2,4-thiadiazoles, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 102.
1H NMR(CDCl 3)δ：2.65(3H，s)，4.08(3H，s)，6.90-7.05(1H，m)，7.10-7.30(2H，m)，7.70-7.80(1H，m)，8.39(1H，s)，8.63(1H，brs)
ESI-MS(m/e)：459[M+H] +
Preparation example 103
Figure C20048000385001872
3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 3-cyclopropyl- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-cyclopropyl-1,2,4-thiadiazoles, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 103.
1H NMR(CDCl 3)δ：0.90-1.20(4H，m)，2.20-2.35(1H，m)，2.64(3H，s)，6.99(1H，d，J＝8.8Hz)，7.20-7.30(2H，m)，7.76(1H，dd，J＝2.4，8.0Hz)，8.38(1H，s)，8.62(1H，brs)
ESI-MS(m/e)：469[M+H] +
Preparation example 104
Figure C20048000385001881
3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulphur Base)-preparation of N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 4-dimethylamino ethoxy-thiophenol and 3-sulfydryl-5-methyl isophthalic acid, 2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 104.
1H NMR(CDCl 3)δ：2.41(6H，s)，2.58(3H，s)，2.59(3H，s)，2.83(2H，t，J＝5.5Hz)，4.12(2H，t，J＝5.5Hz)，6.91(2H，d，J＝8.8Hz)，6.94(1H，d，J＝8.6Hz)，7.17(1H，d，J＝8.6Hz)，7.40(2H，d，J＝8.8Hz)
ESI-MS(m/e)：529[M+H] +
Preparation example 105
3-(2-fluoro-pyridin-4-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2- The preparation of pyridine carboxamide
6-chloro-3-(4-methoxyl group-phenyl methyl sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide, 2-fluoro-4-iodo-pyridine and 3-sulfydryl-1 that use makes by the method the same with preparation example 1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 105 based on its method or with these methods with preparation example 66.
1H NMR(CDCl 3)δ：6.95-7.10(2H，m)，7.20-7.26(2H，m)，7.30-7.42(1H，m)，7.40-7.50(1H，m)，8.10-8.26(1H，m)，8.38-8.45(1H，m)
ESI-MS(m/e)：432[M+H] +
Preparation example 106
Figure C20048000385001901
3-(2-methoxyl group-pyrimidine-5-base sulfenyl)-6-(2H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole-2- Base)-preparation of 2-pyridine carboxamide
6-chloro-3-(4-methoxyl group-phenyl methyl sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide, 5-iodo-2-methoxyl group-pyrimidine and 3-sulfydryl-1 that use makes by the method the same with preparation example 1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 106 based on its method or with these methods with preparation example 66.
1H NMR(CDCl 3)δ：4.10(3H，s)，7.02(1H，d，J＝8.4Hz)，7.06(1H，d，J＝3.6Hz)，7.32(1H，d，J＝8.4Hz)，7.50(1H，d，J＝3.6Hz)，8.39(1H，s)，8.65(2H，s)
ESI-MS(m/e)：445[M+H] +
Preparation example 107
Figure C20048000385001902
3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N- The preparation of ([1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-1,2,4-thiadiazoles, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-5-methyl isophthalic acid, 2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 107.
1H NMR(CDCl 3)δ：2.62(3H，s)，2.64(3H，s)，6.99(1H，d，J＝8.8Hz)，7.20-7.35(2H，m)，7.77(1H，dd，J＝2.0，8.0Hz)，8.35(1H，s)，8.63(1H，brs)
ESI-MS(m/e)：443[M+H] +
Preparation example 108
3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 3-methyl- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 4-hydroxyl-oxethyl-thiophenol and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 108.
1H NMR(CDCl 3)δ：2.63(3H，s)，3.99(2H，m)，4.13(2H，m)，7.00-7.08(3H，m)，7.25(1H，d，J＝8.4Hz)，7.49(2H，d，J＝8.7Hz)，8.36(1H，s)
ESI-MS(m/e)：488[M+H] +
Preparation example 109
Figure C20048000385001921
3-(4-diethylamino formyl radical methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulphur Base)-preparation of N-(thiazol-2-yl)-2-pyridine carboxamide
Use 3; 6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-diethylamino formyl radical methoxyl group-thiophenol and 3-sulfydryl-1; 2; the 4-triazole; by the method the same, combine with ordinary method, can make the compound of preparation example 109 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.72(6H，s)，7.02(1H，d，J＝3.6Hz)，7.03(1H，d，J＝8.0Hz)，7.20(1H，d，J＝8.0Hz)，7.44(1H，d，J＝3.6Hz)，7.66(2H，d，J＝8.4Hz)，7.78(2H，d，J＝8.4Hz)，8.31(1H，s)
ESI-MS(m/e)：542[M+H] +
Preparation example 110
Figure C20048000385001931
3-(6-cyclopropyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole-2- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 6-cyclopropyl-3-sulfydryl-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 110 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：0.70-1.38(4H，m)，1.98-2.18(1H，m)，6.96-7.08(2H，m)，7.46(1H，d，J＝3.2Hz)，7.70(1H，dd，J＝2.0，8.4Hz)，8.36(1H，s)，8.56(1H，d，J＝2.0Hz)
ESI-MS(m/e)：4.53[M+H] +
Preparation example 111
Figure C20048000385001932
3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole -2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-5-methyl isophthalic acid, 2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 111 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.57(3H，s)，2.64(3H，s)，6.96(1H，d，J＝8.8Hz)，7.02(1H，d，J＝3.6Hz)，7.20(1H，d，J＝8.8Hz)，7.25-7.29(1H，m)，7.46(1H，d，J＝3.6Hz)，7.76(1H，dd，J＝2.4，7.6Hz)，8.63(1H，brs)
ESI-MS(m/e)：442[M+H] +
Preparation example 112
Figure C20048000385001941
3-(6-methyl-pyridin-3-yl sulfenyl)-6-(pyrazoles-4-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine first The preparation of acid amides
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 3-sulfydryl-6-methyl-pyridine and 4-sulfydryl-pyrazoles, by the method the same, combine with ordinary method, can make the compound of preparation example 112 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.62(3H，s)，6.88(1H，m)，7.05(1H，m)，7.24(1H，d，J＝8.9Hz)，7.30-7.68(3H，m)，7.72(1H，dd，J＝1.1，8.9Hz)，7.76-7.82(1H，m)，8.60(1H，d，J＝1.1Hz)
ESI-MS(m/e)：427[M+H] +
Preparation example 113
Figure C20048000385001951
3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 3-methyl- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-hydroxyl-1,2,4-thiadiazoles, 6-oxyethyl group-3-sulfydryl-pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 113.
1H NMR(CDCl 3)δ：1.43(3H，t，J＝6.9Hz)，2.06(3H，s)，4.42(2H，q，J＝6.9Hz)，6.85(1H，d，J＝9.0Hz)，7.08(1H，d，J＝9.0Hz)，7.29(1H，d，J＝9.0Hz)，7.69(1H，dd，J＝9.0，2.1Hz)，8.31(1H，d，J＝2.1Hz)，8.37(1H，s)
ESI-MS(m/e)：473[M+H] +
Preparation example 114
Figure C20048000385001961
3-(4-dimethylamino alkylsulfonyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiophene Azoles-2-yl)-preparation of 2-pyridine carboxamide
Use 3; 6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-dimethylamino alkylsulfonyl-thiophenol and 3-sulfydryl-1; 2; the 4-triazole; by the method the same, combine with ordinary method, can make the compound of preparation example 114 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.72(6H，s)，7.02(1H，d，J＝3.6Hz)，7.03(1H，d，J＝8.0Hz)，7.20(1H，d，J＝8.0Hz)，7.44(1H，d，J＝3.6Hz)，7.66(2H，d，J＝8.4Hz)，7.78(2H，d，J＝8.4Hz)，8.33(1H，s)
ESI-MS(m/e)：520[M+H] +
Preparation example 115
3-(5-fluoro-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]- Thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 5-fluoro-3-sulfydryl-pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 115.
1H NMR(CDCl 3)δ：2.59(3H，s)，7.02(1H，d，J＝8.8Hz)，7.30(1H，d，J＝8.4Hz)，7.60-7.75(1H，m)，8.41(1H，s)，8.50-8.65(2H，m)
ESI-MS(m/e)：447[M+H] +
Preparation example 116
Figure C20048000385001972
3-(2,3-Dihydrobenzofuranes-5-base sulfenyl)-6-(4H-[1,2,4]) triazole-3-base sulfenyl)-N-(3-first Base-[1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
6-chloro-3-(4-methoxyl group-phenyl methyl sulfenyl)-N-(3-methyl isophthalic acid that use makes by the method the same with preparation example 1,2,4-thiadiazoles-5-yl)-2-pyridine carboxamide, 5-iodo-2,3-Dihydrobenzofuranes and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 66, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 116.
1H NMR(CDCl 3)δ：2.61(3H，s)，3.25(2H，t，J＝8.4Hz)，4.65(2H，t，J＝8.4Hz)，6.85(1H，d，J＝8.4Hz)，7.05(1H，d，J＝8.4Hz)，7.06-7.33(3H，m)，7.78(1H，dd，J＝2.4，8.5Hz)，8.31(1H，s)
ESI-MS(m/e)：470[M+H] +
Preparation example 117
Figure C20048000385001981
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4]-triazine-3- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1,2,4-triazine, 4-methoxyl group-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 117 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.84(3H，s)，6.95(2H，d，J＝8.8Hz)，7.00(1H，d，J＝8.8Hz)，7.17(1H，d，J＝8.8Hz)，7.44(2H，d，J＝8.8Hz)，8.40(1H，s)，8.63(1H，d，J＝2.4Hz)，8.96(1H，d，J＝2.4Hz)
ESI-MS(m/e)：439[M+H] +
Preparation example 118
Figure C20048000385001991
3-(4-carboxyl-phenyl sulfenyl)-6-(5-methyl-[1,2,4] triazole-3-base sulfenyl)-N-(the 3-methyl- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 4-carboxyl-thiophenol and 3-sulfydryl-5-methyl isophthalic acid, 2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 118.
1H NMR(CDCl 3)δ：2.46(3H，s)，2.52(3H，s)，7.00(1H，d，J＝8.8Hz)，7.13(1H，d，J＝8.8Hz)，7.52(2H，d，J＝7.8Hz)，8.01(2H，d，J＝8.0Hz)
ESI-MS(m/e)：486[M+H] +
Preparation example 119
Figure C20048000385002001
3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(pyrazine-2- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-pyrazino, 6-oxyethyl group-3-sulfydryl-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 119 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：1.43(3H，t，J＝6.9Hz)，4.41(2H，q，J＝6.9Hz)，6.83(1H，d，J＝8.7Hz)，7.06(1H，d，J＝8.7Hz)，7.27(1H，d，J＝8.7Hz)，7.69(1H，m)，8.29-8.35(2H，m)，8.40(1H，m)，8.42(1H，s)，9.75(1H，m)
ESI-MS(m/e)：453[M+H] +
Preparation example 120
Figure C20048000385002011
3-(imidazo-[1,2-a]-pyridine-6-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-first Base-[1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
6-chloro-3-(4-methoxyl group-phenyl methyl sulfenyl)-N-(3-methyl isophthalic acid that use makes by the method the same with preparation example 1,2,4-thiadiazoles-5-yl)-2-pyridine carboxamide, 6-iodo-imidazo-[1,2,-a]-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 120 based on its method or with these methods with preparation example 66.
1H NMR(DMSO-d 6)δ：3.30(3H，s)，7.10-7.40(3H，m)，7.60-7.80(2H，m)，7.97(1H，s)，8.60-8.80(1H，m)，8.93(1H，s)
ESI-MS(m/e)：468[M+H] +
Preparation example 121
Figure C20048000385002012
3-(2-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 3-methyl- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 3-sulfydryl-2-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 121.
1H NMR(CDCl 3)δ：2.59(3H，s)，2.62(3H，s)，6.84(1H，d，J＝8.8Hz)，7.20-7.35(2H，m)，7.80-7.92(1H，m)，8.43(1H，s)，8.60-8.68(1H，m)
ESI-MS(m/e)：443[M+H] +
Preparation example 122
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-(thiazole is [4,5-b] also for N- Pyridine-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine also [4,5-b] pyridine, 4-methoxyl group-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 122 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.88(3H，s)，7.01(2H，d，J＝8.8Hz)，7.03(1H，d，J＝8.0Hz)，7.02-7.26(1H，m)，7.50(2H，d，J＝8.8Hz)，8.23(1H，d，J＝8.0Hz)，8.52(1H，s)，8.59(1H，s)
ESI-MS(m/e)：494[M+H] +
Preparation example 123
Figure C20048000385002031
3-(5-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 3-methyl- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 3-sulfydryl-5-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 123.
1H NMR(CDCl 3)δ：2.40(3H，s)，2.60(3H，s)，6.99(1H，d，J＝8.4Hz)，7.22-7.30(1H，m)，7.71(1H，s)，8.40(1H，s)，8.55(2H，m)
ESI-MS(m/e)：443[M+H] +
Preparation example 124
Figure C20048000385002041
3-(4,4-difluoro-methoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(pyrazine-2- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-pyrazino, 4,4-difluoro-methoxy-thiophenol and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 124.
1H NMR(CDCl 3)δ：6.62(1H，t，J＝73Hz)，7.05(1H，d，J＝9.0Hz)，7.20-7.30(3H，m)，7.60(2H，d，J＝8.7Hz)，8.30-8.43(2H，m)，8.41(1H，brs)，9.78(1H，brs)
ESI-MS(m/e)：474[M+H] +
Preparation example 125
3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H- [1,2]-pyrazole-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1-methyl isophthalic acid H-[1,2] pyrazoles, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 125 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.64(3H，s)，3.89(3H，s)，6.91(1H，m)，6.97(1H，d，J＝8.4Hz)，7.17-7.36(3H，m)，7.79(1H，m)，8.31(1H，s)，8.63(1H，m)
ESI-MS(m/e)：425[M+H] +
Preparation example 126
Figure C20048000385002061
3-(6-hydroxyethyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 3-methyl- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 6-hydroxyethyl-3-sulfydryl-pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 126.
1H NMR(CDCl 3)δ：2.57(3H，s)，3.04(2H，t，J＝6.0Hz)，3.97(2H，t，J＝6.0Hz)，6.98(1H，d，J＝8.8Hz)，7.20(1H，d，J＝8.8Hz)，7.30(1H，d，J＝8.0Hz)，7.78(1H，dd，J＝2.4，8.0Hz)，8.32(1H，s)，8.57(1H，d，J＝2.4Hz)
ESI-MS(m/e)：473[M+H] +
Preparation example 127
Figure C20048000385002071
3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrrole Azoles-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-sulfydryl-1-methyl isophthalic acid H-[1,2] pyrazoles, 4-fluoro-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 127 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.85(3H，s)，6.89(1H，brs)，6.97(1H，d，J＝8.7Hz)，7.11-7.21(3H，m)，7.30(1H，d，J＝8.7Hz)，7.57(2H，m)，8.35(1H，s)
ESI-MS(m/e)：428[M+H] +
Preparation example 128
Figure C20048000385002072
3-(2-methyl-imidazo-[1,2-a]-pyridine-6-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)- The preparation of N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 6-sulfydryl-2-methyl-imidazo-[1,2 ,-a] pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 128.
1H NMR(DMSO-d 6)δ：2.34(3H，s)，2.50(3H，s)，7.10-7.20(2H，m)，7.28(1H，d，J＝8.4Hz)，7.49(1H，d，J＝9.2Hz)，7.70(1H，s)，8.70(1H，brs)，8.83(1H，s)
ESI-MS(m/e)：482[M+H] +
Preparation example 129
Figure C20048000385002081
3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 3-hydroxymethyl- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 129.
1H NMR(CDCl 3)δ：2.59(3H，s)，4.65(2H，s)，6.97(1H，d，J＝8.4Hz)，7.23(1H，d，J＝8.4Hz)，7.26(1H，d，J＝7.6Hz)，7.74(1H，dd，J＝2.0，7.6Hz)，8.34(1H，s)，8.54(1H，d，J＝2.0Hz)
ESI-MS(m/e)：459[M+H] +
Preparation example 130
Figure C20048000385002091
3-[4-(2-hydroxyethyl)-phenyl sulfenyl]-6-(4-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N- The preparation of (3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 4-hydroxyethyl-thiophenol and 3-sulfydryl-4-methyl isophthalic acid, 2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 130.
1H NMR(CDCl 3)δ：2.61(3H，s)，2.93(2H，t，J＝6.4Hz)，3.72(3H，s)，3.92(2H，t，J＝6.4Hz)，7.06(1H，d，J＝8.4Hz)，7.11(1H，d，J＝8.4Hz)，7.35(2H，d，J＝8.0Hz)，7.47(2H，d，J＝8.0Hz)，8.38(1H，s)
ESI-MS(m/e)：486[M+H] +
Preparation example 131
3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-hydroxyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-first Base-[1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl-thiadiazoles, 3-sulfydryl-6-methyl-pyridine and 5-hydroxyl-3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 131 based on its method or with these methods with preparation example 1.
1H NMR(DMSO-d 6)δ：2.53(3H，s)，2.65(3H，s)，7.13-7.71(3H，m)，7.84-7.98(1H，m)，8.43-8.63(1H，m)
ESI-MS(m/e)：459[M+H] +
Preparation example 132
Figure C20048000385002102
3-(1-methyl isophthalic acid H-indazole-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 3-methyl- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-sulfydryl-1,2,4-thiadiazoles, 5-sulfydryl-1-methyl isophthalic acid H-indazole and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 132.
1H NMR(CDCl 3)δ：2.53(3H，s)，4.03(3H，s)，6.87(1H，d，J＝8.8Hz)，7.06(1H，d，J＝8.8Hz)，7.39-7.45(2H，m)，7.94(2H，m)，8.27(1H，s)
ESI-MS(m/e)：482[M+H] +
Preparation example 133
Figure C20048000385002111
3-(3-methyl-[1,2,4]-triazolo-[4,3-a]-pyridine-7-base sulfenyl)-6-(4H-[1,2,4] triazole-3- The base sulfenyl)-preparation of N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-sulfydryl-1,2,4-thiadiazoles, 7-sulfydryl-3-methyl-[1,2,4]-triazolo-[4,3-a]-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 133 based on its method or with these methods with preparation example 1.
1H NMR(DMSO-d 6)δ：2.49(3H，s)，2.67(3H，s)，6.82-6.87(1H，m)，7.19(1H，d，J＝8.8Hz)，7.57(1H，d，J＝8.8Hz)，7.86(1H，s)，8.35(1H，d，J＝7.2Hz)，8.70-8.90(1H，brs)
ESI-MS(m/e)：483[M+H] +
Preparation example 134
Figure C20048000385002121
3-(1-oxygen base-6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-first Base-[1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl-thiadiazoles, 3-sulfydryl-6-methyl isophthalic acid-oxygen base-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 134 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.58(3H，s)，2.61(3H，s)，7.16(1H，d，J＝8.4Hz)，7.32(1H，d，J＝8.4Hz)，7.40-7.45(2H，m)，8.38(1H，s)，8.43(1H，brs)
ESI-MS(m/e)：459[M+H] +
Preparation example 135
3-(6-hydroxymethyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 3-methyl- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl-thiadiazoles, 6-hydroxymethyl-3-sulfydryl-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 135 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.62(3H，s)，4.80(2H，s)，7.01(1H，d，J＝8.8Hz)，7.26(1H，d，J＝8.8Hz)，7.56(1H，d，J＝8.0Hz)，7.91(1H，dd，J＝8.0Hz；1.2Hz)，8.36(1H，s)，8.65(1H，d，J＝1.2Hz)
ESI-MS(m/e)：459[M+H]
Preparation example 136
Figure C20048000385002141
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H- [1,2]-pyrazole-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1-methyl isophthalic acid H-[1,2] pyrazoles, 4-methoxyl group-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 136 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.82(3H，s)，3.83(3H，s)，6.80(1H，d，J＝2.4Hz)，6.93(1H，d，J＝8.4Hz)，6.94(2H，d，J＝8.8Hz)，7.08(1H，d，J＝8.4Hz)，7.25(1H，d，J＝2.4Hz)，7.43(2H，d，J＝8.8Hz)，8.32(1H，s)
ESI-MS(m/e)：440[M+H] +
Preparation example 137
Figure C20048000385002142
3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1H-[1,2]-pyrazoles-3- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1H-[1,2] pyrazoles, 4-fluoro thiophenol and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 137.
1H NMR(CDCl 3)δ：6.87(1H，bs)，6.94(1H，d，J＝8.4Hz)，7.12-7.18(3H，m)，7.45-7.53(3H，m)，8.30(1H，s)
ESI-MS(m/e)：414[M+H] +
Preparation example 138
Figure C20048000385002151
3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-(the 3-methyl- [1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl-thiadiazoles, 3-sulfydryl-6-methoxyl group-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 138 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.63(3H，s)，4.00(3H，s)，6.88(1H，d，J＝8.7Hz)，7.07(1H，d，J＝8.7Hz)，7.29(1H，d，J＝8.7Hz)，7.70(1H，dd，J＝8.7，2.1Hz)，8.31-8.40(2H，m)
ESI-MS(m/e)：459[M+H] +
Preparation example 139
Figure C20048000385002161
3-[4-(1H-imidazoles-1-yl)]-the phenyl sulfenyl)-6 (4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-first Base-[1,2,4]-thiadiazoles-5-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 5-amino-3-methyl isophthalic acid, 2,4-thiadiazoles, 4-(1H-imidazoles-1-yl) thiophenol and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 139.
1H NMR(CDCl 3)δ：2.57(3H，s)，7.03(1H，d，J＝8.8Hz)，7.16(2H，brs)，7.31(1H，brs)，7.48(1H，d，J＝8.4Hz)，7.65(2H，d，J＝8.4Hz)，7.92(1H，s)，8.32(1H，s)
ESI-MS(m/e)：494[M+H] +
Preparation example 140
Figure C20048000385002171
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1H-[1,2]-pyrazoles- The 3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1H-[1,2]-pyrazoles, 4-methoxyl group-thiophenol and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 140.
1H NMR(CDCl 3)δ：6.86(1H，d，J＝2.6Hz)，6.98(2H，d，J＝8.8Hz)，6.99(1H，d，J＝8.8Hz)，7.17(1H，d，J＝8.8Hz)，7.47(2H，d，J＝8.8Hz)，7.50(1H，d，J＝2.6Hz)，8.34(1H，s)
ESI-MS(m/e)：426[M+H] +
Preparation example 141
Figure C20048000385002181
3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 1-methyl- The 1H-pyrazole-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1-methyl isophthalic acid H-pyrazoles, 3-sulfydryl-6-methoxyl group-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 141 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.81(3H，s)，3.95(3H，s)，6.76(1H，d，J＝2.4Hz)，6.80(1H，d，J＝8.4Hz)，6.93(1H，d，J＝8.4Hz)，7.10(1H，d，J＝8.4Hz)，7.25(1H，d，J＝2.4Hz)，7.65(1H，dd，J＝8.4Hz，2.0Hz)，8.28(1H，d，J＝2.0Hz)，8.36(1H，s)，10.11(1H，s)
ESI-MS(m/e)：441[M+H]
Preparation example 142
Figure C20048000385002191
3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 1-methyl- The 1H-pyrazole-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1-methyl isophthalic acid H-pyrazoles, 3-sulfydryl-6-oxyethyl group-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 142 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：1.43(3H，t，J＝6.9Hz)，3.87(3H，s)，4.42(2H，q，J＝6.9Hz)，6.83(1H，d，J＝8.7Hz)，6.93(1H，d，J＝2.1Hz)，7.02(1H，d，J＝8.7Hz)，7.22(1H，d，J＝8.7Hz)，7.32(1H，d，J＝2.1Hz)，7.69(1H，dd，J＝8.7，2.4Hz)，8.25-8.39(2H，m)
ESI-MS(m/e)：455[M+H] +
Preparation example 143
Figure C20048000385002201
3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 1-methyl- The 1H-pyrazole-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1-methyl isophthalic acid H-pyrazoles, 4-methoxymethyl-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 143 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.45(3H，s)，3.82(3H，s)，4.49(2H，s)，6.83(1H，d，J＝2.0Hz)，6.96(1H，d，J＝8.8Hz)，7.09(2H，d，J＝8.8Hz)，7.25(1H，d，J＝2.0Hz)，7.40(2H，d，J＝7.6Hz)，7.51(2H，d，J＝7.6Hz)，8.31(1H，s)，10.14(1H，s)
ESI-MS(m/e)：440[M+H] +
Preparation example 144
3-(4-p-methoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(4,5-diformazan thiophene L azoles-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4,5-dimethyl-thiazole, 4-methoxyl group-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 144 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：2.29(3H，s)，2.33(3H，s)，3.87(3H，s)，6.98-7.03(3H，m)，7.21(1H，d，J＝8.6Hz)，7.48(2H，d，J＝8.6Hz)，8.29(1H，s)
ESI-MS(m/e)：471[M+H] +
Preparation example 145
Figure C20048000385002212
3-(4-fluoro-phenyl sulfenyl)-6-(4,5-dimethyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxy Ylmethyl-thiazol-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-methoxymethyl-thiazole, 4-fluoro-thiophenol and 3-sulfydryl-4,5-dimethyl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 145 based on its method or with these methods with preparation example 1.
1H NMR(CDCl3)δ：2.60(3H，s)，3.47(3H，s)，3.62(3H，s)，4.50(2H，s)，6.93(1H，s)，6.98(1H，d，J＝8.8Hz)，7.07(1H，d，J＝8.8Hz)，7.16(2H，dd，J＝8.8、8.8Hz)，7.53(2H，dd，J＝5.2、8.8Hz)
ESI-MS(m/e)：503[M+H] +
Preparation example 146
Figure C20048000385002221
3-(4-(1-methoxy ethyl)-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole- The 2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-(1-methoxy ethyl)-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 146 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：1.27(3H，d，J＝6.4Hz)，3.30(3H，s)，4.36(1H，d，J＝6.4Hz)，7.03(1H，d，J＝3.6Hz)，7.05(1H，d，J＝8.8Hz)，7.23(1H，d，J＝8.8Hz)，7.41(2H，d，J＝8.0Hz)，7.47(1H，d，J＝3.6Hz)，7.54(2H，d，J＝8.0Hz)，8.35(1H，s)
ESI-MS(m/e)：471[M+H] +
Preparation example 147
Figure C20048000385002231
3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-hydroxymethyl-thiazole- The 2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-hydroxy methyl-thiazole, 4-fluoro-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 147 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：4.60(2H，s)，6.84(1H，s)，6.93(1H，d，J＝8.8Hz)，7.06-7.16(3H，m)，7.40-7.60(2H，m)，8.31(1H，s)
ESI-MS(m/e)：461[M+H] +
Preparation example 148
Figure C20048000385002241
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-trifluoromethyl thiophene Azoles-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-5-trifluoromethyl-thiazole, 4-methoxyl group-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 148 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.86(3H，s)，6.97-7.05(3H，m)，7.22-7.27(1H，m)，7.47(2H，d，J＝8.8Hz)，7.80(1H，s)，8.39(1H，s)
ESI-MS(m/e)：509[M-H] -
Preparation example 149
3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-trifluoromethyl thiophene Azoles-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-4-trifluoromethyl-thiazole, 4-methoxyl group-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 149 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.85(3H，s)，6.96-7.00(3H，m)，7.17(1H，d，J＝8.0Hz)，7.44-7.47(3H，m)，8.37(1H，s)
ESI-MS(m/e)：511[M+H] +
Preparation example 150
Figure C20048000385002251
3-(3-fluoro-4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole-2- Base)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, thiazolamine, 3-fluoro-4-methoxyl group-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 150 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.95(3H，s)，7.01-7.06(3H，m)，7.23-7.32(3H，m)，7.47(1H，d，J＝4.0Hz)，8.32(1H，s)
ESI-MS(m/e)：461[M+H]
Preparation example 151
Figure C20048000385002261
3-[4-(1,1-dimethyl-1-hydroxymethyl)-phenyl sulfenyl]-6-(4H-[1,2,4] triazole-3-base-sulfenyl)- The preparation of N-(thiazol-2-yl)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-thiazolyl-, 4-(1,1-dimethyl-1-hydroxymethyl)-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 151 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：1.63(6H，s)，6.99-7.03(2H，m)，7.18(1H，d，J＝8.4Hz)，7.39(1H，d，J＝3.6Hz)，7.51(2H，d，J＝8.4Hz)，7.58(2H，d，J＝8.4Hz)，8.30(1H，s)
ESI-MS(m/e)：471[M+H] +
Preparation example 152
Figure C20048000385002262
3-(3,4-two fluoro-phenyl sulfenyls)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2] Pyrazole-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1-methyl isophthalic acid H-[1,2] pyrazoles, 3,4-two fluoro-thiophenols and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 152.
1H NMR(CDCl 3)δ：3.84(3H，s)，6.82(1H，d，J＝2.0Hz)，6.94(1H，d，J＝8.8Hz)，7.15(1H，d，J＝8.8Hz)，7.20-7.41(4H，m)，8.33(1H，s)
ESI-MS(m/e)：446[M+H] +
Preparation example 153
Figure C20048000385002271
3-(3,5-two fluoro-phenyl sulfenyls)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H- [1,2]-pyrazole-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1-methyl isophthalic acid H-[1,2] pyrazoles, 3,5-two fluoro-thiophenols and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 153.
1H NMR(CDCl 3)δ：3.81(3H，s)，6.81(1H，d，J＝2.8Hz)，6.83-6.90(1H，m)，7.04-7.06(2H，m)，7.16(1H，d，J＝8.8Hz)，7.27(1H，d，J＝2.8Hz)，8.27(1H，s)
ESI-MS(m/e)：446[M+H] +
Preparation example 154
Figure C20048000385002281
3-(1-methyl-2-oxo-2,3-dihydro-1H-indoles-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base Sulfenyl)-preparation of N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1-methyl isophthalic acid H-[1,2] pyrazoles, 5-sulfydryl-1-methyl isophthalic acid, 3-dihydro-indol-2-one and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 154.
1H NMR(CDCl 3)δ：3.15(3H，s)，3.48(2H，s)，3.76(3H，s)，6.75(1H，d，J＝2.4Hz)，6.83(1H，d，J＝8.0Hz)，6.88(1H，d，J＝8.8Hz)，7.02(1H，d，J＝8.8Hz)，7.23(1H，d，J＝2.4Hz)，7.31(1H，d，J＝1.6Hz)，7.41(1H，dd，J＝8.0，1.6Hz)，8.22(1H，s)
ESI-MS(m/e)：479[M+H] +
Preparation example 155
Figure C20048000385002282
3-(6-methyl-pyridine-3-sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] triazolo Pyridine-2-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 2-amino-[1,2,4] Triazolopyridine, 3-sulfydryl-6-methyl-pyridine and 3-sulfydryl-1,2, the 4-triazole by the method the same with preparation example 1, combine with ordinary method based on its method or with these methods, can make the compound of preparation example 155.
1H NMR(CDCl 3)δ：2.58(3H，s)，6.93(1H，d，J＝8.8Hz)，7.01(1H，t，J＝6.4Hz)，7.16(1H，d，J＝8.8Hz)，7.24(1H，d，J＝8.0Hz)，7.51-7.60(2H，m)，7.73(1H，dd，J＝8.0，2.4Hz)，8.32(1H，s)，8.53(1H，s)，8.60(1H，d，J＝6.4Hz)
ESI-MS(m/e)：462[M+H] +
Preparation example 156
Figure C20048000385002291
3-(4-ethoxyl methyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(the 1-methyl- 1H-[1,2]-pyrazole-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1-methyl isophthalic acid H-[1,2] pyrazoles, 4-ethoxyl methyl-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 156 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：1.28(3H，t，J＝6.8Hz)，3.60(2H，q，J＝6.8Hz)，3.83(3H，s)，4.54(2H，s)，6.85(1H，d，J＝2.0Hz)，6.98(1H，d，J＝8.8Hz)，7.10(1H，d，J＝8.8Hz)，7.26(1H，d，J＝2.0Hz)，7.41(2H，d，J＝8.0Hz)，7.51(2H，d，J＝8.0Hz)，8.31(1H，s)
ESI-MS(m/e)：468[M+H] +
Preparation example 157
Figure C20048000385002301
3-(6-oxo-1,6-dihydro-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1- Methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1-methyl isophthalic acid H-[1,2] pyrazoles, 3-sulfydryl-6-methoxyl group-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 157 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.86(3H，s)，6.63(1H，d，J＝9.3Hz)，6.85(1H，d，J＝2.1Hz)，7.21(1H，d，J＝9.0Hz)，7.27(1H，d，J＝9.0Hz)，7.33(1H，m)，7.45(1H，brd，J＝9.3Hz)，7.58(1H，d，J＝2.1Hz)，8.35(1H，s)
ESI-MS(m/e)：427[M+H] +
Preparation example 158
Figure C20048000385002311
3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1H-[1,2]- Pyrazole-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1-methyl isophthalic acid H-[1,2] pyrazoles, 3-sulfydryl-6-methoxyl group-pyridine and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 158 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：4.00(3H，s)，6.84-6.94(2H，m)，7.02(1H，d，J＝9.0Hz)，7.22(1H，d，J＝9.0Hz)，7.52(1H，m)，7.70(1H，m)，8.31-8.40(2H，m)
ESI-MS(m/e)：427[M+H] +
Preparation example 159
Figure C20048000385002312
3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(1- Methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-preparation of 2-pyridine carboxamide
Use 3,6-two chloro-2-pyridine carboxylic acids, 3-amino-1-methyl isophthalic acid H-[1,2] pyrazoles, 4-hydroxyl-oxethyl-thiophenol and 3-sulfydryl-1,2, the 4-triazole, by the method the same, combine with ordinary method, can make the compound of preparation example 159 based on its method or with these methods with preparation example 1.
1H NMR(CDCl 3)δ：3.73(3H，s)，3.85(3H，s)，4.00(2H，m)，4.13(2H，m)，6.87(1H，d，J＝2.1Hz)，6.95-7.06(3H，m)，7.24-7.31(2H，m)，7.46(2H，d，J＝8.7Hz)，8.41(1H，s)
ESI-MS(m/e)：484[M+H] +
Below, the preparation method of the compound that is used to prepare The compounds of this invention is described with reference example 1-6.
Reference example 1
Figure C20048000385002321
5-methoxymethyl-3-sulfydryl-1,2, the preparation of 4-triazole
In the pyridine solution (15ml) of 2.09g (0.0230mol) thiosemicarbazide, add 2.82g (0.023mol) methoxyacetyl chloride, at room temperature stir diel.Concentrated reaction solution, the methanol solution (8ml) of the sodium methylate of adding methyl alcohol (10ml), 25% weight, reflux diel.After being cooled to room temperature, heating up in a steamer and desolvate, add concentrated hydrochloric acid and make it become acid.The solid that filtration is separated out is used distilled water wash, and drying obtains 1.0g (yield 33%) title compound.
1H NMR(DMSO)δ：3.24(3H，s)，4.29(2H，s)
ESI-MS(m/e)：146[M+H] +
Reference example 2
The preparation of 2-amino-4-methoxymethyl thiazole
Add 8.06g (106mmol) thiocarbamide in the glycol dimethyl ether solution (120ml) of 13.4g (106mmol) Dichloro acetone, adding, stirred 3 hours at 55 ℃.Concentration of reaction solution adds methyl alcohol (200ml) and 15.1g (125mmol) sal epsom, reflux 3 days in the gained white solid.Use the diatomite filtration reaction mixture, concentrated filtrate distributes with chloroform and saturated sodium bicarbonate aqueous solution then.Dry, concentrate organic layer, then the gained resistates is carried out purifying by silica gel column chromatography (ethyl acetate) with the crystallization that the mixed solvent (4: 1) of hexane/ethyl acetate carries out, obtain 6.59g (yield: 43%) be the title compound of yellow solid.
1H NMR(CDCl 3)δ：3.44(3H，s)，4.34(2H，s)，6.45(1H，s)
ESI-MS(m/e)：145[M+H] +
Reference example 3
Figure C20048000385002332
The preparation of 4-ethanoyl-thiazolamine
N to 1.30g (5.14mmol) 2-(tert-butoxycarbonyl amino)-4-carboxyl thiazole, in the dinethylformamide solution (30ml), add 660mg (6.77mmol) N successively, O-dimethyl hydroxyl amine hydrochlorate, 1.40ml (9.96mmol) triethylamine, 1.10g (8.14mmol) N-hydroxy benzotriazole hydrate and 1.60g (8.35mmol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride at room temperature stirred 5 days then.Concentration of reaction solution adds ethyl acetate in resistates, washs with 1N-aqueous hydrochloric acid, water, the saturated common salt aqueous solution, and drying, concentrating under reduced pressure obtains 1.35g (yield: 91%) be the amide compound of oily matter.
The tetrahydrofuran solution (40ml) of the previous gained amide compound of 920mg (3.20mmol) is cooled to-78 ℃, adds 18.0ml (18.0mmol) lithium methide/diethyl ether solution, stirred 7 hours.In reaction solution, add ammonium chloride saturated aqueous solution, use ethyl acetate extraction.Wash organic layer with water, dry then, concentrated, obtain 666mg (yield: 86%) be the acetyl compounds of oily matter.
In the chloroformic solution (10ml) of previous gained acetyl compounds, add the 5ml trifluoroacetic acid, at room temperature stirred 1.5 hours.Concentration of reaction solution neutralizes with saturated sodium bicarbonate aqueous solution, filters, and obtains 149mg (yield: 59%) be the title compound of white solid.
1H NMR(CDCl 3)δ：2.48(3H，s)，7.35(1H，s)
ESI-MS(m/e)：143[M+H] +
Reference example 4
The preparation of 4-methyl sulphonyl benzenethiol
Figure C20048000385002341
In the chloroformic solution (150ml) of 5.0g (36mmol) 4-methylbenzene thiophenol, add 18ml 35% aqueous hydrogen peroxide solution and 180mg (0.72mmol) methyltrioxolenium down ice-cooled, at room temperature stirred then 30 minutes.In reaction solution, add Manganse Dioxide down ice-cooled, at room temperature stirred 4 hours, add saturated aqueous common salt then, use chloroform extraction.With saturated common salt solution washing organic layer, dry afterwards and concentrated, obtain 5.0g (yield: 81%) be the 4-methyl sulphonyl phenol of white solid.
N to 5.0g (29mmol) gained 4-methyl sulphonyl phenol; add 6.5g (58mmol) 1 in the dinethylformamide solution (100ml); 4-diazabicyclo [2.2.2] octane and 5.4g (44mmol) dimethyl sulphide stirred 4 hours at 75 ℃ then for urea chloride.In reaction solution, add entry, use ethyl acetate extraction, water, saturated sodium bicarbonate aqueous solution, saturated common salt solution washing organic layer.After dry and concentrated,, obtain 4.8g (yield: 63%) be the O-4-methyl sulphonyl phenyl dimethyl thiocarbamate of white solid with the mixed solvent recrystallization of gained resistates with hexane/chloroform.
Gained 4.8g (18mmol) O-4-methyl sulphonyl phenyl dimethyl thiocarbamate was stirred 10 hours at 180 ℃, return back to room temperature, add 10ml methyl alcohol.In this reaction soln, add 2N-aqueous sodium hydroxide solution (10ml), reflux 8 hours 30 minutes.In reaction soln, add the 1N-aqueous hydrochloric acid, use ethyl acetate extraction, with saturated common salt solution washing organic layer.After dry and concentrated, (hexane: ethyl acetate=2: 1-chloroform: purifying methyl alcohol=10: 1) obtains 3.6g (yield: title compound 100%) by silica gel column chromatography with the gained resistates.
1H NMR(CDCl 3)δ：3.04(3H，s)，3.69(1H，s)，7.63(2H，d，J＝7.6Hz)，7.87(2H，d，J＝7.6Hz)
Reference example 5
Figure C20048000385002351
The preparation of 4-formyl-dimethylamino benzenethiol
In the tetrahydrofuran solution (50ml) of 1.30g (5.14mmol) 4-methylthio-benzoic acid, add the tetrahydrofuran solution of 1.50g (6.77mmol) carbonyl dimidazoles and 4.70ml (8.35mmol) dimethylamine successively, at room temperature stirred then 2 hours 30 minutes.In reaction soln, add ethyl acetate, wash with 1N aqueous hydrochloric acid, water, the saturated common salt aqueous solution.Dry, concentrated organic layer obtains the amide compound that 960mg is the crude product of oily matter.
At room temperature, in the chloroformic solution (50ml) of previous gained amide compound, slowly add 980mg (4.90mmol) 3-chloroperoxybenzoic acid, stirred 1 hour.In reaction soln, add saturated sodium bicarbonate aqueous solution, stirred 30 minutes, use ethyl acetate extraction then, water, saturated common salt water washing organic layer.Drying concentrates, and obtains the sulfoxide compound that 910mg is the crude product of oily matter.
Add 1.56ml (13.4mmol) 2 successively in the chloroformic solution (20ml) of previous gained sulfoxide compound, 6-lutidine and 1.80ml (12.9mmol) trifluoroacetic anhydride at room temperature stirred 1 hour.Concentrated reaction solution adds 5ml triethylamine and 5ml methyl alcohol, stirs 30 minutes.Concentrated reaction solution adds diethyl ether in the gained resistates, wash with 1N-aqueous hydrochloric acid, saturated sodium bicarbonate aqueous solution.Dry, concentrated organic layer obtains 487mg (yield: 62%) be the title compound of orange oily compound.The crude product that obtains like this is purified and be used for subsequent reaction.
1H NMR(CDCl 3)δ：3.03(3H，s)，3.14(3H，s)，7.22-7.38(3H，m)，7.46-7.52(1H，m)ESI-MS(m/e)：182[M+H] +
Reference example 6
The preparation of 4-dimethylamino ethoxy-benzenethiol
To the N of 3.00g (13.6mmol) 4-iodophenol, add 2.40g (17.1mmol) dimethyl aminoethyl villaumite hydrochlorate and 5.83g (42.2mmol) salt of wormwood in the dinethylformamide solution (70ml) successively, stirred 15 hours at 70 ℃.The dilute with water reaction solution is used ethyl acetate extraction.Water, saturated common salt water washing organic layer, dry then, concentrated.(chloroform: purifying methyl alcohol=30: 1) obtains 840mg (yield: 21%) be the iodine derivative of oily matter by silica gel column chromatography with the gained resistates.
Adding 120 μ l (2.15mmol) ethylene glycol, 305mg (2.21mmol) salt of wormwood, 150 μ l (1.08mmol) 4-methoxyl group-α-Ben Jialiuchuns and 20mg (0.105mmol) cupric iodide in the 2-propanol solution (8ml) of the previous gained iodine derivative of 317mg (1.08mmol) were with reaction solution reflux 40 hours.Use the diatomite filtration reaction solution, then filtrate is distributed between chloroform and saturated aqueous common salt.Dry organic layer, concentrating under reduced pressure adds phenylmethylether (180 μ l) and trifluoroacetic acid (1.5ml) successively in gained 298mg oily matter, stirred 2 hours at 70 ℃ then.Concentration of reaction solution, the gained crude product is purified and be used for subsequent reaction.
ESI-MS(m/e)：198[M+H] +
Industrial applicability
It is active that Novel 2-pyridinecarboxamide derivatives of the present invention shown in formula (I) demonstrates excellent glucokinase, can be used for the treatment of and/or prevent diabetes, diabetic complication or obesity at field of medicaments.

Claims (38)

1. compound or its pharmacy acceptable salt shown in the formula (I),
Figure C2004800038500002C1
X in the formula 1Expression N, S or O or expression carbonatoms are the divalent saturated hydrocarbyl of 1-6, and when the carbonatoms of described divalent saturated hydrocarbyl is 2 when above, a carbon atom in this divalent saturated hydrocarbyl is optional is replaced by nitrogen-atoms, Sauerstoffatom or sulphur atom;
R 1The aryl of expression 6-10 unit, the heteroaryl of 5-10 unit, cycloalkyl or the C1-C6 alkyl that carbonatoms is 3-7, this R 1Choose wantonly at R 1On have 1 or 2 and be selected from following group: amino; the C1-C6 alkyl; the C1-C6 alkoxyl group; formamyl; the C1-C6 alkyl-carbamoyl; two C1-C6 alkyl-carbamoyls; formamyl amino; carbamoyloxy; carboxyl; cyano group; sulfamyl; trifluoromethyl; halogen atom; hydroxyl; formyl radical; the C2-C6 alkyloyl; the N-C2-C6 alkanoylamino; the C1-C6 alkylthio; the N-C1-C6 alkylsulfamoyl group; N; N-two-C1-C6 alkylsulfamoyl group; C1-C6 alkyl sulfinyl; the C1-C6 alkyl sulphonyl; the N-C1-C6 alkyl sulfonyl-amino; the C1-C6 alkoxy carbonyl; N-C1-C6 alkylamino and N; N-two-C1-C6 alkylamino
The hydrogen atom of described C1-C6 alkyl is optional by hydroxyl, C1-C6 alkoxyl group, halogen atom, formamyl, one or two C1-C6 alkyl-carbamoyls, carboxyl, C1-C6 alkoxy carbonyl, C2-C6 alkyloyl, amino or one or the replacement of two-C1-C6 alkylamino, and
Constituting the methylene radical of described C1-C6 alkoxyl group or the hydrogen atom of methyl chooses wantonly by hydroxyl, halogen atom, formamyl, one or two C1-C6 alkyl-carbamoyls, carboxyl, C1-C6 alkoxy carbonyl, C2-C6 alkyloyl, amino or the replacement of one or two C1-C6 alkylaminos;
D represents O or S;
R 2And R 3Identical or different, expression hydrogen atom, C1-C6 alkyl, C1-C6 alkoxyl group, halogen atom;
Formula (II)
Figure C2004800038500003C1
Expression is chosen wantonly has 1 or 2 substituent 5-7 unit's heteroaryl or 6-10 unit aryl that is selected from following groups in this ring: C1-C6 alkyl, C1-C6 alkoxyl group, trifluoromethyl, hydroxyl, hydroxyl C1-C6 alkyl and halogen atom, and the hydrogen atom of the hydroxyl in the described hydroxyl C1-C6 alkyl is optional further to be replaced by the C1-C6 alkyl;
Formula (III)
Figure C2004800038500003C2
Expression thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl group, triazolyl,  azoles base, different  azoles base, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl, pyrimidyl, pyrido thiazolyl or benzothiazolyl;
Choose wantonly on the described B ring and have 1 or 2 substituting group that is selected from following groups: C1-C6 alkyl, C1-C6 alkoxyl group, halogen atom, trifluoromethyl, hydroxyl C1-C6 alkyl, amino C1-C6 alkyl, C2-C6 alkyloyl, carboxyl, C1-C6 alkoxy carbonyl and cyano group;
The hydrogen atom of the hydroxyl in the described hydroxyl C1-C6 alkyl is optional further to be replaced by the C1-C6 alkyl; And
Described amino is optional to be replaced by the C1-C6 alkyl.
2. the compound of claim 1, wherein D is S.
3. claim 1 or 2 compound, wherein R 2And R 3It all is hydrogen atom.
4. claim 1 or 2 compound, wherein the A ring is chosen wantonly and have 1 or 2 group that is selected from C1-C6 alkyl, C1-C6 alkoxyl group, trifluoromethyl, hydroxyl, hydroxyl C1-C6 alkyl and halogen atom on this ring, is phenyl, isothiazolyl, imidazolyl,  azoles base, thiadiazolyl group, thienyl, triazolyl, tetrazyl, pyridyl, pyrimidyl, furyl, thiazolyl, different  azoles base or pyrazolyl; The hydrogen atom of the hydroxyl in the described hydroxyl C1-C6 alkyl is optional further to be replaced by the C1-C6 alkyl.
5. claim 1 or 2 compound, wherein X 1For be selected from nitrogen-atoms, sulphur atom, Sauerstoffatom ,-CH 2-,-N-CH 2-,-S-CH 2-,-O-CH 2-,-CH 2-N-,-CH 2-O-and-CH 2The group of-S-.
6. claim 1 or 2 compound, wherein the B ring is thiazolyl, thiadiazolyl group, different  azoles base, pyrazinyl, pyrido thiazolyl or pyridyl.
7. claim 1 or 2 compound, wherein R 1For the aryl of 6-10 unit, the heteroaryl or the carbonatoms of 5-10 unit are the cycloalkyl of 3-7.
8. claim 1 or 2 compound, wherein R 1Be the aryl of 6-10 unit or the heteroaryl of 5-10 unit.
9. claim 1 or 2 compound, wherein R 1Aryl for 6-10 unit.
10. claim 1 or 2 compound, wherein R 1Heteroaryl for 5-10 unit.
11. the compound of claim 1 or 2, wherein the substituting group of A ring is C1-C6 alkyl, C1-C6 alkoxyl group, hydroxyl or hydroxyl C1-C6 alkyl, and the hydrogen atom of hydroxyl is optional in the described hydroxyl C1-C6 alkyl is further replaced by the C1-C6 alkyl.
12. the compound of claim 1 or 2, wherein the B ring is thiazolyl, thiadiazolyl group, different  azoles base or pyrido thiazolyl.
13. the compound of claim 1 or 2, wherein the substituting group of B ring is hydrogen atom, C1-C6 alkyl, halogen atom, hydroxyl C1-C6 alkyl, amino C1-C6 alkyl or C2-C6 alkyloyl.
14. the compound of claim 1 or 2, wherein R 1The substituting group that is had is hydroxyl C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxyl group, formamyl, C1-C6 alkyl-carbamoyl, two C1-C6 alkyl-carbamoyls, cyano group, trifluoromethyl, halogen atom, C2-C6 alkyloyl, N-C2-C6 alkanoylamino, C1-C6 alkyl sulphonyl, N-C1-C6 alkylamino or amino C1-C6 alkyl.
15. the compound of claim 1 or 2 or its pharmacy acceptable salt, compound is a following compounds shown in its Chinese style (I),
Figure C2004800038500005C1
1) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
2) 3-(4-fluoro-phenyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
3) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
4) 3-(4-fluoro-phenyl sulfenyl)-6-(1-methyl-imidazoles-2-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
5) 3-(4-fluoro-phenyl sulfenyl)-6-(1-methyl isophthalic acid H-tetrazolium-5-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
6) 3-(cyclohexyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
7) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
8) 3-(thiazol-2-yl-sulfenyl)-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
9) 3-(2-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
10) 3-phenyl sulfenyl-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
11) 3-(4-fluoro-phenoxy group)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
12) 3-(4-methoxyl group-phenyl methyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
13) 3-(3-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
14) 3-(2,4-two fluoro-phenyl sulfenyls)-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
15) 3-(4-fluoro-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
16) 3-(4-cyano group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
17) 3-(pyridin-4-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
18) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole is [5,4-b] pyridine-2-yl also)-2-pyridine carboxamide,
19) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
20) 3-(4-ethanoyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
21) 3-(thiophene-2-base-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
22) 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
23) 3-(4-fluoro-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazole is [5,4-b] pyridine-2-yl also)-2-pyridine carboxamide,
24) 3-(4-methyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
25) 3-(4-chloro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
26) 3-(4-fluoro-phenyl sulfenyl)-6-(3H-[1,2,3] triazole-4-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
27) 3-(4-methyl sulphonyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
28) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-hydroxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
29) 3-(4-fluoro-phenyl sulfenyl)-6-(5-methoxymethyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
30) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
31) 3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
32) 3-(4-trifluoromethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
33) 3-(4-methylamino formyl radical-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
34) 3-(hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
35) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-dimethylaminomethyl-thiazol-2-yl)-2-pyridine carboxamide,
36) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
37) 3-(4-hydroxyethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
38) 3-(4-methyl sulfamyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
39) 3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)-2-pyridine carboxamide,
40) 3-(4-hydroxyl-cyclohexyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
41) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4]-triazole-3-base-sulfenyl)-N-(pyridazine-3-yl)-2-pyridine carboxamide,
42) 3-(pyrazine-2-base-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
43) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(pyrazine-2-yl)-2-pyridine carboxamide,
44) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
45) 3-[4-(1-hydroxyethyl-phenyl sulfenyl)]-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
46) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(2-methyl-thiazole-4-yl)-2-pyridine carboxamide,
47) 3-(4-formyl-dimethylamino-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(2-methyl-thiazole-4-yl)-2-pyridine carboxamide,
48) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
49) 3-(1-methyl isophthalic acid H-tetrazolium-5-base-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
50) 3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)-2-pyridine carboxamide,
51) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)-2-pyridine carboxamide,
52) 3-(4-fluoro-phenyl sulfenyl)-6-phenoxy group-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
53) 3-(2-chloro-phenyl methyl-amino)-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
54) 3,6-two-(pyridine-2-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
55) 3,6-two-(4-fluoro-phenyl sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide,
56) 3,6-two-(thiazol-2-yl-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
57) 3,6-two-(5-methyl-[1,3,4] thiadiazoles-2-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
58) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-methyl-thiazol-2-yl)-2-pyridine carboxamide,
59) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(different  azoles-3-yl)-2-pyridine carboxamide,
60) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-([1,3,4] thiadiazoles-2-yl)-2-pyridine carboxamide,
61) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-([1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
62) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl carbonyl-thiazol-2-yl)-2-pyridine carboxamide,
63) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(pyrimidine-4-yl)-2-pyridine carboxamide,
64) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(pyridine-2-yl)-2-pyridine carboxamide,
65) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-ethoxy carbonyl-thiazol-2-yl)-2-pyridine carboxamide,
66) 3-(pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
67) 3-(6-methoxyl group-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
68) 3-(pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
69) 3-phenoxymethyl-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
70) 3-phenyl sulfenyl methyl-6-(4-methyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
71) 3-phenyl methyl-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
72) 3-(4-fluoro-phenyl methyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
73) 3-(4-dimethyl aminoethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
74) 3-(4-dimethylaminomethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
75) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole-4-yl)-2-pyridine carboxamide,
76) 3-(4-formyl-dimethylamino methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
77) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(4-hydroxyethyl-thiazol-2-yl)-2-pyridine carboxamide,
78) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-hydroxyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
79) 3-(6-methoxycarbonyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
80)3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
81) 3-(pyrimidine-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
82) 3-(6-hydroxymethyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
83) 3-[4-(1-methylpyrrolidin-3-base oxygen base)-phenyl sulfenyl]-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
84) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
85) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
86) 3-(1-oxygen base-6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
87) 3-(4-diethyl amino base oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
88) 3-(4-tetramethyleneimine oxyethyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
89) 3-(6-dimethylamino ethoxy-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
90) 3-(pyrazoles-4-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
91) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
92) 3-(4-carbamyl ylmethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
93) 3-(5-bromo-6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
94) 3-[4-(2-hydroxyethyl-phenyl sulfenyl)]-6-(4H-[1,2,4]-triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
95) 3-[4-(2-hydroxyethyl-phenyl sulfenyl)]-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
96) 3-(pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
97) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
98) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole is [5,4-b] pyridine-2-yl also)-2-pyridine carboxamide,
99) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
100) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,5] thiadiazoles-3-yl)-2-pyridine carboxamide,
101) 3-(2,3-Dihydrobenzofuranes-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
102) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methoxyl group-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
103) 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-cyclopropyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
104) 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
105) 3-(2-fluoro-pyridin-4-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
106) 3-(2-methoxyl group-pyrimidine-5-base sulfenyl)-6-(2H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
107) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
108) 3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
109) 3-(4-diethylamino formyl radical methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
110) 3-(6-cyclopropyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
111) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
112) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(pyrazoles-4-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
113) 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
114) 3-(4-dimethylamino alkylsulfonyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
115) 3-(5-fluoro-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
116) 3-(2,3-Dihydrobenzofuranes-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
117) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] triazine-3-yl)-2-pyridine carboxamide,
118) 3-(4-carboxyl-phenyl sulfenyl)-6-(5-methyl-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
119) 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(pyrazine-2-yl)-2-pyridine carboxamide,
120) 3-(imidazo-[1,2-a] pyridine-6-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
121) 3-(2-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
122) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazole is [4,5-b] pyridine-2-yl also)-2-pyridine carboxamide,
123) 3-(5-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
124) 3-(4,4-difluoro-methoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(pyrazine-2-yl)-2-pyridine carboxamide,
125) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
126) 3-(6-hydroxyethyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
127) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
128) 3-(2-methyl-imidazo-[1,2-a]-pyridine-6-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
129) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-hydroxymethyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
130) 3-[4-(2-hydroxyethyl)-phenyl sulfenyl]-6-(4-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
131) 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(5-hydroxyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
132) 3-(1-methyl isophthalic acid H-indazole-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
133) 3-(3-methyl-[1,2,4]-triazolo-[4,3-a]-pyridine-7-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
134) 3-(1-oxygen base-6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide,
135) 3-(6-hydroxymethyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
136) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
137) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
138) 3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
139) 3-[4-(1H-imidazoles-1-yl)-phenyl sulfenyl]-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide,
140) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
141) 3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide,
142) 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide,
143) 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide,
144) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(4,5-dimethyl-thiazol-2-yl)-2-pyridine carboxamide,
145) 3-(4-fluoro-phenyl sulfenyl)-6-(4,5-dimethyl-4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
146) 3-(4-(1-methoxy ethyl)-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
147) 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-2-pyridine carboxamide,
148) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(5-trifluoromethyl thiazole-2-yl)-2-pyridine carboxamide,
149) 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-trifluoromethyl thiazole-2-yl)-2-pyridine carboxamide,
150) 3-(3-fluoro-4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
151) 3-[4-(1,1-dimethyl-1-hydroxymethyl)-phenyl sulfenyl]-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide,
152) 3-(3,4-two fluoro-phenyl sulfenyls)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
153) 3-(3,5-two fluoro-phenyl sulfenyls)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
154) 3-(1-methyl-2-oxo-2,3-dihydro-1H-indoles-5-base sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
155) 3-(6-methyl-pyridine-3-sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] Triazolopyridine-2-yl)-2-pyridine carboxamide,
156) 3-(4-ethoxyl methyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
157) 3-(6-oxo-1,6-5 hydrogen-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
158) 3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide,
159) 3-(4-hydroxyl-oxethyl-phenyl sulfenyl)-6-(4-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-[1,2]-pyrazole-3-yl)-2-pyridine carboxamide.
16. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide.
17. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(4-fluoro-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide.
18. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(4-methoxyl group-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methoxymethyl-thiazol-2-yl)-2-pyridine carboxamide.
19. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-(thiazol-2-yl)-2-pyridine carboxamide.
20. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide.
21. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(hydroxyl-oxethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide.
22. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide.
23. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(4-hydroxyethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(thiazol-2-yl)-2-pyridine carboxamide.
24. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(6-methyl-pyridin-3-yl-sulfenyl)-6-(4H-[1,2,4] triazole-3-base-sulfenyl)-N-(4-methyl-thiazol-2-yl)-2-pyridine carboxamide.
25. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide.
26. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-2-pyridine carboxamide.
27. the compound of claim 1 or its pharmacy acceptable salt, described compound is 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-([1,2,4] thiadiazoles-5-yl)-the 2-pyridine carboxamide.
28. the compound of claim 1 or its pharmacy acceptable salt, described compound is 3-(4-dimethylamino ethoxy-phenyl sulfenyl)-6-(4H-[1,2,4]-triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4] thiadiazoles-2-yl)-the 2-pyridine carboxamide.
29. the compound of claim 1 or its pharmacy acceptable salt, described compound is 3-[4-(a 2-hydroxyethyl-phenyl sulfenyl)]-6-(5-methyl-4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-the 2-pyridine carboxamide.
30. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(6-methyl-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide.
31. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(3-methyl-[1,2,4]-thiadiazoles-5-yl)-2-pyridine carboxamide.
32. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(6-oxyethyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(pyrazine-2-yl)-2-pyridine carboxamide.
33. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(6-methoxyl group-pyridin-3-yl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide.
34. the compound of claim 1 or its pharmacy acceptable salt, described compound are 3-(4-methoxymethyl-phenyl sulfenyl)-6-(4H-[1,2,4] triazole-3-base sulfenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-2-pyridine carboxamide.
35. be used for the pharmaceutical composition that contains following (1)-(3) of treatment, prevention and/or the delayed onset of type ii diabetes:
(1) compound shown in the formula of claim 1 (I),
(2) be selected from one or more compounds of following (a)-(g),
(a) other activators of glucokinase,
(b) biguanides,
(c) the PPAR agonist,
(d) Regular Insulin,
(e) somatostatin,
(f) alpha-glucosidase inhibitor and
(g) secretion of insulin promotor,
(3) pharmaceutically acceptable carrier.
36. activators of glucokinase, this activator is an effective constituent with the compound of claim 1 or 2.
37. treatment of diabetes and/or preventive, this treats and/or prevents agent is effective constituent with the compound of claim 1 or 2.
38. fat treat and/or prevent agent, this treats and/or prevents agent is effective constituent with the compound of claim 1 or 2.
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Citations (2)

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Publication number Priority date Publication date Assignee Title
JPS5795984A (en) * 1980-12-05 1982-06-15 Tanabe Seiyaku Co Ltd Pyridinecarboxamide derivative and its preparation
JPS58121215A (en) * 1982-01-14 1983-07-19 Tanabe Seiyaku Co Ltd Antiallergic agent

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5795984A (en) * 1980-12-05 1982-06-15 Tanabe Seiyaku Co Ltd Pyridinecarboxamide derivative and its preparation
JPS58121215A (en) * 1982-01-14 1983-07-19 Tanabe Seiyaku Co Ltd Antiallergic agent

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