CN102666485A - Alkene oxindole derivatives and their uses to treat obesity, diabetes and hyperlipidemia - Google Patents

Alkene oxindole derivatives and their uses to treat obesity, diabetes and hyperlipidemia Download PDF

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Publication number
CN102666485A
CN102666485A CN2010800418192A CN201080041819A CN102666485A CN 102666485 A CN102666485 A CN 102666485A CN 2010800418192 A CN2010800418192 A CN 2010800418192A CN 201080041819 A CN201080041819 A CN 201080041819A CN 102666485 A CN102666485 A CN 102666485A
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China
Prior art keywords
phenyl
dihydro
fork
oxo
indoles
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Chinese (zh)
Inventor
陈力
冯立春
黄孟伟
李佳
南法俊
庞涛
于立芳
张玫
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Priority claimed from PCT/CN2009/074060 external-priority patent/WO2011032320A1/en
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Abstract

A compound of formula (I) as well as pharmaceutically acceptable salt thereof, wherein R1 to R7 have the significance given in claim 1, can be used as a medicament.

Description

Alkene oxindole derivatives and be used for treatment of obesity, the application of mellitus and hyperlipidaemia
The present invention relates to as the acvator of AMP-activated protein kinase (AMPK) and can be used for treatment or prophylactic compound, said disease relates to AMPK regulates, like obesity, and dyslipidemia, hyperglycemia, 1 type or diabetes B.
The present invention relates to formula (I) compound particularly
Figure BDA0000145086800000011
Wherein
R 1Be hydrogen, halogen, alkoxyl group, cyanic acid, haloalkyl, alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy or alkyl-carbonyl;
R 2Be hydrogen, halogen, alkoxyl group, cyanic acid, haloalkyl, alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy or alkyl-carbonyl;
R 3Be hydrogen, halogen, alkoxyl group, cyanic acid, haloalkyl, alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy or alkyl-carbonyl;
R 4Be hydrogen, halogen, alkoxyl group, cyanic acid, haloalkyl, alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy or alkyl-carbonyl;
R 5Be alkyl, hydroxyalkyl, naphthenic base, phenylalkyl, halogenophenyl alkyl; Phenyl, substituted phenyl, thienyl or pyridyl, wherein substituted phenyl is by 1 to 3 substituted phenyl of substituting group, and said substituting group is independently selected from: alkyl; Alkoxyl group, halogen, cyanic acid, haloalkyl; Alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy and alkyl-carbonyl;
R 6Be alkyl, hydroxyalkyl, naphthenic base, phenylalkyl, halogenophenyl alkyl; Phenyl, substituted phenyl, thienyl or pyridyl, wherein substituted phenyl is by 1 to 3 substituted phenyl of substituting group, and said substituting group is independently selected from: alkyl; Alkoxyl group, halogen, cyanic acid, haloalkyl; Alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy and alkyl-carbonyl;
Condition is R 5And R 6All not p-methoxy-phenyl simultaneously;
R 7Be substituted phenyl, pyridyl, substituted pyridyl, thiazolyl; Substituted thiazolyl or carboxyl, wherein substituted phenyl is by 1 to 3 substituted phenyl of substituting group, and said substituting group is independently selected from: alkyl; Hydroxyl, alkoxyl group, carboxyl; Alkoxy carbonyl alkyl, alkyl amino-carbonyl, carboxyl alkoxyl group; Alkoxy carbonyl, the amino carbonyl of alkoxy carbonyl alkoxyl group and alkyl sulfonyl, wherein substituted pyridyl and substituted thiazolyl are the pyridyl and the thiazolyls of alkoxy carbonyl or carboxyl substituted; And
Condition is to work as R 5And R 6In one be that phenyl and another are phenyl, when aminomethyl phenyl or alkoxyl phenyl, R then 7It is alkoxycarbonylphenyl;
N is 0 or 1;
Or its medicinal salt or ester.
The invention still further relates to the medicine that is used to prepare the method for these novel cpds and contains them.The compounds of this invention has activation to AMP (amp)-activated protein kinase, and this causes blood sugar to reduce.Therefore, the invention still further relates to these compounds and be used for treatment or prophylactic application, said disease relates to AMPK regulates, like obesity, and dyslipidemia, hyperglycemia, 1 type or diabetes B.
Obesity and diabetes B, hypertension and cardiovascular diseases are to be characterised in that glucose and the serious disorderly disease of lipid metabolism, and this seriously influences the Health and Living quality of affected individuals.The increased popularity of these diseases makes finds that being used to treat this syndromic novel drugs target becomes eager task.
The AMP-activated protein kinase is taken on cellular energy sensor and instrumentality.It is inductive cell AMP by passing through metabolic stress: the ATP ratio increases and activation.In case activation; AMPK just connects the catabolic pathway that produces ATP and cuts off the metabolic pathway of synthesizing (Hardie that consumes ATP through the expression of the crucial transcription factor of activity and the chronic adjusting of acute adjusting key enzyme in metabolism; DG.Nature reviews 8 (2007b), 774-785; Woods, A etc., Molecular and cellular biology 20 (2000), 6704-6711).The growth evidence of the AMPK of glucose and lipid metabolism being regulated influence makes it become potential drug target (Carling, D.Trends Biochem Sci 29 (2004), the 18-24 that is used to treat mellitus and metabolism syndrome; Hardie, DG.Annual review of pharmacology and toxicology 47 (2007a), 185-210; Kahn, BB etc., Cellmetabolism 1 (2005), 15-25; Long, YC etc., The Journal of clinical investigation 116 (2006), 1776-1783).
On the physiology level; This notion has obtained two kinds of adipocyte factors (adipokines); Be the support of Leptin and adiponectin, said two kinds of adipocyte factors are all brought into play excellent influence (Friedman, JM and Halaas for glucose and lipid metabolism; JL.Nature 395 (1998), 763-770; Muoio, DM etc., Diabetes 46 (1997), 1360-1363; Yamauchi, T etc., Nature medicine 7 (2001), 941-946).Recent researchs and proposes: Leptin and adiponectin are brought into play their antidiabetic effect through activation AMPK.(Nature 415 (2002) for Minokoshi, Y etc., 339-343) through direct activation AMPK and through hypothalamus-adrenergic approach and stimulated muscle Fatty Acid Oxidation for Leptin.Adiponectin is stimulated in vitro glucose uptake and Fatty Acid Oxidation through activation AMPK.In addition, it brings into play its hypoglycemia effect through reducing PEPCK and G6Pase expression, and (Nature medicine 8 (2002) for Yamauchi, T etc., 1288-1295) and the administration of dominant negative α 1 adenovirus reverses this effect in vivo.
On the pharmacology level; AMPK has further obtained the support of discovery of the existing antidiabetic medicine of two kinds of main types as the notion of the potential target that is used to treat metabolism syndrome: U 25560 (rosiglitazone, troglitazone and pioglitazone) and biguanides (N1,N1-Dimethylbiguanide and phenformin) be activation AMPK in cultured cells and in the body.Rosiglitazone is considered to the PPAR gamma agonist traditionally, and through the differentiation of adipocyte bring into play its antidiabetic effect (Semple, RK etc., The Journal of clinical investigation 116 (2006), 581-589).Recent discovery indicates: in the antidiabetic effect of rosiglitazone, possibly relate to AMPK (Brunmair, B etc., The Journal of biological chemistry 277 (2002), 25226-25232; Kadowaki, T etc., The Journal of clinical investigation 116 (2006), 1784-1792).At N1,N1-Dimethylbiguanide; Under a kind of situation of the existing anti-diabetic medicament that does not have the fixed mechanism of action; Recent research proves: it can be through suppressing title complex I activation AMPK (El-Mir in vitro and in vivo; MY etc., The Journal of biological chemistry 275 (2000), 223-228; Owen, MR etc., The Biochemical journal 348Pt 3 (2000), 607-614; Zhou, G etc., The Journal of clinical investigation 108 (2001); 1167-1174); And the hypoglycemia effect can be blocked through knocking out its upper reaches kinases LKB1 fully, thereby proof AMPK is keying action (Shaw, RJ etc. aspect the antidiabetic effect of mediation N1,N1-Dimethylbiguanide; Science (New York) N.Y.310 (2005), 1642-1646).
Recently, Cool and co-worker identify a kind of little direct AMPK acvator, A-769662, and it brings into play antidiabetic effect in vivo, and (Cell metabolism 3 (2006), 403-416) for Cool, B etc.A kind of little AMPK acvator is identified in the laboratory of Jia Li; PT1; It is with the AMPK α 2398 and α 1394 of the active activation inactive form of micro-molar concentration, and brings into play some cytosiies (Pang, T etc.; The Journal of biological chemistry 283 (2008), 16051-16060).
Have been found that compound of the present invention is effective AMPK acvator.Therefore, compound of the present invention can be used to treat or prevent to relate to the disease that AMPK regulates, like obesity, and dyslipidemia, hyperglycemia, 1 type or diabetes B.
As used herein, term " alkyl " representes to contain 1 to 8 alone or in combination, and preferred 1 to 6, the more preferably saturated straight chain or the branched-chain alkyl of 1 to 4 carbon atom, methyl for example, ethyl, propyl group, sec.-propyl, 1-butyl, the 2-butyl and the tertiary butyl.Preferably " alkyl " is methyl, ethyl, sec.-propyl and the tertiary butyl.
Group alkyl-O-represented alone or in combination in term " alkoxyl group ", and wherein " alkyl " as above defines; Methoxyl group for example, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, 2-butoxy and tert.-butoxy.Preferred alkoxyl group is methoxyl group and oxyethyl group, and more preferably methoxyl group.
Term " naphthenic base " is meant alone or in combination and contains 3 to 7 carbon atoms, the saturated carbon ring of preferred 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.Preferred naphthenic base is a cyclohexyl.
Term " halogen " is meant fluorine, chlorine, bromine or iodine.Halogen is fluorine or chlorine preferably.
Term " carboxyl " is meant group-COOH alone or in combination.
Term " carbonyl " be meant alone or in combination group-C (O)-.
Term " amino " is meant primary amino (NH alone or in combination 2-), secondary amino group (NH-) or uncle amino (N-).
Term " alkylthio " is meant group-S-alkyl alone or in combination.
Term " alkylsulfonyl " is meant group-S (O) alone or in combination 2-.
Can exist with their form of pharmaceutical salts according to compound of the present invention.Term " pharmaceutical salts " is meant biological effectiveness and the characteristic of hold mode (I) compound and conventional acid additive salt or the base addition salt that is formed by suitable nontoxicity organic or inorganic acid or organic or inorganic alkali.Acid salt for example comprises that salt that those derive from mineral acid example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, thionamic acid, phosphoric acid and nitric acid and those derive from the salt of organic acid such as tosic acid, Whitfield's ointment, methylsulfonic acid, oxalic acid, succsinic acid, Hydrocerol A, oxysuccinic acid, lactic acid, fumaric acid etc.Base addition salt comprises that those derive from ammonium, potassium, sodium and quaternary ammonium hydroxide such as tetramethylammonium hydroxide those.With medical compounds chemically modified salify is physics and chemicalstability, water absorbability, flowability and the deliquescent technology that the well-known acquisition compound of pharmaceutical chemistry teacher improves.It for example is described in Bastin R.J. etc., and Organic Process Research & Development 2000,4 is among the 427-435; Or in Ansel, H. etc., In:Pharmaceutical Dosage Forms and Drug Delivery Systems, the 6th edition (1995), the 196th with the 1456-1457 page or leaf in.The sodium salt of formula (I) compound preferably.
" medicinal ester " is meant that formula (I) compound can derive at functional group place, so that the verivate that can transform back into parent compound in vivo to be provided.These examples for compounds comprise on the physiology unsettled ester derivative in acceptable and the metabolism, like the methoxyl group methyl esters, and methylthio group methyl esters and new pentane acyloxy methyl esters.In addition, any physiologically acceptable Equivalent of general formula (I) compound is similar to unsettled ester in the metabolism, and it can generate the parent compound of general formula (I) in vivo, within the scope of the invention.The preferably methyl esters and the ethyl ester of formula (I) compound.
Preferably according to the compound of formula (I), R wherein 1Be hydrogen, halogen or alkoxyl group.
Further preferably formula (I) compound, wherein R 1Be hydrogen, fluorine or chlorine.
Further preferably formula (I) compound, wherein R again 1Be hydrogen.
Preferred formula (I) compound, wherein R 2Be hydrogen, halogen or alkoxyl group.
Further preferably formula (I) compound, wherein R 2Be hydrogen or fluorine.
Also particularly preferably be formula (I) compound, wherein R 3Be hydrogen, halogen or alkoxyl group.
Also preferred formula (I) compound, wherein R 3Be hydrogen, fluorine, chlorine or methoxyl group.
Especially, preferably formula (I) compound, wherein R 3Be hydrogen.
In addition, preferably formula (I) compound, wherein R 4Be hydrogen, halogen or alkoxyl group.
Preferred formula (I) compound, wherein R 4Be hydrogen or fluorine.
Further preferred formula (I) compound, wherein R 5Be alkyl, halogenophenyl alkyl, phenyl, substituted phenyl; Thienyl or pyridyl, wherein substituted phenyl is by 1 to 3 substituted phenyl of substituting group, and said substituting group is independently selected from: alkyl, alkoxyl group; Halogen, cyanic acid, haloalkyl, alkylthio; Amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy and alkyl-carbonyl.
Especially, preferably formula (I) compound, wherein R 5Be phenyl, chloro-phenyl-, p-methoxy-phenyl, aminomethyl phenyl, cyano-phenyl, trifluoromethyl; The chlorofluorobenzene base, trimethoxyphenyl, difluorophenyl, dichlorophenyl, bromophenyl, chloro-trifluoromethyl benzene base; The methylthio group phenyl, aminosulfonyl phenyl, methylsulfonyl phenyl, thienyl, fluorophenyl, pyridyl; Two (trifluoromethyl) phenyl, isopropyl phenyl, neo-pentyl, isopentyl, the methyl carbonyl phenyl or the tertiary butyl.
Further preferably formula (I) compound, wherein R 5Be halogenophenyl or cyano-phenyl.
Also preferred formula (I) compound, wherein R 5Be chloro-phenyl-or cyano-phenyl.
In addition, preferably formula (I) compound, wherein R 6Be alkyl, hydroxyalkyl, naphthenic base, phenyl or halogenophenyl.
And, go back preferred formula (I) compound, wherein R 6It is alkyl or phenyl.
Have again, also preferred formula (I) compound, wherein R 6Be sec.-propyl or phenyl.
Especially, preferably formula (I) compound, wherein R 6Be methyl, phenyl, p-methoxy-phenyl, chloro-phenyl-, neo-pentyl, sec.-propyl, cyclohexyl, hydroxypropyl or the tertiary butyl.
Particularly preferably be formula (I) compound, wherein R 7Be substituted phenyl, substituted pyridyl, substituted thiazolyl or carboxyl, wherein substituted phenyl is by 1 to 3 substituted phenyl of substituting group; Said substituting group is independently selected from alkyl, hydroxyl, alkoxyl group, carboxyl; Alkoxy carbonyl alkyl, alkyl amino-carbonyl, carboxyl alkoxyl group; Alkoxy carbonyl, the amino carbonyl of alkoxy carbonyl alkoxyl group and alkyl sulfonyl, wherein substituted pyridyl and substituted thiazolyl are the pyridyl and the thiazolyls of alkoxy carbonyl or carboxyl substituted.
Also particularly preferably be formula (I) compound, wherein R 7Be carboxyl phenyl, alkoxycarbonylphenyl or carboxyl pyridine base.
Further preferably according to the compound of formula (I), R wherein 7Be carboxyl phenyl, methoxycarbonyl phenyl or carboxyl pyridine base.
Further preferably formula (I) compound, wherein R 7Be the ethoxy carbonyl phenyl, the methoxycarbonyl aminomethyl phenyl is by methyl and the substituted phenyl of methoxycarbonyl, carboxyl; The methoxycarbonyl phenyl, ethoxycarbonyl methoxy phenyl, sec.-propyl aminocarbonyl-phenyl, methoxycarbonyl pyridyl; The ethoxy carbonyl thiazolyl, p-methoxy-phenyl, trihydroxy-phenyl, hydroxy phenyl; Carboxyl phenyl, carboxyl p-methoxy-phenyl, carboxyl thiazolyl, carboxyl pyridine base or methanesulfonamido carbonyl phenyl.
Formula (I) compound further preferably, wherein n is 1.
Particularly preferably be formula (I) compound, said compound is selected from:
3-{2-oxo-3-[1-phenyl-second-(E)-fork]-2,3-dihydro-indoles-1-yl }-ethyl benzoate;
(3-{2-oxo-3-[1-phenyl-second-(E)-fork]-2,3-dihydro-indoles-1-yl }-phenyl)-methyl acetate;
2-methyl-5-{2-oxo-3-[1-phenyl-second-(E)-fork]-2,3-dihydro-indoles-1-yl }-oil of Niobe;
[2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indoles-1-yl]-acetate;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-7-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-(3-diphenylmethylene-2-oxo-2,3-dihydro-indoles-1-ylmethyl)-oil of Niobe;
3-{3-[1-(4-methoxyl group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{2-oxo-3-[1-phenyl-1-p-methylphenyl-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-(2-methoxyl group-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-cyanic acid-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{2-oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(3-chloro-4-fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{2-oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(3,4-two fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(3-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(2-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(3,5-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(2,3-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-methoxyl group-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(2-bromo-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(2-chloro-5-trifluoromethyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-4-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-6-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(3-bromo-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(2-methylthio group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{7-chloro-3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{2-oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{2-oxo-3-[1-phenyl-1-(4-sulfamyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(2-methylsulfonyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{2-oxo-3-[1-phenyl-1-thiene-3-yl--first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
(4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenoxy)-ETHYLE ACETATE;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-N-sec.-propyl-BM;
6-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-nicotinic acid methyl ester;
2-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-thiazole-4-ethyl formate;
3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(4-methoxyl group-benzyl)-1, the 3-dihydro-indol-2-one;
3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(3,4,5-trihydroxy--benzyl)-1, the 3-dihydro-indol-2-one;
3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-1-(3,4,5-trihydroxy--benzyl)-1, the 3-dihydro-indol-2-one;
3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(4-hydroxyl-benzyl)-1, the 3-dihydro-indol-2-one;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-methoxyl group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-(2-methoxyl group-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{2-oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{2-oxo-3-[1-phenyl-1-(2-trifluoromethoxy-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(3-chloro-4-fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{2-oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(3-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(3,5-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(2,3-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
2-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-methoxyl group-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
6-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-nicotinic acid;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-4-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-6-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(2-methylthio group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{2-oxo-3-[1-phenyl-1-pyridin-3-yl-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(2-chloro-5-trifluoromethyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(3,5-couple-trifluoromethyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{2-oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{2-oxo-3-[1-phenyl-1-(4-sulfamyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
(4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenoxy)-acetate;
3-{3-[1-(4-sec.-propyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(3,4-two fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-7-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{5-chloro-3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(2-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
2-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-thiazole-4-formic acid;
3-{3-[4-methyl isophthalic acid-phenyl-penta-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[3,3-dimethyl--1-phenyl-Ding-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[2-(4-chloro-phenyl)-1-phenyl-second-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[3,3-dimethyl--1-phenyl-Ding-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[4-methyl isophthalic acid-phenyl-penta-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-benzyl)-2-methyl-third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-fluoro-phenyl)-second-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl } phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[2-methyl isophthalic acid-phenyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-ethanoyl-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-cyclohexyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[2-methyl isophthalic acid-(4-trifluoromethyl-phenyl)-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-2-hydroxy-2-methyl-third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-cyanic acid-phenyl)-2-hydroxy-2-methyl-third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-cyanic acid-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-cyanic acid-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
6-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-pyridine-2-formic acid;
6-{3-[1-(4-cyanic acid-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-pyridine-2-formic acid;
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-cyanic acid-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-fluoro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
6-{3-[1-(4-fluoro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-pyridine-2-formic acid;
3-{3-[2-methyl isophthalic acid-pyridin-3-yl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-cyclohexyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[2-methyl isophthalic acid-(4-trifluoromethyl-phenyl)-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[2-methyl isophthalic acid-thiene-3-yl-)-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{5-chloro-3-[2-methyl isophthalic acid-(4-trifluoromethyl-phenyl)-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-ethanoyl-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
N-(3-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-benzoyl-)-Toluidrin;
N-(3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-benzoyl-)-Toluidrin; And
N-(3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-benzoyl-)-Toluidrin;
Or its medicinal salt or ester.
Also particularly preferably be formula (I) compound, said compound is selected from:
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-cyanic acid-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
6-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-pyridine-2-formic acid; And
6-{3-[1-(4-cyanic acid-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-pyridine-2-formic acid;
Or its medicinal salt or ester.
Compound of the present invention can be prepared by the mode of any routine.The proper method of synthetic these compounds provides in an embodiment.Usually, formula (I) compound can be according to the preparation of the scheme shown in following.
In following scheme, Ar is a phenyl, substituted phenyl, pyridyl; Substituted pyridyl, thiazolyl or substituted thiazolyl, wherein substituted phenyl is by 1 to 3 substituted phenyl of substituting group, and said substituting group is independently selected from alkyl; Hydroxyl, alkoxyl group, carboxyl; Alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl amino-carbonyl; The carboxyl alkoxyl group, the amino carbonyl of alkoxy carbonyl alkoxyl group and alkyl sulfonyl, wherein substituted pyridyl and substituted thiazolyl are the pyridyl and the thiazolyls of alkoxy carbonyl or carboxyl substituted.R8 is independently selected from: alkyl, and alkoxyl group, halogen, cyanic acid, haloalkyl, alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy or alkyl-carbonyl, as list-substituting group, two-substituting group or three-substituting group.R 1To R 7As above definition is only if point out in addition.
Scheme 1
Figure BDA0000145086800000141
A kind of method that is used for synthetic The compounds of this invention is shown in scheme 1, wherein prepares oxindole Ia.In this method, the condensation reaction between substituted oxindole II and the substituted methyl phenyl ketone III obtains intermediate compound IV, and it carries out linked reaction subsequently in the presence of copper salt catalyst, with preparation compound I a.
In the first step shown in the scheme 1, intermediate compound IV can be prepared by the condensation reaction between substituted oxindole II and the substituted methyl phenyl ketone III.Reaction can be in the presence of organic bases such as piperidines or tetramethyleneimine, and at organic solvent such as methyl alcohol, ethanol in toluene or its mixture, spends the night under refluxing.
Intermediate compound IV and aryl halide V coupling are to provide formula Ia compound.Linked reaction can with part as 2,2 '-dipyridyl, proline(Pro), N; The copper catalyst of N '-N-methylsarcosine or terepthaloyl moietie combination such as cuprous iodide (I) (CuI) exist down, and at suitable alkali such as yellow soda ash, salt of wormwood, cesium carbonate; Sodium methylate, sodium tert-butoxide, potassium tert.-butoxide, sodium hydride; Triethylamine, or 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) exists down, at suitable organic solvent such as acetonitrile; Methylene dichloride, THF, toluene, benzene; 1,4-two
Figure BDA0000145086800000151
alkane, N, dinethylformamide; Methyl-sulphoxide, in N-Methyl pyrrolidone or its mixture, the temperature between 100 to 180 ℃ was carried out under microwave exposure 15 to 60 minutes.Alternatively, do not having under the condition of microwave exposure, reaction can be carried out the longer reaction times (Angew.Chem.Int.Ed.42 (2003) 5400 for Ley, S.V. etc.) as 80 ℃ in the temperature that raises.
Scheme 2
Figure BDA0000145086800000152
Formula Ib compound can be according to scheme 2 preparations.In this method, the condensation reaction between compound IV and the commercially available reagent VI obtains midbody VII, and its reaction that is hydrolyzed subsequently is to provide formula Ib compound.
In the first step shown in the scheme 2, raw material IV can be through obtaining in the compound method shown in the scheme 1.Midbody VII can be through the preparation of the alkylated reaction between VI and the IV, and condition is to use alkali such as sodium hydride, salt of wormwood or cesium carbonate, and at organic solvent such as THF, N in dinethylformamide or its mixture, carried out several hours in room temperature.
At last, the hydrolysis of methyl esters VII provides compounds ib.The hydrolysis of methyl esters can be at mineral alkali such as Lithium Hydroxide MonoHydrate; The aqueous solution of sodium hydroxide or Pottasium Hydroxide exists down; At solvent such as methyl alcohol; 1, carried out several hours in room temperature in 4-two
Figure BDA0000145086800000161
alkane or the THF.
Scheme 3
Formula Ic compound can be according to scheme 3 preparations.This route is synthetic by the effective palladium catalysis of the height of the raw material that can obtain easily based on asymmetric substituted 3-(Diarylmethylidene (methylenyl)) dihydroindole ketone.Many combinations of substituted aniline XII and substituted iodobenzene XIII are used in this reaction.This reaction can be used N successfully in the presence of the Pd of catalytic amount (OAc) 2, dinethylformamide carries out as alkali as solvent and NaOAc.(Artur Pinto etc., Org.Lett.4927,2006) take place and need to accomplish in several hours at 110 ℃ in reaction usually.Acid amides X can through at coupling reagent as 1, the 3-NSC 57182 exists down, the linked reaction preparation between aniline VIII and the carboxylic acid IX.
Intermediate X II can be through the preparation of the alkylated reaction between XI and the X.Reaction needs sodium hydride usually, and salt of wormwood or cesium carbonate be as alkali, and in room temperature, at organic solvent such as THF or N, carries out several hours in the dinethylformamide.
Scheme 4
Figure BDA0000145086800000171
XIV can be by the method preparation of in scheme 3, describing.XIV successfully provides Id with the processing of boron tribromide in methylene dichloride.
Scheme 5
XV can be by the method preparation of in scheme 3, describing.At mineral alkali such as Lithium Hydroxide MonoHydrate; The aqueous solution of sodium hydroxide or Pottasium Hydroxide exists down; XV is at solvent such as methyl alcohol; 1, in 4-two alkane or the THF, sour Ie hour successfully is provided in the room temperature water skill.
Scheme 6
Formula And if Ig compound can be according to scheme 6 preparations.This route is based on nickel catalyzed carbon cyclisation (carboannulation) reaction (Ruixue Deng. etc., Org.Lett.5207,2007) of zincon XVII and undersaturated compounds X VI.
Raw material XVI can be according to the method preparation of in scheme 3, describing.
Scheme 7
Figure BDA0000145086800000181
Formula Ih and Ii compound can be according to scheme 7 preparations.At mineral alkali such as Lithium Hydroxide MonoHydrate; The aqueous solution of sodium hydroxide or Pottasium Hydroxide exists down; And if Ig are at solvent such as methyl alcohol; 1, in the room temperature water skill sour Ih and Ii hour are provided successfully in 4-two alkane or the THF.
Scheme 8
Figure BDA0000145086800000183
Formula Ij compound can be according to scheme 8 preparations.Committed step is in the presence of the Pd (PPh3) 4 at catalytic amount, palladium catalysis Heck-carbocyclic ringization (the Carbocyclization)/Suzuki-linked reaction between iodide XVIII and the boric acid XIX.This reacting balance ground carries out, and condition is to use CsF or thiophene-2-carboxylic acid copper as alkali (Reiko, Y. etc., J.Org.Chem.70,6972,2005; WingS.Cheung. etc., J.Org.Chem.70,3741,2005).
At mineral alkali such as Lithium Hydroxide MonoHydrate; The aqueous solution of sodium hydroxide or Pottasium Hydroxide exists down; XX is at solvent such as methyl alcohol; 1, in the room temperature water skill sour Ij hour is provided successfully in 4-two
Figure BDA0000145086800000184
alkane or the THF.Raw material XVIII can be according to the program preparation of in scheme 3, describing.
Scheme 9
Figure BDA0000145086800000191
Formula Ik compound can be according to scheme 9 preparations.Committed step is in the presence of the Pd (PPh3) 4 at catalytic amount, the palladium catalysis Heck-carbocyclic ringization/Suzuki-linked reaction between iodide XXVI and the boric acid XXVII.This reacting balance ground carries out, and condition is to use CsF or thiophene-2-carboxylic acid copper as alkali (Reiko, Y. etc., J.Org.Chem.70,6972,2005; Wing S.Cheung. etc., J.Org.Chem.70,3741,2005).
Acid amides XXVI can prepare through the alkylation between acid amides XXIV and the bromotoluene XXV described in scheme 3.Acid amides XXIV can be through making isocyanic ester XXII and the lithium reagent XXIII prepared in reaction that is produced by n-Butyl Lithium and acetylene.Isocyanic ester XXII can be through in organic solvent such as methylene dichloride, in the presence of saturated sodium bicarbonate aqueous solution, with TRIPHOSGENE 99.5 processing 2-iodo-aniline XXI and prepare.
Scheme 10
Figure BDA0000145086800000192
Formula Il compound can be according to scheme 10 preparations.At mineral alkali such as Lithium Hydroxide MonoHydrate; The aqueous solution of sodium hydroxide or Pottasium Hydroxide exists down; Ester Ik is at solvent such as methyl alcohol; 1, in room temperature water skill hour, sour Il is provided successfully in 4-two
Figure BDA0000145086800000193
alkane or the THF.
Scheme 11
Figure BDA0000145086800000201
Formula Im compound can be according to scheme 11 preparations.Acid Il handled several hours in the presence of coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride and organic bases such as DMAP with sulfonyloxy methyl amine, and compound I m successfully is provided.
The invention still further relates to a kind of method for preparing formula (I) compound, said method one of comprises the following steps:
(a) according to the compound of formula (A)
Figure BDA0000145086800000202
At R 7Reaction under-X and copper catalyst exist;
(b) according to the compound of formula (B)
Figure BDA0000145086800000203
At R 8Reaction under-I and palladium catalyst exist;
(c) according to the compound of formula (C)
Figure BDA0000145086800000211
Reaction in the presence of boron tribromide;
(d) according to the compound of formula (D)
At R 6Reaction under-ZnBr and nickel catalyzator exist;
(e) according to the compound of formula (E)
Figure BDA0000145086800000213
Reaction in the presence of alkali;
(f) according to the compound of formula (F)
At R 8-B (OH) 2With the reaction under the palladium catalyst existence;
(g) according to the compound of formula (G)
Figure BDA0000145086800000221
At MeSO 2NH 2With the reaction under the coupling reagent existence;
R wherein 1To R 7As above definition, wherein Ar is a phenyl, substituted phenyl, pyridyl or thiazolyl; Wherein substituted phenyl is by 1 or 2 substituted phenyl of substituting group, and described substituting group is independently selected from: alkyl, hydroxyl, alkoxyl group; Carboxyl, alkoxy carbonyl alkyl, alkyl amino-carbonyl, carboxyl alkoxyl group; Alkoxy carbonyl, alkoxy carbonyl alkoxyl group and alkyl sulfonyl amino carbonyl, wherein R 10By 1 to 3 substituted phenyl of substituting group, said substituting group is independently selected from: alkyl, alkoxyl group, halogen, cyanic acid, haloalkyl, alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy and alkyl-carbonyl, wherein R 9Be alkyl, R wherein 11Be alkyl, and wherein X is a chlorine or bromine.
R 9Preferably methyl or ethyl.R 11C preferably 1-C 4Alkyl, preferable methyl or ethyl, more preferably methyl.
The reaction of step (a) can with part as 2,2 '-dipyridyl, proline(Pro), N; The coupling reagent of N '-N-methylsarcosine or terepthaloyl moietie combination such as copper catalyst such as cuprous iodide (I) (CuI) exist down, and at suitable alkali such as yellow soda ash, salt of wormwood, cesium carbonate; Sodium methylate, sodium tert-butoxide, potassium tert.-butoxide, sodium hydride; Triethylamine, or 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) exists down, at suitable organic solvent such as acetonitrile; Methylene dichloride, THF, toluene, benzene; 1,4-two
Figure BDA0000145086800000222
alkane, N; Dinethylformamide, methyl-sulphoxide carries out in N-Methyl pyrrolidone or its mixture.Under microwave exposure, temperature of reaction can for example be carried out 15 to 60 minutes for example between 100 to 180 ℃.Alternatively, do not having under the condition of microwave exposure, reaction can be carried out the longer reaction times as 80 ℃ in the temperature that raises.
The reaction of step (b) can be used N in the presence of the Pd of catalytic amount (OAc) 2, dinethylformamide carries out as alkali as solvent and NaOAc.Reaction takes place and possibly accomplish in several hours in 110 ℃ usually.
Step (c) is preferably carried out in methylene dichloride.
Step (e) can be at solvent such as methyl alcohol; 1; In 4-two
Figure BDA0000145086800000223
alkane or the THF, for example carried out several hours in room temperature.Alkali is mineral alkali such as Lithium Hydroxide MonoHydrate preferably, the aqueous solution of sodium hydroxide or Pottasium Hydroxide.
The reaction of step (f) can be carried out in the presence of the Pd of catalytic amount (PPh3) 4.The preferred alkali that adopts.This reacting balance ground carries out, and condition is to use CsF or thiophene-2-carboxylic acid copper as alkali.
The reaction of step (g) can realize in the presence of coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride and organic bases such as DMAP.
The invention still further relates to formula (I) compound as therapeutic active substance.
The invention still further relates to a kind of pharmaceutical composition, said pharmaceutical composition comprises formula (I) compound and treatment inert support.
The application that formula (I) compound is used to prepare medicine is an one object of the present invention, and said medicine can be used for treating or preventing to relate to the disease that AMPK regulates.
The present invention relate to particularly formula (I) compound be used for the preparation be used for the treatment or prevents obesity, dyslipidemia, hyperglycemia, the application of the medicine of 1 type or diabetes B, particularly diabetes B.
Said medicine for example with the form of pharmaceutical prepn can be for example with the form oral administration of tablet, coated tablet, dragee, hard and soft gelatin capsule, solution, emulsion or suspensoid.But administration also can use the compound of as above definition of significant quantity for example with the suppository form rectal administration, perhaps for example carries out with the form administered parenterally of injection liquid.
Aforementioned pharmaceutical compositions can through will compound according to the present invention with inert pharmaceutically inorganic or organic carrier process and obtain.Lactose, the W-Gum or derivatives thereof, talcum, Triple Pressed Stearic Acid or its salt etc. can be as this type carriers that for example is used for tablet, coated tablet, dragee and hard gelatin capsule.The appropriate carriers of soft gelatin capsule does, vegetables oil for example, wax, fat, semisolid and liquid polyol etc.But depending on the character of active substance does not need carrier usually under the situation of soft gelatin capsule.Be used to prepare solution and syrupy appropriate carriers does, water for example, polyvalent alcohol, glycerine, plant wet goods.The suitable carrier that is used for suppository is for example natural or winterized stearin, wax, fat, semiliquid or liquid polyol etc.
In addition, pharmaceutical composition can contain sanitas, solubilizing agent, and stablizer, wetting agent, emulsifying agent, sweeting agent, tinting material, seasonings is used to change salt, buffer reagent, sequestering agent or the inhibitor of osmotic pressure.They can also contain valuable material on the other treatment.
Dosage depends on various factors such as administering mode, species, age and/or personal health state.The dosage of administration every day is about 5-400mg/kg, preferably about 10-100mg/kg, and can absorb singlely or in administration several times, distribute.
Formula (I) compound of making according to aforesaid method also is an one object of the present invention.
In addition, the invention still further relates to a kind of method that is used to treat or prevent to relate to the disease that AMPK regulates, said method comprises formula (I) compound of effective dosage.
The invention further relates to a kind of treatment or prevents obesity of being used for, dyslipidemia, hyperglycemia, the method for 1 type or diabetes B, particularly diabetes B, said method comprise formula (I) compound of effective dosage.
In addition, the invention still further relates to a kind of formula (I) compound that is used to prepare the medicine that can be used for treating the cancer that relates to the AMPK adjusting, and a kind of method for cancer that relates to the AMPK adjusting that is used to treat is provided.
The present invention is by the following example example that does not have restricted characteristic.Only if spell out in addition, respond, the known implication of those of ordinary skill that reaction conditions, abbreviation and symbol have organic chemistry filed.
Embodiment
Midbody uses one of following instrument purifying with final compound by hurried chromatogram: i) Biotage SP1 system and Quad 12/25Cartridge assembly.Ii) ISCO makes up (combi)-hurried chromatographic apparatus.The silica gel trade mark and pore size: i) KP-SIL
Figure BDA0000145086800000241
size of particles: 40-60uM; Ii) CAS registration number: silica gel: 63231-67-4, size of particles: 47-60 micron silica gel; Iii) ZCX is from Qingdao Haiyang Chemical Co., Ltd, hole: 200-300 or 300-400.
Midbody and final compound on reversed-phase column, use X BridgeTMPerp C by preparation HPLC 18(5um, OBDTM 30 * 100mm) posts or SunFire TMPerp C 18(5um, OBDTM 30 * 100mm) column purification.
The LC/MS spectrum uses MicroMass Plateform LC (WatersTM alliance2795-ZQ2000) to obtain.Standard LC/MS condition is (6min working time) as follows:
Acidic conditions: A: at H 20.1% formic acid among the O; B: 0.1% formic acid in acetonitrile;
Alkaline condition: A: at H 20.01%NH among the O 3.H 2O; B: acetonitrile;
Neutrallty condition: A:H 2O; B: acetonitrile.
Mass spectrum (MS): only report the ion of indication parent material usually, only and if point out that in addition the substance ion of quoting is positive substance ion (M+H) +
Being reflected among the Biotage Initiator Sixty of microwave-assisted carried out.
The NMR spectrum uses Bruker Avance 400MHz to obtain.
All that comprise air sensitive reagent are reflected under the argon gas atmosphere carries out.Only if point out in addition, reagent uses from commercial supplier former state under situation about not being further purified.
In reaction process, prepare under the situation of mixture of E and Z isomer, these isomer by described in this paper or method known to those skilled in the art such as chromatogram or Crystallization Separation.
Embodiment 1
3-[2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indoles-1-yl]-ethyl benzoate
Figure BDA0000145086800000251
3-(1-phenyl-ethylidene)-1, the 3-dihydro-indol-2-one
With oxindole (0.1332g, 1mmol), (1.4ml 1.2mmol) mixes in toluene methyl phenyl ketone; Add then tetramethyleneimine (0.17ml, 2mmol).With the mixture 3h that refluxes; Reaction is monitored by TLC.When reaction is accomplished, under reduced pressure remove and desolvate.Residuum is separated by hurried chromatographic column (gradient elution, the 10-25% ETHYLE ACETATE in sherwood oil), obtain 3-(1-phenyl-ethylidene)-1, the 3-dihydro-indol-2-one is yellow powder (200mg, 85%). 1H?NMR(400MHz，DMSO-d 6)δppm?2.70(s，3H)5.96(d，J＝7.83Hz，1H)6.51-6.57(m，1H)6.77(d，J＝7.58Hz，1H)7.00-7.10(m，1H)7.30-7.37(m，2H)7.44-7.58(m，3H)10.54(br.s.，1H)。MS is for C 16H 13NO calculated value 235, measured value (ESI +) [(M+H) +] 236.3-[2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indoles-1-yl]-ethyl benzoate
In the Schlenk pipe, the CuI that packs into (9.6mg, 0.050mmol, 5.0mol%), 3-(1-phenyl-ethylidene)-1, the 3-dihydro-indol-2-one (352.7mg, 1.5mmol), and K 2CO 3(276mg, 2.0mmol), emptying, and inflate again with argon gas.Under argon gas, add N, N '-dimethyl-ethylenediamine (11uL, 0.10mmol, 10mol%), the 3-iodo ethyl benzoate (278.8mg, 1.01mmol), and acetonitrile (1.5ml).With the effective ZX 21 of Schlenk (Teflon) valve seal, and reaction mixture stirred 23h in 80 ℃.Reaction is monitored by HPLC.When reaction is accomplished, under reduced pressure remove and desolvate.Residuum is separated by hurried chromatographic column (gradient elution, the 5-10% ETHYLE ACETATE in sherwood oil), obtain 3-[2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indoles-1-yl]-ethyl benzoate, be yellow powder (344mg, 90%). 1H?NMR(400MHz，CDCl 3)δppm?1.42(t，J＝7.20Hz，3H)2.87(s，3H)4.42(q，J＝7.07Hz，2H)6.25(d，J＝7.58Hz，1H)6.68-6.78(m，2H)7.09(t，J＝7.71Hz，1H)7.34-7.40(m，2H)7.47-7.58(m，3H)7.62-7.72(m，2H)8.11-8.19(m，2H)。MS is for C 25H 21NO 3Calculated value 383, measured value (ESI +) [(M+H) +] 383.9.
Embodiment 2
(3-{2-oxo-3-[1-phenyl-second-(E)-fork]-2,3-dihydro-indoles-1-yl }-phenyl)-methyl acetate
Figure BDA0000145086800000261
Be similar to embodiment 1, by (3-bromo-phenyl)-methyl acetate (commercially available) and 3-[1-phenyl-second-(E)-fork]-1, the 3-dihydro-indol-2-one begins, the preparation title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?2.77(s，3H)3.65(s，3H)3.81(s，2H)6.08(d，J＝7.33Hz，1H)6.66-6.72(m，2H)7.11(t，J＝7.33Hz，1H)7.35-7.44(m，5H)7.51-7.61(m，4H)。
Embodiment 3
2-methyl-5-{2-oxo-3-[1-phenyl-second-(E)-fork]-2,3-dihydro-indoles-1-yl }-oil of Niobe
Figure BDA0000145086800000262
Be similar to embodiment 1, by 5-bromo-2-methyl-oil of Niobe (commercially available) and 3-[1-phenyl-second-(E)-fork]-1, the 3-dihydro-indol-2-one begins, the preparation title compound. 1H NMR (400MHz, δ ppm 2.71 (s, 3H) 2.86 (s, 3H) 3.91 (s, 3H) 6.24 (d of chloroform-d); J=7.83Hz, 1H) 6.67-6.75 (m, 2H) 7.08 (t, J=7.83Hz, 1H) 7.34-7.37 (m; 2H) 7.43-7.47 (m, 1H) 7.49-7.56 (m, 4H) 8.05 (d, J=2.27Hz, 1H).
Embodiment 4
[2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indoles-1-yl]-acetate
Figure BDA0000145086800000271
3-(1-phenyl-ethylidene)-1, the 3-dihydro-indol-2-one
3-(1-phenyl-ethylidene)-1, the compound method of 3-dihydro-indol-2-one is described among the embodiment 1.[2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indoles-1-yl]-methyl acetate
With 3-(1-phenyl-ethylidene)-1, the 3-dihydro-indol-2-one (294mg 1mmol) is dissolved in the dry DMF, add then methyl bromoacetate (184mg, 1.2mmol).At last, with Cs 2CO 3(488mg 1.5mmol) adds with portion.With mixture in stirred overnight at room temperature.Reaction is monitored by HPLC.When reaction is accomplished, under reduced pressure remove and desolvate.Residuum is separated by hurried chromatographic column (gradient elution, the 5-10% ETHYLE ACETATE in sherwood oil), obtain [2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indoles-1-yl]-methyl acetate, be yellow powder (230mg, 75%).MS is for C 19H 17NO 3Calculated value 307, measured value (ESI +) [(M+1) +] 308.1.
[2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indoles-1-yl]-acetate
(50mg 0.16mmol) is dissolved among the Therapeutic Mineral Ice 1ml with [2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indoles-1-yl]-methyl acetate; Add 0.1ml water then.At last, add Lithium Hydroxide MonoHydrate (10mg).With the mixture stirred overnight.Reaction is monitored by HPLC.When reaction is accomplished, under reduced pressure remove and desolvate.Residuum is dissolved among the 2ml DMF is used for preparation HPLC, obtain [2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indoles-1-yl]-acetate, be white powder (11mg). 1H?NMR(400MHz，CDCl 3)δppm?2.82(s，3H)4.61(s，2H)6.20(d，J＝7.58Hz，1H)6.66-6.73(m，2H)7.14(t，J＝7.58Hz，1H)7.31(s，2H)7.46-7.54(m，3H)。MS is for C 18H 15NO 3Calculated value 293, measured value (ESI +) [(M+H) +] 294.1.
Embodiment 5
3-((3-((4-chloro-phenyl-) (phenyl) first-(E)-fork)-2-oxoindoline-1-yl) methyl) oil of Niobe
Figure BDA0000145086800000281
3-phenyl-propynoic acid phenyl amide
With aniline (1.86g, 20mmol) with the phenyl propynoic acid (3.22g 22mmol) is dissolved in the methylene dichloride (50ml), and in 0 ℃ with 1, (4.8g 23.2mmol) adds with portion the 3-NSC 57182.With mixture stirring at room 14h.Mixture toppled in the entry and with methylene dichloride (3x 15ml) extract.Organic layer is merged, with anhydrous sodium sulfate drying and concentrated in a vacuum.By hurried column chromatography purifying on silica gel,, 3-phenyl-propynoic acid phenyl amide 2.7g (62%) is provided with hexane-EtOAc (6: 1,4: 1 then) wash-out.
3-{ [phenyl-(3-phenyl-propioloyl)-amino]-methyl }-oil of Niobe
With 3-phenyl-propynoic acid phenyl amide (951.4mg, 4.3mmol), 3-brooethyl-oil of Niobe (1.2g, 5.16mmol) and Cs 2CO 3(2.1g 6.45mmol) is dissolved among the DMF (20ml).With mixture in stirring at room 16h.Mixture is toppled over entry and used ethyl acetate extraction, with anhydrous sodium sulfate drying and under reduced pressure concentrated.By hurried column chromatography purifying on silica gel,, 3-{ [phenyl-(3-phenyl-propioloyl)-amino]-methyl is provided with hexane-EtOAc (6: 1,4: 1 then) wash-out }-oil of Niobe 1.03g (65%).
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
To 3-{ [phenyl-(3-phenyl-propioloyl)-amino]-methyl }-(369.4mg 1mmol) in the solution in THF (5ml), adds acid chloride (II) (11.2mg in room temperature to oil of Niobe; 0.05mmol); Triphenyl phosphine (26.2mg, 0.1mmol), 1-chloro-4-iodobenzene (262.3mg; 1.1mmol) and cesium fluoride (456mg, 3mmol).With solution in 110 ℃, under argon gas atmosphere, stir 3h.After the water quencher, mixture is used ethyl acetate extraction, with dried over mgso and under reduced pressure concentrated.With residuum by hurried column chromatography purifying on silica gel; With (hexane/ethyl acetate=5/1) wash-out; Obtain 3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe, yield 297mg (62%); 1H NMR (CDCl 3, 300MHz) δ ppm8.00 (s, 1H), 7.92 (d, 1H), 7.50 (d, 1H), 7.26-7.43 (m, 10H), 7.08 (dt, 1H), 6.71 (dt, 1H), 6.59 (d, 1H), 6.52 (d, 1H), 4.95 (s, 2H), 3.90 (s, 3H).
Embodiment 6
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-7-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000291
Be similar to embodiment 5, by 1-chloro-4-iodo-benzene (commercially available) and 3-{ [(2-fluoro-phenyl)-(3-phenyl-propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?3.88(s，3H)，5.11(s，2H)，6.22(d，1H)，6.61-6.67(m，1H)，6.82-6.89(dd，1H)，7.26-7.43(m，10H)，7.52(d，1H)，7.92(d，1H)，8.01(s，1H)。
Embodiment 7
3-(3-diphenylmethylene-2-oxo-2,3-dihydro-indoles-1-ylmethyl)-oil of Niobe
Be similar to embodiment 5, by iodo-benzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm8.01(s，1H)，8.00(d，1H)，7.93(d，1H)，7.33-7.52(m，12H)，7.05(dt，1H)，6.66(m，2H)，6.43(d，2H)，4.96(s，2H)，3.91(s，3H)。
Embodiment 8
3-{3-[1-(4-methoxyl group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000301
Be similar to embodiment 5, by 1-iodine 4-methoxyl group-benzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.01(s，1H)，7.94(d，1H)，7.49(d，1H)，7.26-7.38(m，8H)，7.06(m，1H)，6.94(m，2H)，6.63-6.70(m，3H)，4.97(s，2H)，3.91(s，3H)，3.88(s，3H)。
Embodiment 9
3-{2-oxo-3-[1-phenyl-1-p-methylphenyl-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000302
Be similar to embodiment 5, by 1-methyl-4-iodo-benzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.01(s，1H)，7.92(d，1H)，7.24-7.52(m，11H)，7.05(t，1H)，7.56-7.71(m，3H)，4.96(s，2H)，3.91(s，3H)，2.44(s，3H)。
Embodiment 10
3-{3-[1-(4-chloro-phenyl)-1-(2-methoxyl group-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000303
Be similar to embodiment 5, begin, the preparation title compound by 1-chloro-4-iodo-benzene (commercially available) and 3-({ [3-(2-methoxyl group-phenyl)-propioloyl]-phenyl-amino }-methyl)-oil of Niobe. 1H?NMR(CDCl 3，300MHz)δppm?7.99(s，1H)，7.92(d，1H)，7.26-7.49(m，7H)，6.93-7.15(m，4H)，6.72(t，1H)，6.61-6.64(m，2H)，4.93(dd，2H)，3.90(s，3H)，3.63(s，3H)。
Embodiment 11
3-{3-[1-(4-cyanic acid-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000311
Be similar to embodiment 5, by 4-iodo-cyanobenzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.00(s，1H)，7.93(d，1H)，7.74-7.76(m，2H)，7.35-7.51(m，9H)，7.10(t，1H)，6.56-6.72(m，2H)，6.35(d，1H)，4.95(s，2H)，3.91(s，3H)
Embodiment 12
3-{2-oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000312
Be similar to embodiment 5, by 1-iodo-4-trifluoromethyl-benzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)δppm?3.91(s，3H)，4.96(s，2H)，6.37(d，1H)，6.67(dd，2H)，7.08(t，1H)，7.35-7.40(m，7H)，7.49(d，2H)，7.71(d，2H)，7.95(d，1H)，8.01(s，1H)。
Embodiment 13
3-{3-[1-(3-chloro-4-fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Be similar to embodiment 5, by 2-chloro-1-fluoro-4-iodo-benzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.00(s，1H)，7.93(d，1H)，7.50(d，1H)，7.22-7.42(m，9H)，7.09(dt，1H)，6.73(dt，1H)，6.66(d，1H)，6.51(d，1H)，4.95(s，2H)，3.91(s，3H)。
Embodiment 14
3-{2-oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000322
Be similar to embodiment 5,, 3-trimethoxy-benzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl by 5-iodo-1,2 }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?3.76(s，6H)，3.91(s，3H)，3.94(s，3H)，4.96(s，2H)，6.55(s，2H)，6.61-6.71(m，4H)，7.06(t，1H)，7.38-7.40(m，5H)，7.53(d，1H)，7.91(d，1H)，8.02(s，1H)。
Embodiment 15
3-{3-[1-(3,4-two fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000331
Be similar to embodiment 5,, 2-two fluoro-4-iodo-benzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl by 1 }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?3.90(s，3H)，4.96(s，2H)，6.58(d，1H)，6.70(m，2H)，7.07-7.32(m，4H)，7.34-7.43(m，6H)，7.50(d，1H)，7.94(d，1H)，8.02(s，1H)。
Embodiment 16
3-{3-[1-(3-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000332
Be similar to embodiment 5, by 1-chloro-3-iodo-benzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.01(s，1H)，7.93(d，1H)，7.50(d，1H)，7.26-7.46(m，10H)，7.08(t，1H)，6.70(t，1H)，6.65(d，1H)，6.44(d，1H)，4.96(s，2H)，3.90(s，3H)。
Embodiment 17
3-{3-[1-(2-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000341
Be similar to embodiment 5, by 1-chloro-2-iodo-benzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.01(s，1H)，7.92(d，1H)，7.50-7.52(m，4H)，7.37-7.42(m，7H)，7.07(t，1H)，6.62-6.69(m，1H)，6.05(d，1H)，4.96(dd，2H)，3.91(s，3H)。
Embodiment 18
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000342
Be similar to embodiment 5, by 1-chloro-4-iodo-benzene (commercially available) and 3-{ [(4-fluoro-phenyl)-(3-phenyl-propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?3.91(s，3H)，4.94(s，2H)，6.25(dd，1H)，6.54(dd，2H)，6.75-6.80(m，1H)，7.10(d，2H)，7.33-7.54(m，8H)，7.94(d，1H)，7.98(s，1H)。
Embodiment 19
3-{3-[1-(3,5-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000343
Be similar to embodiment 5,, 3-two chloro-5-iodobenzenes (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl by 1 }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?3.92(s，3H)，4.95(s，2H)，6.47(d，1H)，6.65-6.78(m，2H)，7.13(t，2H)，7.33-7.43(m，8H)，7.52(d，1H)，7.93(d，1H)，8.01(s，1H)。
Embodiment 20
3-{3-[1-(2,3-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000351
Be similar to embodiment 5,, 2-two chloro-3-iodobenzenes (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl by 1 }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.00(s，1H)，7.92(d，1H)，7.33-7.54(m，9H)，7.23(dd，1H)，7.10(t，1H)，6.74(t，1H)，6.66(d，1H)，6.55(d，1H)，4.95(s，2H)，3.90(s，3H)。
Embodiment 21
4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000352
Be similar to embodiment 5, by 1-chloro-4-iodobenzene (commercially available) and 4-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?7.97(d，1H)，7.25-7.43(m，12H)，7.07(dt，1H)，6.71(dt，1H)，6.61(d，1H)，6.54(d，1H)，4.97(s，2H)，3.89(s，3H)。
Embodiment 22
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-methoxyl group-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000361
Be similar to embodiment 5, by 1-chloro-4-iodobenzene (commercially available) and 3-{ [(4-methoxyl group-phenyl)-(3-phenyl-propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?3.49(s，3H)，3.91(s，3H)，4.92(s，2H)，6.10(dd，1H)，6.51(d，1H)，6.62(dd，1H)，7.25-7.50(m，11H)，7.93(d，1H)，7.99(s，1H)。
Embodiment 23
3-{3-[1-(2-bromo-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000362
Be similar to embodiment 5, by 1-bromo-2-iodobenzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.01(s，1H)，7.93(d，1H)，7.71(d，1H)，7.30-7.53(m，11H)，7.04-7.09(m，2H)，6.62-7.04(m，3H)，6.42(d，1H)，6.02(d，1H)，4.88-5.05(m，2H)，3.91(s，3H)。
Embodiment 24
3-{3-[1-(2-chloro-5-trifluoromethyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000371
Be similar to embodiment 5, by 1-chloro-2-iodo-4-trifluoromethyl-benzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.01(s，1H)，7.93(d，1H)，7.63-7.67(m，2H)，7.33-7.52(m，7H)，7.10(t，1H)，6.64-6.71(m，2H)，5.98(d，1H)，4.87-5.04(m，2H)，3.91(s，3H)。
Embodiment 25
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-4-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000372
Be similar to embodiment 5, by 1-chloro-4-iodo-benzene (commercially available) and 3-{ [(3-fluoro-phenyl)-(3-phenyl-propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?4.97(s，2H)，6.39-6.51(m，2H)，7.25-7.45(m，11H)，7.53(d，1H)，7.99(d，1H)，8.00(s，1H)。
Embodiment 26
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-6-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000373
Be similar to embodiment 5, by 1-chloro-4-iodo-benzene (commercially available) and 3-{ [(3-fluoro-phenyl)-(3-phenyl-propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?3.90(s，3H)，4.96(s，2H)，6.48(d，1H)，7.10(d，1H)，7.19(d，1H)，7.31-7.50(m，11H)，7.94(d，1H)，7.98(s，1H)。
Embodiment 27
3-{3-[1-(3-bromo-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000381
Be similar to embodiment 5, by 1-bromo-3-iodobenzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.01(s，1H)，7.93(d，1H)，7.31-7.61(m，11H)，7.08(t，1H)，6.64-6.73(m，2H)，6.44(d，1H)，4.95(s，2H)，3.91(s，3H)。
Embodiment 28
3-{3-[1-(2-methylthio group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000382
Be similar to embodiment 5, by 1-iodo-2-methylthio group-benzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?2.31(s，3H)，3.90(s，3H)，5.00(dd，2H)，6.03(d，1H)，6.60-6.64(m，2H)，7.04(t，1H)，7.26-7.30(m，2H)，7.33-7.56(m，9H)，7.95(d，1H)，8.01(s，1H)。
Embodiment 29
3-{7-chloro-3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000391
Be similar to embodiment 5, by 1-chloro-4-iodo-benzene (commercially available) and 3-{ [(2-chloro-4-fluoro-phenyl)-(3-phenyl-propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?3.90(s，3H)，5.38(s，2H)，6.01(dd，1H)，6.80(dd，1H)，7.27-7.40(m，9H)，7.45-7.50(m，3H)，7.92(m，2H)。
Embodiment 30
3-{2-oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000392
Be similar to embodiment 5, by 1-iodo-3-trifluoromethyl-benzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.01(s，1H)，7.95(d，1H)，7.72(d，1H)，7.50-7.63(m，3H)，7.36-7.42(m，4H)，7.08(t，1H)，6.64-6.68(m，2H)，6.42(d，1H)，4.96(s，2H)，3.91(s，3H)。
Embodiment 31
3-{2-oxo-3-[1-phenyl-1-(4-sulfamyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000401
Be similar to embodiment 5, by 4-iodo-benzsulfamide (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?3.90(s，3H)，4.95(s，2H)，5.02(s，2H)，6.41(d，1H)，6.65-6.71(m，2H)，7.09(t，1H)，7.26-7.33(m，2H)，7.35-7.42(m，6H)，7.58-7.60(m，3H)，7.99(d，1H)，8.07(s，1H)。
Embodiment 32
3-{3-[1-(2-methylsulfonyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000402
Be similar to embodiment 5, by 1-iodo-2-methylsulfonyl-benzene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?1.89(s，1.5H)，2.50(s，1.5H)，3.90(s，3H)，4.98(dd，2H)，5.98(dd，1H)，6.65-6.68(m，2H)，7.07(m，1H)，7.35-7.58(m，8H)，7.61(t，1H)，7.78(t，1H)，7.99(d，1H)，8.02(d，1H)，8.20(d，1H)。
Embodiment 33
3-{2-oxo-3-[1-phenyl-1-thiene-3-yl--first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000411
Be similar to embodiment 5, by 3-iodo-thiophene (commercially available) and 3-{ [phenyl-(3-phenyl propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?3.91(s，3H)，4.96(s，2H)，6.65(d，1H)，6.76-6.82(m，2H)，7.06-7.11(m，2H)，7.33-7.43(m，8H)，7.50(d，1H)，7.92(d，1H)，8.01(s，1H)。
Embodiment 34
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000412
Be similar to embodiment 5, by 1-chloro-4-iodo-benzene (commercially available) and 3-{ [phenyl-(3-phenyl-propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?3.91(s，3H)，4.96(s，2H)，6.42(d，1H)，6.63-6.66(m，2H)，7.06(t，1H)，7.33-7.52(m，11H)，7.92(d，1H)，8.01(s，1H)。
Embodiment 35
3-{3-[1-(4-chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Be similar to embodiment 5, begin, the preparation title compound by 1-iodo-4-trifluoromethyl-benzene (commercially available) and 3-({ [3-(4-chloro-phenyl)-propioloyl]-phenyl-amino }-methyl)-oil of Niobe. 1H?NMR(300Hz，CDCl 3)：δppm?3.91(s，3H)，4.96(s，2H)，6.37(d，1H)，6.66-6.71(m，2H)，7.08(t，1H)，7.26-7.52(m，9H)，7.73(d，2H)，7.94(d，1H)，8.01(s，1H)。
Embodiment 36
(4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenoxy)-ETHYLE ACETATE
Figure BDA0000145086800000421
Be similar to embodiment 5, begin, the preparation title compound by 1-chloro-4-iodo-benzene (commercially available) and (4-{ [phenyl-(3-phenyl-propioloyl)-amino]-methyl }-phenoxy)-ETHYLE ACETATE. 1H?NMR(300Hz，CDCl 3)：δppm?1.28(t，3H)，4.26(q，2H)，4.57(s，2H)，4.84(s，2H)，6.51(d，1H)，6.67-6.71(m，2H)，6.83(d，2H)，7.08(t，1H)，7.24-7.42(m，11H)。
Embodiment 37
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-N-sec.-propyl-BM
Figure BDA0000145086800000422
Be similar to embodiment 5, by 1-chloro-4-iodo-benzene (commercially available) and N-sec.-propyl-3-{ [phenyl-(3-phenyl-propioloyl)-amino]-methyl }-BM begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?7.74(s，1H)，7.60(d，1H)，7.26-7.43(m，10H)，7.07(dt，2H)，6.70(t，1H)，6.68(d，1H)，6.53(d，1H)，5.99(d，1H)，4.94(s，2H)，4.26(m，1H)，1.26(s，3H)，1.24(s，3H)。
Embodiment 38
6-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-nicotinic acid methyl ester
Figure BDA0000145086800000431
Be similar to embodiment 5, by 1-chloro-4-iodo-benzene (commercially available) and 6-{ [phenyl-(3-phenyl-propioloyl)-amino]-methyl }-nicotinic acid methyl ester begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?3.93(s，3H)，5.10(s，2H)，6.54(d，1H)，6.57-6.75(m，2H)，7.08(t，1H)，7.28-7.44(m，10H)，8.20(d，1H)，9.16(s，1H)。
Embodiment 39
2-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-thiazole-4-ethyl formate
Be similar to embodiment 5, by 1-chloro-4-iodo-benzene (commercially available) and 2-{ [phenyl-(3-phenyl-propioloyl)-amino]-methyl }-thiazole-4-ethyl formate begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?1.39(t，3H)，4.44(q，2H)，5.27(s，2H)，6.58(d，1H)，6.78(t，1H)，6.88(d，1H)，7.13(t，1H)，7.31-7.43(m，9H)，8.10(s，1H)。
Embodiment 40
3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(4-methoxyl group-benzyl)-1, the 3-dihydro-indol-2-one
Figure BDA0000145086800000441
Be similar to embodiment 5, begin, the preparation title compound by 1-chloro-4-iodo-benzene (commercially available) and 3-phenyl-propynoic acid (4-methoxyl group-benzyl)-phenyl-acid amides. 1H?NMR(300Hz，CDCl 3)：δppm3.77(s，3H)，4.88(s，2H)，6.53(d，1H)，6.67-6.71(m，2H)，6.80(dd，1H)，6.85-6.90(m，2H)，7.07(t，1H)，7.19-7.43(m，10H)。
Embodiment 41
3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(3,4,5-trihydroxy--benzyl)-1, the 3-dihydro-indol-2-one; And
Embodiment 42
3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-1-(3,4,5-trihydroxy--benzyl)-1, the 3-dihydro-indol-2-one
Figure BDA0000145086800000442
3-phenyl-propynoic acid phenyl-(3,4,5-trimethoxy-benzyl)-acid amides
With 3-phenyl-propynoic acid phenyl amide (951.4mg, 4.3mmol), 5-brooethyl-1,2,3-trimethoxy-benzene (1.35g, 5.16mmol), and Cs 2CO 3(2.1g 6.45mmol) is dissolved among the DMF (20ml).With mixture in stirring at room 16h.Mixture is toppled in the entry and used ethyl acetate extraction, with anhydrous sodium sulfate drying and under reduced pressure concentrate.By hurried column chromatography purifying on silica gel,, 3-phenyl-propynoic acid phenyl-(3,4,5-trimethoxy-benzyl)-acid amides 1.03g (65%) is provided with hexane-EtOAc (6: 1,4: 1 then) wash-out.
3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(3,4,5-trimethoxy-benzyl)-1,3-dihydro-indol-2-one and 3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-1-(3,4,5-trimethoxy-benzyl)-1, the 3-dihydro-indol-2-one
To 3-phenyl-propynoic acid phenyl-(3,4,5-trimethoxy-benzyl)-acid amides (401.5mg; 1mmol) in the solution in THF (5ml), in room temperature add acid chloride (II) (11.2mg, 0.05mmol); Triphenyl phosphine (26.2mg, 0.1mmol), 1-chloro-4-iodobenzene (262.3mg; 1.1mmol) and cesium fluoride (456mg, 3mmol).With solution in 110 ℃, under argon gas atmosphere, stir 3h.After the water quencher, mixture is used ethyl acetate extraction, with dried over mgso and under reduced pressure concentrated.Residuum by hurried column chromatography purifying on silica gel, with (hexane/ethyl acetate=5/1) wash-out, is obtained 3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(3; 4,5-trimethoxy-benzyl)-1,3-dihydro-indol-2-one and 3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-1-(3; 4; 5-trimethoxy-benzyl)-1, the mixture of 3-dihydro-indol-2-one, yield 317mg (62%);
3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(3,4,5-trihydroxy--benzyl)-1,3-dihydro-indol-2-one and 3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-1-(3,4,5-trihydroxy--benzyl)-1, the 3-dihydro-indol-2-one
To 3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(3,4,5-trimethoxy-benzyl)-1; 3-dihydro-indol-2-one and 3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-1-(3,4,5-trimethoxy-benzyl)-1; 3-dihydro-indol-2-one (317mg; 0.62mmol) in the solution in methylene dichloride (5ml), (1M is at CH to add the solution of boron tribromide in room temperature 2Cl 2In, 3ml).With mixture in stirring at room 5h.Through pouring in the frozen water after the quencher, mixture is used ethyl acetate extraction, with dried over mgso and under reduced pressure concentrate.Residuum by hurried column chromatography purifying on silica gel, with (hexane/ethyl acetate=1/1) wash-out, is obtained 3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(3,4,5-trihydroxy--benzyl)-1,3-dihydro-indol-2-one (60mg). 1H NMR (300Hz, CDCl 3): δ ppm4.66 (s, 2H), 5.60 (b, 1H), 6.31 (s, 2H), 6.56 (d, 1H), 6.67-6.82 (m, 2H), 7.00-7.23 (m, 8H), 7.38 (d, 2H); And 3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-1-(3,4,5-trihydroxy--benzyl)-1,3-dihydro-indol-2-one (40mg). 1H?NMR(300Hz，CDCl 3)：δppm?4.72(s，2H)，5.33(b，1H)，6.05(b，1H)，6.40(s，2H)，6.44(d，1H)，6.67(t，1H)，6.82(d，1H)，7.00(d，2H)，7.10-7.15(m，3H)，7.23-7.26(m，2H)，7.37-7.46(m，3H)。
Embodiment 43
3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(4-hydroxyl-benzyl)-1, the 3-dihydro-indol-2-one
Figure BDA0000145086800000461
Be similar to embodiment 41, by 3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(4-methoxyl group-benzyl)-1, the 3-dihydro-indol-2-one begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?4.81(s，2H)，6.51(d，1H)，6.53-6.74(m，4H)，7.08-7.11(m，3H)，7.24-7.42(m，9H)。
Embodiment 44
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
With 3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe (94mg 0.2mmol) is dissolved in THF (2ml) and the water (2ml), and with LiOH.H 2(42mg 1mmol) adds with portion O.Mixture is stirred 16h in 50 ℃.Mixture is under reduced pressure concentrated, and be acidified to pH=3.By the preparation HPLC purifying 3-((3-((4-chloro-phenyl-) (phenyl) first-(E)-fork)-2-oxoindoline-1-yl) methyl) is provided phenylformic acid, is pale yellow powder.Yield 30mg (70%). 1H?NMR(CDCl 3，300MHz)δppm?8.06(s，1H)，7.99(d，1H)，7.55(d，1H)，7.29-7.43(m，10H)，7.09(t，1H)，6.74-6.65(m，2H)，6.55(d，1H)，
Embodiment 45
3-{3-[1-(4-fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000471
Be similar to embodiment 44, by 3-{3-[1-(4-fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.07(s，1H)，8.00(d，1H)，7.56(d，1H)，7.33-7.48(m，8H)，7.07-7.17(m，3H)，6.66-6.74(m，2H)，6.52(d，1H)，4.99(s，2H)。
Embodiment 46
3-{3-[1-(4-methoxyl group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000472
Be similar to embodiment 44, by 3-{3-[1-(4-methoxyl group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.07(s，1H)，8.00(d，1H)，7.55(d，1H)，7.26-7.38(m，8H)，7.07(m，1H)，6.94(m，2H)，6.65-6.71(m，3H)，4.98(s，2H)，3.88(s，3H)。
Embodiment 47
3-{3-[1-(4-chloro-phenyl)-1-(2-methoxyl group-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000473
Be similar to embodiment 44, by 3-{3-[1-(4-chloro-phenyl)-1-(2-methoxyl group-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.04(s，1H)，7.99(d，1H)，7，54(d，1H)，7.32-7.44(m，6H)，7.07-7.15(m，2H)，6.93-7.01(m，2H)，6.73(t，1H)，6.64(t，2H)，4.95(dd，2H)，3.90(s，3H)，3.72(s，3H)。
Embodiment 48
3-{2-oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Be similar to embodiment 44, by 3-{2-oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?4.98(s，2H)，6.40(d，1H)，6.68(dd，2H)，7.10(t，1H)，7.35-7.55(m，9H)，7.71(d，2H)，7.99(d，1H)，8.07(s，1H)。
Embodiment 49
3-{2-oxo-3-[1-phenyl-1-(2-trifluoromethoxy-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Be similar to embodiment 44, by 3-{2-oxo-3-[1-phenyl-1-(2-trifluoromethoxy-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1HNMR(300Hz，CDCl 3)：δppm?3.91(s，3H，)，5.96(s，2H)，6.37(d，1H)，6.64-6.72(m，2H)，7.07(dt，1H)，7.51-7.33(m，H)，7.70(d，2H)7.93(d，1H)，8.01(s，1H)。
Embodiment 50
3-{3-[1-(3-chloro-4-fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000491
Be similar to embodiment 44, by 3-{3-[1-(3-chloro-4-fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.07(s，1H)，8.01(d，1H)，7.56(d，1H)，7.34-7.45(m，6H)，7.22-7.28(m，3H)，7.11(dt，1H)，6.74(dt，1H)，6.68(d，1H)，6.53(d，1H)，4.98(s，2H)。
Embodiment 51
3-{2-oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Be similar to embodiment 44, by 3-{2-oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1HNMR(300Hz，CDCl 3)：δppm?3.79(s，6H)，3.94(s，3H)，4.98(s，2H)，6.55(s，2H)，6.61-6.72(m，4H)，7.08(t，1H)，7.40-7.45(m，5H)，7.58(d，1H)，7.99(d，1H)，8.07(s，1H)。
Embodiment 52
3-{3-[1-(3-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000501
Be similar to embodiment 44, by 3-{3-[1-(3-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.07(s，1H)，7.90(d，1H)，7.56(d，1H)，7.26-7.50(m，10H)，7.09(t，1H)，6.66-6.70(m，2H)，6.45(d，1H)，4.98(s，2H)。
Embodiment 53
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Be similar to embodiment 44, by 3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?4.97(s，2H)，6.26(dd，1H)，6.55(dd，2H)，6.77-6.80(m，1H)，7.10(d，2H)，7.33-7.48(m，7H)，7.53(d，2H)，8.01(d，1H)，8.04(s，1H)。
Embodiment 54
3-{3-[1-(3,5-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Be similar to embodiment 44, by 3-{3-[1-(3,5-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?4.96(s，2H)，6.48(d，1H)，6.65-6.78(m，2H)，7.13(t，2H)，7.33-7.43(m，8H)，7.56(d，1H)，7.98(d，1H)，8.08(s，1H)。
Embodiment 55
3-{3-[1-(2,3-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000512
Be similar to embodiment 44, by 3-{3-[1-(2,3-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.07(s，1H)，8.01(d，1H)，7.33-7.57(m，9H)，7.22-7.26(m，1H)，7.12(t，1H)，6.75(t，1H)，6.68(d，1H)，6.56(d，1H)，4.97(s，2H)。
Embodiment 56
2-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000521
Be similar to embodiment 44, by 2-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.10(d，1H)，7.32-7.48(m，11H)，7.18(d，1H)，7.11(t，1H)，6.75(t，1H)，6.65(d，1H)，6.58(d，1H)，5.39(s，2H)。
Embodiment 57
4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000522
Be similar to embodiment 44, by 4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.05(d，2H)，7.29-7.44(m，11H)，7.09(t，1H)，6.72(t，1H)，7.29(d，1H)，6.59(d，1H)，4.98(s，2H)，3.89(s，3H)。
Embodiment 58
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-methoxyl group-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Be similar to embodiment 44, by 3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-methoxyl group-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1HNMR(300Hz，CDCl 3)：δppm?3.49(s，3H)，4.95(s，2H)，6.10(dd，1H)，6.51(d，1H)，6.64(dd，1H)，7.25-7.45(m，10H)，7.54(d，1H)，8.00(d，1H)，8.05(s，1H)。
Embodiment 59
6-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-nicotinic acid
Figure BDA0000145086800000532
Be similar to embodiment 44, by 6-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-nicotinic acid methyl ester begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?5.19(s，2H)，6.56(d，1H)，6.58-6.77(m，2H)，7.09(t，1H)，7.28-7.44(m，10H)，8.30(d，1H)，9.26(s，1H)。
Embodiment 60
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-4-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000533
Be similar to embodiment 44, by 3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-4-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?4.97(s，2H)，6.39-6.51(m，2H)，7.25-7.45(m，11H)，7.53(d，1H)，7.99(d，1H)，8.00(s，1H)。
Embodiment 61
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-6-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000541
Be similar to embodiment 44, by 3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-6-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?4.88(s，2H)，6.40-6.429(m，1H)，7.08-7.10(m，1H)，7.20(d，1H)，7.31-7.38(m，10H)，7.42(d，1H)，7.90(d，1H)，7.94(s，1H)。
Embodiment 62
3-{3-[1-(2-methylthio group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000542
Be similar to embodiment 44, by 3-{3-[1-(2-methylthio group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?2.31(s，3H)，5.00(dd，2H)，6.04(d，1H)，6.63-6.64(m，2H)，7.07(t，1H)，7.26-7.30(m，2H)，7.33-7.46(m，6H)，7.58-7.60(m，2H)，7.99(d，1H)，8.07(s，1H)。
Embodiment 63
3-{2-oxo-3-[1-phenyl-1-pyridin-3-yl-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000551
Be similar to embodiment 44, by 3-{2-oxo-3-[1-phenyl-1-pyridin-3-yl-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?4.98(s，2H)，6.40(d，1H)，6.65-6.68(m，2H)，7.07(t，1H)，7.35-7.42(m，8H)，7.58(d，2H)，7.69(d，1H)，7.99(d，1H)，8.04(s，1H)。
Embodiment 64
3-{3-[1-(2-chloro-5-trifluoromethyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Be similar to embodiment 44, by 3-{3-[1-(2-chloro-5-trifluoromethyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.06(s，1H)，8.00(d，1H)，7.40-7.67(m，10H)，7.11(t，1H)，6.66-6.72(m，2H)，5.98(d，1H)，4.89-5.06(m，2H)，3.91(s，3H)。
Embodiment 65
3-{3-[1-(3,5-couple-trifluoromethyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000561
Be similar to embodiment 44, by 3-{3-[1-(3,5-is two-trifluoromethyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.24(s，1H)，7.95-8.10(m，4H)，7.78-7.87(m，3H)，7.67(d，2H)，7.29-7.58(m，6H)，7.21(t，1H)，6.68-6.71(m，2H)，6.27(d，1H)，4.98(s，2H)，3.91(s，3H)。
Embodiment 66
3-{2-oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000562
Be similar to embodiment 44, by 3-{2-oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.08(s，1H)，8.01(d，1H)，7.72(d，1H)，7.64-7.56(m，4H)，7.35-7.54(m，4H)，7.10(dt，1H)，6.66-6.70(m，2H)，6.33(dd，1H)，4.98(s，2H)。
Embodiment 67
3-{2-oxo-3-[1-phenyl-1-(4-sulfamyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000571
Be similar to embodiment 44, by 3-{2-oxo-3-[1-phenyl-1-(4-sulfamyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?4.97(s，2H)，5.17(s，2H)，6.42(d，1H)，6.64-6.71(m，2H)，7.08(t，1H)，7.26-7.60(m，11H)，7.97(s，1H)，8.00(s，1H)。
Embodiment 68
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000572
Be similar to embodiment 44, by 3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?4.96(s，2H)，6.42(d，1H)，6.63-6.66(m，2H)，7.06(t，1H)，7.33-7.52(m，11H)，7.92(d，1H)，8.01(s，1H)。
Embodiment 69
3-{3-[1-(4-chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Be similar to embodiment 44, by 3-{3-[1-(4-chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?4.98(s，2H)，6.38(d，1H)，6.68-6.73(m，2H)，7.08(t，1H)，7.26-7.52(m，9H)，7.72(d，2H)，8.01(d，1H)，8.08(s，1H)。
Embodiment 70
(4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenoxy)-acetate
Figure BDA0000145086800000582
Be similar to embodiment 44, begin the preparation title compound by (4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenoxy)-methyl acetate. 1HNMR(300Hz，CDCl 3)：δppm?4.56(s，2H)，4.85(s，2H)，6.51(d，1H)，6.53-6.73(m，2H)，6.83(d，2H)，7.08(t，1H)，7.24-7.42(m，11H)。
Embodiment 71
3-{3-[1-(4-sec.-propyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000591
Be similar to embodiment 44, by 3-{3-[1-(4-sec.-propyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?1.31(d，6H)，2.94-3.01(m，1H)，4.99(s，2H)，6.56(d，1H)，6.67(dd，2H)，7.08(t，1H)，7.27(s，4H)，7.38-7.42(m，6H)，7.51(d，1H)，7.99(d，1H)，8.08(s，1H)
Embodiment 72
3-{3-[1-(3,4-two fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000592
Be similar to embodiment 44, by 3-{3-[1-(3,4-two fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?4.97(s，2H)，6.51(d，1H)，6.71(m，2H)，7.08-7.26(m，4H)，7.34-7.43(m，6H)，7.56(d，1H)，8.00(d，1H)，8.05(s，1H)。
Embodiment 73
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-7-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000601
Be similar to embodiment 44, by 3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-7-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?5.13(s，2H)，6.32(d，1H)，6.63-6.67(m，1H)，6.82-6.89(dd，1H)，7.26-7.43(m，10H)，7.59(d，1H)，7.99(d，1H)，8.08(s，1H)。
Embodiment 74
3-{5-chloro-3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000602
Be similar to embodiment 44, by 3-{5-chloro-3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?4.97(s，2H)，6.58(m，2H)，7.05(dd，1H)，7.20(m，1H)，7.27-7.46(m，9H)，7.52(d，1H)，8.01(d，1H)，8.04(s，1H)。
Embodiment 75
3-{3-[1-(2-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000603
Be similar to embodiment 44, by 3-{3-[1-(2-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.06(s，1H)，7.99(d，1H)，7.50-7.57(m，3H)，7.37-7.44(m，7H)，7.07(t，1H)，6.63-6.70(m，2H)，6.05(d，1H)，4.97(dd，2H)。
Embodiment 76
2-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-thiazole-4-formic acid
Figure BDA0000145086800000611
Be similar to embodiment 44, by 2-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-thiazole-4-methyl-formiate begins the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?5.27(s，2H)，6.59(d，1H)，6.78(t，1H)，6.87(d，1H)，7.15(t，1H)，7.31-7.43(m，9H)，8.22(s，1H)。
Embodiment 77
3-[3-(4-methyl isophthalic acid-phenyl-penta-(Z)-fork)-2-oxo-2,3-dihydro-indoles-1-ylmethyl]-oil of Niobe
Figure BDA0000145086800000612
To 3-{ [(2-iodo-phenyl)-(3-phenyl-propioloyl)-amino]-methyl }-oil of Niobe (100mg, 0.2mmol) and Ni (PPh 3) 2I 2(16mg is 0.02mmol) at CH 2Cl 2In the degassing reflux solution (8ml), be added in CH 2Cl 23-methylbutyl zinc bromide (1ml) (151mg, 0.7mmol).Reactant in 40 ℃ of stirring 6h, is cooled to room temperature with solution then.Gained solution is diluted with ETHYLE ACETATE (50ml).(4%, 10ml), (3 * 10ml) wash salt solution with the HCl aqueous solution with organic layer.(3 * 10ml) strip with ETHYLE ACETATE with water layer.The organic layer that merges is used anhydrous sodium sulfate drying.After the filtration; Under reduced pressure remove desolvate and with residuum by column chromatography purifying on silica gel; Use the petroleum ether-ethyl acetate wash-out, obtain 3-{3-[4-methyl isophthalic acid-phenyl-penta-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl-oil of Niobe (24mg; 28%), is faint yellow solid. 1H NMR (300Hz, CDCl 3): δ ppm 0.88 (d, 6H), 1.43-1.55 (m, 2H), 1.68-1.72 (m, 1H), 2.93-2.99 (m, 2H); 3.91 (s, 3H), 4.89 (s, 2H), 6.64 (d, 1H), 7.05 (t; 1H), 7,15 (t, 1H), 7.28-7.38 (m, 4H), 7.40-7.47 (m; 3H), 7.62 (d, 1H), 7.91 (d, 1H), 7.95 (s, 1H); And 3-{3-[4-methyl isophthalic acid-phenyl-penta-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe (29mg, 33%), be faint yellow solid. 1H?NMR(300Hz，CDCl 3)：δppm0.88(d，6H)，1.36-1.44(m，2H)，1.64-1.68(m，1H)，3.33-3.38(m，2H)，3.91(s，3H)，5.04(s，2H)，6.01(d，1H)，6.58-6.61(m，2H)，6.96-7.02(t，1H)，7.26-7.29(m，2H)，7.37(t，2H)，7.43-7.52(m，3H)，7.93(d，1H)，8.03(s，1H)。
Embodiment 78
3-{3-[3,3-dimethyl--1-phenyl-Ding-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Be similar to embodiment 77, by tertiary butyl bromination zinc (commercially available) and 3-{ [(2-iodo-phenyl)-(3-phenyl-propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?0.80(s，9H)，2.74(s，2H)，3.90(s，3H)，5.67(s，2H)，6.98(t，1H)，7.12-7.52(m，10H)，7.93(d，1H)，8.03(s，1H)。
Embodiment 79
3-{3-[2-(4-chloro-phenyl)-1-phenyl-second-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000631
Be similar to embodiment 77, by 4-chloro-benzyl zinc bromide (commercially available) and 3-{ [(2-iodo-phenyl)-(3-phenyl-propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?3.92(s，3H)，4.73(s，2H)，5.07(s，2H)，5.99(d，1H)，6.58-6.65(m，2H)，7.08-7.20(m，7H)，7.37-7.43(m，4H)，7.52(d，1H)，7.93(d，1H)，8.06(s，1H)。
Embodiment 80
3-{3-[3,3-dimethyl--1-phenyl-Ding-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000632
Be similar to embodiment 77, by tertiary butyl bromination zinc (commercially available) and 3-{ [(2-iodo-phenyl)-(3-phenyl-propioloyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?0.91(s，9H)，3.48(s，2H)，3.90(s，3H)，5.03(s，2H)，6.22(d，1H)，6.56-6.62(m，2H)，6.98(t，1H)，7.36-7.50(m，7H)，7.92(d，1H)，8.02(s，1H)。
Embodiment 81
3-[3-(4-methyl isophthalic acid-phenyl-penta-(Z)-fork)-2-oxo-2,3-dihydro-indoles-1-ylmethyl]-phenylformic acid
Figure BDA0000145086800000641
With 3-{3-[4-methyl isophthalic acid-phenyl-penta-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe (24mg 0.05mmol) is dissolved in THF (1ml) and the water (1ml), and with LiOH.H 2(14mg 0.33mmol) adds with portion O.Mixture is stirred 16h in 50 ℃.Mixture is under reduced pressure concentrated, and be acidified to pH=3.By the preparation HPLC purifying 3-[3-(4-methyl isophthalic acid-phenyl-penta-(Z)-fork)-2-oxo-2,3-dihydro-indoles-1-ylmethyl]-phenylformic acid 10mg is provided. 1H?NMR(300Hz，CDCl 3)：δppm?0.88(d，6H)，1.36-1.44(m，2H)，1.64-1.68(m，1H)，3.33-3.38(m，2H)，5.04(s，2H)，6.01(d，1H)，6.58-6.61(m，2H)，6.96-7.02(t，1H)，7.26-7.29(m，2H)，7.37(t，2H)，7.43-7.52(m，3H)，7.93(d，1H)，8.03(s，1H)。
Embodiment 82
3-{3-[1-(4-chloro-benzyl)-2-methyl-third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000642
Be similar to embodiment 81, by 3-{3-[1-(4-chloro-benzyl)-2-methyl-third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?1.14(d，6H)，3.62-3.71(m，1H)，4.577(s，2H)，5.018(s，2H)，6.82(d，1H)，7.04(t，1H)，7.21-7.26(m，5H)，7.43(t，1H)，7.53(d，1H)，7.63(d，1H)，8.01(d，1H)，8.07(s，1H)。
Embodiment 83
3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000651
Fourth-2-acetylenic acid (2-iodo-phenyl)-acid amides
With 2-iodo-aniline (10g, 45.7mmol) and fourth-2-acetylenic acid (4.6g, 54.8mmol) mixture in methylene dichloride (50ml) is cooled to 0 ℃.Add 1 then, and the 3-NSC 57182 (14g, 68.6mmol).After stirring at room 3 hours, mixture water (20ml) is washed.Organic layer with dried over sodium sulfate and concentrated, is obtained rough product fourth-2-acetylenic acid (2-iodo-phenyl)-acid amides (13.0g, 100%), be yellow solid, it is not having to be used for next step under the situation of purifying.MS is for C 10H 8INO calculated value 285.1, measured value (ESI +) [(M+H) +] 286.0.
3-{ [(2-iodo-phenyl)-(1-oxo-Ding-2-alkynyl)-amino]-methyl }-oil of Niobe
With fourth-2-acetylenic acid (2-iodo-phenyl)-acid amides (2.85g, 10mmol) and cesium carbonate (4.89g, 15mmol) mixture in DMF (20ml) stirred 10 minutes.Adding 3-brooethyl-oil of Niobe (2.52g, 11mmol).Then with mixture in stirring at room 12 hours.After removing solid, extracted with diethyl ether is handled and used to filtrate water.Organic layer with dried over sodium sulfate and concentrated, is obtained residuum, and it is by hurried chromatogram purification; With ethyl acetate/hexane=1: 4 wash-out; Product 3-{ [(2-iodo-phenyl)-(1-oxo-Ding-2-alkynyl)-amino]-methyl is provided }-oil of Niobe, be yellow solid (3.03,70%).MS is for C 19H 16INO 3Calculated value 433.3, measured value (ESI +) [(M+H) +] 434.1.
3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
With 3-{ [(2-iodo-phenyl)-(1-oxo-Ding-2-alkynyl)-amino]-methyl }-oil of Niobe (0.5g; 1.15mmol); 4-fluorophenyl boric acid (0.32g, 2.3mmol), four (triphenyl phosphine) palladium (0.13g; 0.115mmol) and thiophene-2-carboxylic acid copper (0.46g, 2.42mmol) mixture in THF stirred 5 hours in 60 ℃.Remove desolvate after, with residuum by hurried chromatogram purification, with ethyl acetate/hexane=1: 5 wash-out; Product 3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2 is provided; 3-dihydro-indoles-1-ylmethyl }-oil of Niobe (0.28g, 60%), be yellow solid.MS is for C 25H 20FNO 3Calculated value 401.4, measured value (ESI +) [(M+H) +] 402.2.
3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
With 3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-(0.33g, solution 0.82mmol) is dissolved among the THF 5ml oil of Niobe.Add Lithium Hydroxide MonoHydrate (0.35g, 8.2mmol) solution in water (2.0ml) then.After stirring 12 hours, under reduced pressure remove and desolvate.Residuum is dissolved among the 2ml DMF is used for preparation HPLC, obtain 3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indoles-1-ylmethyl-phenylformic acid, be yellow powder (100mg). 1H?NMR(400MHz，DMSO-d 6)δppm?2.78(s，3H)5.06(s，2H)6.08(d，J＝7.83Hz，1H)6.68(t，J＝7.45Hz，1H)6.92(d，J＝7.83Hz，1H)7.11(t，J＝7.45Hz，1H)7.38(t，J＝8.84Hz，2H)7.43-7.51(m，1H)7.46(dd，J＝8.72，5.68Hz，2H)7.60(d，J＝7.58Hz，1H)7.85(d，J＝7.83Hz，1H)7.92(s，1H)13.03(s，1H)。MS is for C 24H 18FNO 3Calculated value 387.4, measured value (ESI +) [(M+H) +] 388.2.
Embodiment 84
3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
1-iodo-2-isocyanato-benzene
(30g, 0.14mol) in the solution in methylene dichloride (800ml), (14.6g is 49.3mmol) with saturated sodium hydrogencarbonate (544ml) to add TRIPHOSGENE 99.5 in 0 ℃ for 2-iodo-aniline.The mixture that obtains was stirred 4 hours.Organic layer is washed and uses dried over sodium sulfate with salt solution (200ml).Except that after desolvating, obtain rough product 1-iodo-2-isocyanato-benzene (32.3g, 96%), be yellow oil, it is not having to be used for next step under the situation of purifying.
4-methyl-penta-2-acetylenic acid (2-iodo-phenyl)-acid amides
3-methyl-Ding-1-alkynes (11g, 0.16mol) in THF (100ml), in 0 ℃ add n-BuLi (2.5M is in hexane) (59ml, 0.15mol).The mixture that obtains was stirred 30 minutes.Be added dropwise to 1-iodo-2-isocyanato-benzene (33g, 0.14mol) solution in THF (100ml) then.After 0 ℃ is stirred 2 hours, mixture is handled with salt solution (100ml), extract with ether (200ml).Organic layer with dried over sodium sulfate and concentrated, is obtained rough product 4-methyl-penta-2-acetylenic acid (2-iodo-phenyl)-acid amides (38g, 90%), be yellow oil, it is not having to be used for next step under the situation of purifying.MS is for C 12H 12INO calculated value 313.1, measured value (ESI +) [(M+H) +] 314.0.
3-{ [(2-iodo-phenyl)-(4-methyl-penta-2-alkynes acyl group)-amino]-methyl }-oil of Niobe
With 4-methyl-penta-2-acetylenic acid (2-iodo-phenyl)-acid amides (21g, 67.1mmol) and cesium carbonate (33.0g, 100.7mmol) mixture in DMF (170ml) stirred 10 minutes.Adding 3-brooethyl-oil of Niobe (16.9g, 73.8mmol).Then with mixture in stirring at room 12 hours.After removing solid, extracted with diethyl ether is handled and used to filtrate water.Organic layer with dried over sodium sulfate and concentrated, is obtained residuum, and it is by hurried chromatogram purification; With ethyl acetate/hexane=1: 4 wash-out; Product 3-{ [(2-iodo-phenyl)-(4-methyl-penta-2-alkynes acyl group)-amino]-methyl is provided }-oil of Niobe, be yellow solid (15.9g, 51%).MS is for C 21H 20ClNO 3Calculated value 461.3, measured value (ESI +) [(M+H) +] 461.9.
3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
With 3-{ [(2-iodo-phenyl)-(4-methyl-penta-2-alkynes acyl group)-amino]-methyl }-oil of Niobe (0.93g, 2.02mmol), 4-chlorophenylboronic acid (0.63g; 4.04mmol); Triphenyl phosphine (53mg, 0.202mmol), acid chloride (23mg; 0.10mmol) and cesium fluoride (0.92g, 6.06mmol) mixture in THF (15ml) stirred 3 hours in 60 ℃.Remove desolvate after, with residuum by hurried chromatogram purification, with ethyl acetate/hexane=1: 5 wash-out; Product 3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2 is provided; 3-dihydro-indoles-1-ylmethyl }-oil of Niobe (0.40g, 44%), be yellow solid.MS is for C 27H 24ClNO 3Calculated value 445.5, measured value (ESI +) [(M+H) +] 446.0. 1H NMR (400MHz, DMSO-d 6) δ ppm 1.10 (d, J=6.82Hz, 6H) 3.91 (s, 3H) 4.99 (dt, J=13.71,6.92Hz, 1H) 5.06 (s; 2H) 5.73 (d, J=7.58Hz, 1H) 6.62 (t, J=7.71Hz, 1H) 6.73 (d, J=7.83Hz; 1H) 7.05 (t, J=7.71Hz, 1H) 7.19 (d, J=8.34Hz, 2H) 7.46 (t, J=7.83Hz; 1H) 7.55 (3H) 7.94 (1H) 8.02 (s, 1H) MS is for C for d, J=7.58Hz for d, J=8.08Hz 27H 24ClNO 3Calculated value 445.5, measured value (ESI +) [(M+H) +] 446.0.
Embodiment 85
3-{3-[2-methyl isophthalic acid-phenyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000681
Be similar to embodiment 84, by phenyl-boron dihydroxide (commercially available) and 3-{ [(2-iodophenyl)-(4-methyl-penta-2-alkynes acyl group)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.04(s，1H)，7.94(d，1H)，7.48-7.53(m，3H)，7.39(t，1H)，7.15(dd，2H)，6.99(t，1H)，6.59-6.61(d，1H)，6.55(t，1H)，5.59(d，2H)，5.00-5.05(m，3H)，3.97(s，3H)，1.11(s，3H)，1.09(s，3H)。
Embodiment 86
3-{3-[1-(4-ethanoyl-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Be similar to embodiment 84, by 4-ethanoyl-phenyl-boron dihydroxide (commercially available) and 3-{ [(2-iodophenyl)-(4-methyl-penta-2-alkynes acyl group)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1HNMR(CDCl 3，300MHz)δppm?8.03-8.11(m，4H)，7.94(d，1H)，7.71(d，1H)，7.52(d，1H)，7.40(t，1H)，7.29(d，2H)，7.00(t，1H)，6.61(d，1H)，6.54(t，1H)，5.61(d，H)，5.02-5.07(m，3H)，3.90(s，3H)，2.70(s，3H)，1.19(d，3H)，1.17(d，3H)。
Embodiment 87
3-{3-[1-(4-chloro-phenyl)-1-cyclohexyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Be similar to embodiment 84, by 4-chloro-phenyl-boron dihydroxide (commercially available) and 3-{ [(3-cyclohexyl-propioloyl)-(2-iodo-phenyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.02(s，1H)，7.93(d，1H)，7.47-7.51(m，13H)，7.39(t，1H)，7.10(d，2H)，7.01(t，1H)，6.59-6.63(m，2H)，5.71(d，2H)，5.02(s，2H)，4.62(t，1H)，3.91(s，3H)，1.44-1.76(m，6H)，1.01-1.18(m，4H)。
Embodiment 88
3-{3-[2-methyl isophthalic acid-(4-trifluoromethyl-phenyl)-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000692
Be similar to embodiment 84, by 4-trifluoromethyl-phenyl-boron dihydroxide (commercially available) and 3-{ [(2-iodophenyl)-(4-methyl-penta-2-alkynes acyl group)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(DMSO，300MHz)δppm?7.90(s，1H)，7.79-7.86(m，2H)，7.58(d，1H)，7.48(t，1H)，7.42(d，1H)，7.09(t，1H)，7.00(d，1H)，6.89(d，1H)，6.65(t，1H)，5.65(d，1H)，5.03(s，2H)，4.84-4.93(m，1H)，3.57(s，3H)，0.96-1.06(dd，6H)。
Embodiment 89
3-{3-[1-(4-chloro-phenyl)-2-hydroxy-2-methyl-third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000701
Be similar to embodiment 84, by 4-chloro-phenyl-boron dihydroxide (commercially available) and 3-{ [(4-hydroxy-4-methyl-penta-2-alkynes acyl group)-(2-iodo-phenyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1HNMR(400MHz，DMSO-d 6)δppm?1.30(s，6H)3.83(s，3H)5.14(s，2H)5.43(d，J＝7.58Hz，1H)6.68(t，J＝7.58Hz，1H)7.01(d，J＝7.83Hz，1H)7.12(t，J＝7.45Hz，1H)7.27(d，J＝8.34Hz，2H)7.51(t，J＝7.71Hz，1H)7.58-7.65(m，4H)7.87(d，J＝7.58Hz，1H)7.97(s，1H)。
Embodiment 90
3-{3-[1-(4-cyanic acid-phenyl)-2-hydroxy-2-methyl-third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000702
Be similar to embodiment 84, by 4-cyanic acid-phenyl-boron dihydroxide (commercially available) and 3-{ [(4-hydroxy-4-methyl-penta-2-alkynes acyl group)-(2-iodo-phenyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?1.33(s，6H)3.85(s，3H)5.15(s，2H)5.35(d，J＝7.83Hz，1H)6.68(t，J＝7.71Hz，1H)7.03(d，J＝7.83Hz，1H)7.15(t，J＝7.71Hz，1H)7.48-7.55(m，1H)7.52(d，J＝7.58Hz，3H)7.62(d，J＝7.83Hz，1H)7.89(d，J＝7.83Hz，1H)7.99(s，1H)8.05(d，J＝8.34Hz，2H)。
Embodiment 91
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000711
Be similar to embodiment 84, by 4-chloro-phenyl-boron dihydroxide (commercially available) and 3-{ [(4,4-dimethyl--penta-2-alkynes acyl group)-(2-iodo-phenyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1HNMR(400MHz，MeOD)δppm?1.38(s，9H)3.86(s，3H)4.83(d，2H)6.81(d，J＝7.83Hz，1H)6.99(d，J＝7.83Hz，2H)7.10(t，J＝7.58Hz，1H)7.22(t，J＝7.71Hz，1H)7.33-7.42(m，4H)7.84-7.88(m，2H)7.93(d，J＝7.83Hz，1H)。
Embodiment 92
3-{3-[1-(4-cyanic acid-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000712
Be similar to embodiment 84, by 4-cyanic acid-phenyl-boron dihydroxide (commercially available) and 3-{ [(4,4-dimethyl--penta-2-alkynes acyl group)-(2-iodo-phenyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1HNMR(400MHz，DMSO-d 6)δppm?1.35(s，9H)3.84(s，3H)5.07(s，2H)5.19(d，J＝7.83Hz，1H)6.56(t，J＝7.71Hz，1H)6.88(d，J＝7.83Hz，1H)7.06(t，J＝7.71Hz，1H)7.42(d，J＝8.08Hz，2H)7.50(t，J＝7.71Hz，1H)7.59(d，J＝7.58Hz，1H)7.87(d，J＝7.58Hz，1H)7.95-8.05(m，3H)。
Embodiment 93
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe
Figure BDA0000145086800000721
Be similar to embodiment 84, by 4-chloro-phenyl-boron dihydroxide (commercially available) and 3-{ [(4,4-dimethyl--penta-2-alkynes acyl group)-(2-iodo-phenyl)-amino]-methyl }-oil of Niobe begins, the preparation title compound. 1HNMR(400MHz，DMSO-d 6)δppm?1.36(s，9H)3.84(s，3H)5.07(s，2H)5.30(d，J＝7.83Hz，1H)6.57(t，J＝7.83Hz，1H)6.88(d，J＝7.83Hz，1H)7.05(t，J＝7.71Hz，1H)7.21(d，J＝8.08Hz，2H)7.51(t，J＝7.71Hz，1H)7.57-7.64(m，2H)7.87(d，J＝7.58Hz，1H)7.97(s，1H)。
Embodiment 94
3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
With 3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-(0.40g, solution 0.90mmol) is dissolved among the THF 15ml oil of Niobe.Add Lithium Hydroxide MonoHydrate (0.38g, 9.0mmol) solution in water (3.0ml) then.After stirring 12 hours, under reduced pressure remove and desolvate.Residuum is dissolved among the 2ml DMF is used for preparation HPLC, obtain 3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indoles-1-ylmethyl-phenylformic acid, be yellow powder (200mg). 1H?NMR(400MHz，DMSO-d 6)δppm?1.00(d，J＝6.82Hz，6H)4.90-4.99(m，1H)5.05(s，2H)5.59(d，J＝7.83Hz，1H)6.64(t，J＝7.71Hz，1H)6.91(d，J＝7.83Hz，1H)7.10(t，J＝7.71Hz，1H)7.27(d，J＝8.34Hz，2H)7.49(t，J＝7.58Hz，1H)7.63(d，J＝8.34Hz，2H)7.59(d，J＝7.58Hz，1H)7.85(d，J＝7.58Hz，1H)7.92(s，1H)13.05(s，1H)。MS is for C 26H 22ClNO 3Calculated value 431.5, measured value (ESI +) [(M+H) +] 432.0.
Embodiment 95
3-{3-[1-(4-cyanic acid-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Being similar to embodiment 94, by 3-{3-[1-(4-cyanic acid-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-indoline-1-ylmethyl } oil of Niobe begins, the preparation title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?1.01(d，J＝6.82Hz，6H)4.91-5.00(m，1H)5.05(s，2H)5.50(d，J＝7.83Hz，1H)6.64(t，J＝7.58Hz，1H)6.93(d，J＝7.83Hz，1H)7.11(t，J＝7.58Hz，1H)7.48(d，J＝7.58Hz，3H)7.60(d，J＝7.58Hz，1H)7.85(d，J＝7.33Hz，1H)7.93(s，1H)8.05(d，J＝8.08Hz，2H)13.06(br.s.，1H)。
Embodiment 96
6-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-pyridine-2-formic acid
Figure BDA0000145086800000732
Be similar to embodiment 94, by 6-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1 ylmethyl }-pyridine-2-methyl-formiate begins, the preparation title compound. 1H?NMR(400MHz，MeOD)δppm?1.06(d，6H)4.92-5.01(m，1H)5.23(s，2H)5.74(d，1H)6.64(t，1H)6.87(d，1H)7.08(t，1H)7.22(d，2H)7.45(d，1H)7.59(d，2H)7.95(t，1H)8.09(d，1H)。
Embodiment 97
6-{3-[1-(4-cyanic acid-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-pyridine-2-formic acid
Be similar to embodiment 94, by 6-{3-[1-(4-cyanic acid-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-indoline-1-ylmethyl }-pyridine-2-methyl-formiate begins, the preparation title compound. 1H?NMR(400MHz，MeOD)δppm?1.06(d，6H)4.95-5.08(m，1H)5.25(s，2H)5.64(d，1H)6.63(t，1H)6.89(d，1H)7.09(t，1H)7.46(d，3H)7.90-8.00(m，3H)8.09(d，1H)。
Embodiment 98
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000742
Be similar to embodiment 94, by 3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(Z) fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?1.32(s，9H)4.86(s，2H)6.95(d，J＝7.58Hz，1H)7.04(d，J＝8.59Hz，2H)7.13(t，1H)7.29(t，1H)7.38-7.42(m，2H)7.44(d，J＝5.05Hz，2H)7.77-7.84(m，2H)7.88(d，J＝7.83Hz，1H)13.01(s，1H)。
Embodiment 99
3-{3-[1-(4-cyanic acid-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000751
Be similar to embodiment 94, by 3-{3-[1-(4-cyanic acid-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1 ylmethyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?1.35(s，9H)5.06(s，2H)5.19(d，J＝7.83Hz，1H)6.57(t，J＝7.45Hz，1H)6.89(d，J＝7.58Hz，1H)7.07(t，J＝7.45Hz，1H)7.41-7.51(m，3H)7.56(d，1H)7.84(d，J＝7.58Hz，1H)7.93(s，1H)8.03(d，J＝8.34Hz，2H)。
Embodiment 100
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000752
Be similar to embodiment 94, by 3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?1.35(s，9H)5.06(s，2H)5.30(d，J＝7.83Hz，1H)6.57(t，1H)6.88(d，J＝7.83Hz，1H)7.06(t，1H)7.22(d，J＝8.08Hz，2H)7.49(t，1H)7.54-7.63(m，3H)7.84(d，1H)7.93(s，1H)12.97(s，1H)。
Embodiment 101
3-{3-[1-(4-fluoro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000761
Be similar to embodiment 94, by 3-{3-[1-(4-fluoro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?1.01(d，J＝6.82Hz，6H)4.87-4.99(m，1H)5.05(s，2H)5.54(d，J＝7.83Hz，1H)6.63(t，J＝7.33Hz，1H)6.90(d，J＝7.58Hz，1H)7.09(d，J＝1.01Hz，1H)7.24-7.31(m，2H)7.40(t，J＝8.84Hz，2H)7.49(t，J＝7.58Hz，1H)7.59(d，J＝7.58Hz，1H)7.85(d，J＝7.83Hz，1H)7.92(s，1H)13.03(s，1H)。
Embodiment 102
6-{3-[1-(4-fluoro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-pyridine-2-formic acid
Figure BDA0000145086800000762
Being similar to embodiment 94, by 6-{3-[1-(4-fluoro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl } pyridine-2-methyl-formiate begins, the preparation title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?1.01(d，J＝6.82Hz，6H)4.86-5.00(m，1H)5.16(br.s.，2H)5.56(d，J＝7.83Hz，1H)6.63(t，J＝7.71Hz，1H)6.85(d，J＝7.33Hz，1H)7.06(t，J＝7.58Hz，1H)7.29(d，J＝5.56Hz，2H)7.27(d，J＝5.81Hz，1H)7.41(t，J＝8.72Hz，2H)7.81-7.98(m，2H)。
Embodiment 103
3-{3-[2-methyl isophthalic acid-pyridin-3-yl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Be similar to embodiment 94, by 3-{3-[2-methyl isophthalic acid-pyridin-3-yl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(400MHz，MeOD)δppm?1.13(t，J＝7.71Hz，6H)5.01-5.14(m，1H)5.10(s，2H)5.59(d，J＝7.83Hz，1H)6.62(t，J＝7.71Hz，1H)6.83(d，J＝7.83Hz，1H)7.11(t，J＝7.71Hz，1H)7.47(t，J＝7.71Hz，1H)7.59(d，J＝7.58Hz，1H)7.84(br.s.，1H)7.93-8.05(m，2H)7.96(s，1H)8.58(br.s.，1H)8.85(br.s.，1H)。
Embodiment 104
3-{3-[1-(4-chloro-phenyl)-1-cyclohexyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000772
Be similar to embodiment 94, by 3-{3-[1-(4-chloro-phenyl)-1-cyclohexyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.09(s，1H)，8.02(d，1H)，7.57(d，1H)，7.41-7.50(m，3H)，7.11(d，2H)，7.03(t，1H)，6.60-6.64(m，2H)，5.73(d，1H)，5.05(s，2H)，4.63(m，1H)，1.44-1.81(m，6H)，1.01-1.18(m，4H)。
Embodiment 105
3-{3-[2-methyl isophthalic acid-(4-trifluoromethyl-phenyl)-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000781
Be similar to embodiment 94, by 3-{3-[2-methyl isophthalic acid-(4-trifluoromethyl-phenyl)-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.08(s，1H)，8.00(d，1H)，7.77(d，2H)，7.58(d，1H)，7.44(t，1H)，7.31(d，2H)，7.03(t，1H)，6.63(d，1H)，6.58(t，1H)，5.58(d，1H)，5.04-5.08(m，3H)，1.16(s，3H)，1.13(s，1H)。
Embodiment 106
3-{3-[2-methyl isophthalic acid-thiene-3-yl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000782
Be similar to embodiment 94, by 3-{3-[2-methyl isophthalic acid-thiene-3-yl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.08(s，1H)，8.01(d，1H)，7.77(d，2H)，7.58(d，1H)，7.44(t，1H)，7.31(d，2H)，7.03(t，1H)，6.63(d，1H)，6.58(t，1H)，5.58(d，1H)，5.04-5.08(m，3H)，1.10(s，3H)，1.07(s，3H)。
Embodiment 107
3-{5-chloro-3-[2-methyl isophthalic acid-(4-trifluoromethyl-phenyl)-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000791
Be similar to embodiment 94, by 3-{5-chloro-3-[2-methyl isophthalic acid-(4-trifluoromethyl)-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(300Hz，CDCl 3)：δppm?1.11(d，6H)，5.00-5.04(m，1H)，5.01(s，2H)，5.40(d，1H)，6.51(d，1H)，6.98(dd，1H)，7.28(d，2H)，7.42(t，1H)，7.56(m，1H)，7.81(d，2H)，8.01-8.04m，2H)。
Embodiment 108
3-{3-[1-(4-ethanoyl-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid
Figure BDA0000145086800000792
Be similar to embodiment 94, by 3-{3-[1-(4-ethanoyl-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe begins, the preparation title compound. 1H?NMR(CDCl 3，300MHz)δppm?8.00-8.12(m，3H)，7.72(d，1H)，7.57(d，1H)，7.44(t，1H)，7.29(d，2H)，7.02(t，1H)，6.62(d，1H)，6.55(t，1H)，5.63(d，2H)，5.04(m，3H)，2.70(s，3H)，1.10(s，3H)，1.08(s，3H)。
Embodiment 109
N-(3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-benzoyl-)-Toluidrin
Figure BDA0000145086800000801
With 3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid (0.22g, 0.51mmol); 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.20g; 1.02mmol), sulfonyloxy methyl amine (97mg, 1.02mmol); (12.2mg, 0.10mmol) mixture in methylene dichloride (20ml) stirred 72 hours DMAP.Organic solution with salt solution (10ml) washing, is used dried over sodium sulfate then.Remove desolvate after; Residuum is dissolved among the 2ml DMF is used for preparation HPLC, obtain product N-(3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-benzoyl-)-Toluidrin (100mg; 38%), is yellow solid. 1H?NMR(400MHz，DMSO-d 6)δppm1.21(d，J＝6.82Hz，6H)3.50(s，3H)5.00-5.12(m，1H)5.17(s，2H)5.52(s，1H)5.84(d，J＝7.83Hz，1H)6.75(t，J＝7.83Hz，1H)6.85(d，J＝7.83Hz，1H)7.17(t，J＝7.20Hz，1H)7.28(d，J＝8.59Hz，2H)7.60(t，J＝7.71Hz，1H)7.65(d，J＝8.34Hz，2H)7.70(d，J＝7.83Hz，1H)7.94(d，J＝7.83Hz，1H)8.02(s，1H)。MS is for C 27H 25ClN 2O 4S calculated value 508.5, measured value (ESI +) [(M+H) +] 509.2.
Embodiment 110
N-(3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-benzoyl-)-Toluidrin
Figure BDA0000145086800000802
Be similar to embodiment 109, by 3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid begins, the preparation title compound. 1H?NMR(400MHz，MeOD)δppm?1.44(s，9H)3.11(s，3H)5.05(s，2H)5.41(d，J＝7.83Hz，1H)6.52(t，1H)6.74(d，J＝7.58Hz，1H)7.00(t，1H)7.12-7.21(m，2H)7.30-7.39(m，2H)7.51-7.60(m，2H)7.89-7.97(m，1H)8.04(s，1H)。
Embodiment 111
N-(3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-benzoyl-)-Toluidrin
Figure BDA0000145086800000811
Be similar to embodiment 109, by 3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid begins, the preparation title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?1.32(s，9H)3.34(s，3H)4.84(s，2H)6.93(d，J＝7.83Hz，1H)7.04(d，J＝8.34Hz，2H)7.12(t，J＝7.33Hz，1H)7.27(t，J＝7.45Hz，1H)7.37-7.47(m，4H)7.78-7.85(m，2H)7.88(d，J＝8.08Hz，1H)。
Embodiment 112
Estimate the AMPK regulator by AMPK and ACC analysis of Phosphorylation
This method uses the Western engram analysis to estimate AMP-activated protein kinase (AMPK) and endogenous expression and the phosphorylation of acetyl CoA carboxylase (ACC) in L6 clone.It is used for confirming the potentiality and the effect of small molecules AMPK regulator.
Have 10% foetal calf serum (FBS, DMEM Hyclone) (high glucose, Gibco, BRL) in, cultivate and keep L6 cell (ATCC).In analysis, on the 10cm dish with cell with 3x10 6Individual/plate is cultivated at the 10ml middle plateform, and they reached the branch junction of 70-80% in 24 hours.With the cell serum starvation overnight, handle with the AMPK regulator afterwards.Compound concentration was typically handled 1-4 hour in 0 to 100 μ M scope and with cell.In case incubation is accomplished, just with the substratum sucking-off, and with the ice-cold PBS gentle rinsing of cellular layer with 2mL.To contain 150mM NaCl, 5mM EDTA, 2mM EGTA, 25mM NaF, 2mM Na 3VO 4, the Pefabloc of 1mg/ml, molten born of the same parents' damping fluid of the 500 μ l of 1%Triton X-100 and Roche Complete Protease Inhibitor Tablet add and at incubation 10min on ice.With cellular lysate results and subsequently in 4 ℃ with 12, the centrifugal 10min of 000rpm.Preserve supernatant and use Quick Start Bradford protein quantification test kit (Bio-Rad) to measure its protein concentration.Load 40 μ g and be used for 7.5%SDS-PAGE and analyze, and subsequently according to the standard program trace to pvdf membrane.Film in room temperature, is under agitation handled 1h with sealing damping fluid (5% skimmed milk).Use (40H9) rabbit mAb (Cell Signaling) and phosphoric acid-acetyl CoA carboxylase (Ser79) antibody (Cell Signaling) conduct antibody originally of phosphoric acid-AMPK α (Thr172); Through with trace in 4 ℃ of overnight cultures, measure the level of phosphoric acid-AMPK and phosphoric acid-ACC.Trace is peeled off and respectively; Use acetyl CoA carboxylase (C83B 10) rabbit mAb (Cell signaling); AMPK α (23A3) rabbit mAb (Cell Signaling) and beta-actin antibody (Cell Signaling) are detected again; To measure ACC, the total protein level of AMPK and beta-actin.Each protein band in trace is via ECL Plus Western trace assay kit (Amersham) demonstration and by the scanning analysis quantification.With being defined as the EC that produces the half the activator concentration of maximum activation effect 50Value and the Emax sxemiquantitative ground that is defined as the maximum activation effect in infinitely great activator concentration are measured and record.
In above-mentioned AMPK and ACC phosphorylation assay method, all formulas (I) compound be have active.
Embodiment 113
Scintillation proximity assay
The preparation of enzyme
Structure as described before, expression and purification of recombinant human AMPK α 1 β 1 γ 1, α 2 β, 1 γ 1 or the truncate α 1 of AMPK alpha subunit (1-335), α 1 (1-394) and α 2 (1-394) (Pang, T., Zhang, Z.S.; Gu, M., Qiu, B.Y., Yu, L.F.; Cao, P.R., Shao, W., Su, M.B.; Li, J.Y., Nan, F.J., and Li, J. (2008)).Rats'liver AMPK heterotrimer enzyme available from Upstate (Billerica, MA, U.S.A.).
Scintillation proximity assay
Before scintillation proximity assay (SPA) is measured, with 200nM AMPK albumen (α 1 β 1 γ 1, α 2 β 1 γ 1, α 1 (1-335), α 1 (1-394) or α 2 (1-394)) the complete phosphorylation as described before (Pang etc., 2008) of recombinating.In the 96-orifice plate to contain 20mM Tris-HCl pH 7.5,5mM MgCl 2, 1mM DTT, 2 μ M vitamin H-SAMS, 2 μ M ATP, 0.2 μ Ci/ hole [γ- 33P] final volume of 50 μ l of acvator of ATP and various amounts carries out the SPA reaction.Reaction is through initiation in adding 50nM reorganization AMPK albumen to the reaction soln and at 30 ℃ of incubation 2hr.Then, contain SPA bead/hole that 80 μ g streptavidins coat among the PBS pH 7.5 through being added in, 50mMEDTA, the 40 μ l stop buffers of 0.1%Triton X-100 are with the stopping of reaction and incubation 1hr.At last, will in PBS (pH 7.5), contain 2.4M CsCl, the 160ul aaerosol solution of 50mM EDTA and 0.1%Triton X-100 is added in the reaction soln, with the SPA bead that suspends fully.Behind the 30min, measure the SPA signal, be used to calculate the amount of the product of formation with Wallac MicroBeta plate count device (PerkinElmer).The amount of the product that will in 2hr, form is drawn with respect to activator concentration, to confirm for the needed acvator effective concentration of 50% maximum enzyme activity (EC50).
Aforesaid compound has the EC50 value between 0.5uM to 50uM, and preferred compound has the EC50 value between 0.5uM to 10uM, and preferred especially compound has the EC50 value between 0.5uM to 1uM.Through using above-mentioned scintillation proximity assay to obtain these results (uM is meant micro-molar concentration (microMolar)).
The EC50 of representational formula (I) compound is reported in the following table.
Embodiment number EC50(uM)
1 2.21
2 1.49
3 5.61
4 5.25
5 2.3
6 1.51
7 1.54
8 6.47
9 2.16
10 4.44
11 3.11
12 5.34
13 1.86
14 4.34
15 2.47
16 1.53
17 2.34
18 5.66
19 1
20 1.76
21 6.07
22 4.13
23 6.97
24 4.82
25 2.73
26 1.25
27 2.73
28 0.8
29 2.36
30 1.65
31 0.77
32 10.52
33 5.56
34 1.8
35 2.95
36 3.69
37 4.49
38 2.91
39 1.57
41 4.51
42 4.5
43 3.23
44 1.21
45 1.89
46 4.02
47 2.38
48 3.15
49 1.75
50 5.89
51 1.42
52 6.55
53 5.89
54 5.14
55 2.94
56 4.24
57 2.17
58 4.87
59 5.19
60 1.24
61 4.93
62 2.33
63 3.24
64 6.63
65 3.41
66 2.44
67 1.27
68 2.12
69 2.2
70 4.96
71 4.02
72 3.3
73 5.14
74 3.17
75 1.84
76 5.14
77 2.58
78 1.6
79 1.69
80 5.8
81 4.74
82 1.6
85 4.9
86 7.88
87 10.65
88 2.59
104 4.63
105 2.95
106 1.61
107 0.66
108 3.25
Embodiment A
Can use formula (I) compound to be used to prepare the tablet of following composition as activeconstituents in a manner known way:
Figure BDA0000145086800000871
Embodiment B
Can use formula (I) compound to be used to prepare the capsule of following composition as activeconstituents in a manner known way:
Figure BDA0000145086800000872

Claims (27)

1. a formula (I) compound
Figure FDA0000145086790000011
Wherein
R 1Be hydrogen, halogen, alkoxyl group, cyanic acid, haloalkyl, alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy or alkyl-carbonyl;
R 2Be hydrogen, halogen, alkoxyl group, cyanic acid, haloalkyl, alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy or alkyl-carbonyl;
R 3Be hydrogen, halogen, alkoxyl group, cyanic acid, haloalkyl, alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy or alkyl-carbonyl;
R 4Be hydrogen, halogen, alkoxyl group, cyanic acid, haloalkyl, alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy or alkyl-carbonyl;
R 5Be alkyl, hydroxyalkyl, naphthenic base, phenylalkyl, halogenophenyl alkyl; Phenyl, substituted phenyl, thienyl or pyridyl, wherein substituted phenyl is by 1 to 3 substituted phenyl of substituting group, and said substituting group is independently selected from: alkyl; Alkoxyl group, halogen, cyanic acid, haloalkyl; Alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy and alkyl-carbonyl;
R 6Be alkyl, hydroxyalkyl, naphthenic base, phenylalkyl, halogenophenyl alkyl; Phenyl, substituted phenyl, thienyl or pyridyl, wherein substituted phenyl is by 1 to 3 substituted phenyl of substituting group, and said substituting group is independently selected from: alkyl; Alkoxyl group, halogen, cyanic acid, haloalkyl; Alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy and alkyl-carbonyl;
Condition is R 5And R 6All not p-methoxy-phenyl simultaneously;
R 7Be substituted phenyl, pyridyl, substituted pyridyl, thiazolyl; Substituted thiazolyl or carboxyl, wherein substituted phenyl is by 1 to 3 substituted phenyl of substituting group, and said substituting group is independently selected from alkyl, hydroxyl; Alkoxyl group, carboxyl, alkoxy carbonyl alkyl, alkyl amino-carbonyl; The carboxyl alkoxyl group, alkoxy carbonyl, the amino carbonyl of alkoxy carbonyl alkoxyl group and alkyl sulfonyl, wherein substituted pyridyl and substituted thiazolyl are the pyridyl and the thiazolyls of alkoxy carbonyl or carboxyl substituted; And
Condition is to work as R 5And R 6In one be that phenyl and another are phenyl, when aminomethyl phenyl or alkoxyl phenyl, R then 7It is alkoxycarbonylphenyl;
N is 0 or 1;
Or its medicinal salt or ester.
2. according to the compound of claim 1, R wherein 1Be hydrogen, halogen or alkoxyl group.
3. according to the compound of claim 1 or 2, R wherein 1Be hydrogen, fluorine or chlorine.
4. according to any one compound in the claim 1 to 3, wherein R 2Be hydrogen, halogen or alkoxyl group.
5. according to any one compound in the claim 1 to 4, wherein R 2Be hydrogen or fluorine.
6. according to any one compound in the claim 1 to 5, wherein R 3Be hydrogen, halogen or alkoxyl group.
7. according to any one compound in the claim 1 to 6, wherein R 3Be hydrogen, fluorine, chlorine or methoxyl group.
8. according to any one compound in the claim 1 to 7, wherein R 4Be hydrogen, halogen or alkoxyl group.
9. according to any one compound in the claim 1 to 8, wherein R 4Be hydrogen or fluorine.
10. according to any one compound in the claim 1 to 9, wherein R 5Be alkyl, halogenophenyl alkyl, phenyl, substituted phenyl; Thienyl or pyridyl, wherein substituted phenyl is by 1 to 3 substituted phenyl of substituting group, and said substituting group is independently selected from alkyl, alkoxyl group; Halogen, cyanic acid, haloalkyl, alkylthio; Amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy and alkyl-carbonyl.
11. according to any one compound in the claim 1 to 10, wherein R 5Be halogenophenyl or cyano-phenyl.
12. according to any one compound in the claim 1 to 11, wherein R 5Be chloro-phenyl-or cyano-phenyl.
13. according to any one compound in the claim 1 to 12, wherein R 6Be alkyl, hydroxyalkyl, naphthenic base, phenyl or halogenophenyl.
14. according to any one compound in the claim 1 to 13, wherein R 6It is alkyl or phenyl.
15. according to any one compound in the claim 1 to 14, wherein R 6Be sec.-propyl or phenyl.
16. according to any one compound in the claim 1 to 15, wherein R 7Be substituted phenyl, substituted pyridyl, substituted thiazolyl or carboxyl, wherein substituted phenyl is by 1 to 3 substituted phenyl of substituting group; Said substituting group is independently selected from alkyl, hydroxyl, alkoxyl group, carboxyl; Alkoxy carbonyl alkyl, alkyl amino-carbonyl, carboxyl alkoxyl group; Alkoxy carbonyl, the amino carbonyl of alkoxy carbonyl alkoxyl group and alkyl sulfonyl, wherein substituted pyridyl and substituted thiazolyl are the pyridyl and the thiazolyls of alkoxy carbonyl or carboxyl substituted.
17. according to any one compound in the claim 1 to 16, wherein R 7Be carboxyl phenyl, alkoxycarbonylphenyl or carboxyl pyridine base.
18. according to any one compound in the claim 1 to 17, wherein R 7Be carboxyl phenyl, methoxycarbonyl phenyl or carboxyl pyridine base.
19. according to any one compound in the claim 1 to 18, said compound is selected from:
3-{2-oxo-3-[1-phenyl-second-(E)-fork]-2,3-dihydro-indoles-1-yl }-ethyl benzoate;
(3-{2-oxo-3-[1-phenyl-second-(E)-fork]-2,3-dihydro-indoles-1-yl }-phenyl)-methyl acetate;
2-methyl-5-{2-oxo-3-[1-phenyl-second-(E)-fork]-2,3-dihydro-indoles-1-yl }-oil of Niobe;
[2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indoles-1-yl]-acetate;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-7-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-(3-diphenylmethylene-2-oxo-2,3-dihydro-indoles-1-ylmethyl)-oil of Niobe;
3-{3-[1-(4-methoxyl group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{2-oxo-3-[1-phenyl-1-p-methylphenyl-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-(2-methoxyl group-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-cyanic acid-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{2-oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(3-chloro-4-fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{2-oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(3,4-two fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(3-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(2-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(3,5-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(2,3-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-methoxyl group-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(2-bromo-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(2-chloro-5-trifluoromethyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-4-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-6-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(3-bromo-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(2-methylthio group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{7-chloro-3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{2-oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{2-oxo-3-[1-phenyl-1-(4-sulfamyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(2-methylsulfonyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{2-oxo-3-[1-phenyl-1-thiene-3-yl--first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
(4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenoxy)-ETHYLE ACETATE;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-N-sec.-propyl-BM;
6-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-nicotinic acid methyl ester;
2-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-thiazole-4-ethyl formate;
3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(4-methoxyl group-benzyl)-1, the 3-dihydro-indol-2-one;
3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(3,4,5-trihydroxy--benzyl)-1, the 3-dihydro-indol-2-one;
3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-1-(3,4,5-trihydroxy--benzyl)-1, the 3-dihydro-indol-2-one;
3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-1-(4-hydroxyl-benzyl)-1, the 3-dihydro-indol-2-one;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-methoxyl group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-(2-methoxyl group-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{2-oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{2-oxo-3-[1-phenyl-1-(2-trifluoromethoxy-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(3-chloro-4-fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{2-oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(3-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(3,5-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(2,3-two chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
2-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-5-methoxyl group-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
6-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-nicotinic acid;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-4-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-6-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(2-methylthio group-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{2-oxo-3-[1-phenyl-1-pyridin-3-yl-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(2-chloro-5-trifluoromethyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(3,5-couple-trifluoromethyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{2-oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{2-oxo-3-[1-phenyl-1-(4-sulfamyl-phenyl)-first-(E)-fork]-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-first-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
(4-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenoxy)-acetate;
3-{3-[1-(4-sec.-propyl-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(3,4-two fluoro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-7-fluoro-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{5-chloro-3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(2-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
2-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-thiazole-4-formic acid;
3-{3-[4-methyl isophthalic acid-phenyl-penta-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[3,3-dimethyl--1-phenyl-Ding-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[2-(4-chloro-phenyl)-1-phenyl-second-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[3,3-dimethyl--1-phenyl-Ding-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[4-methyl isophthalic acid-phenyl-penta-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-benzyl)-2-methyl-third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-fluoro-phenyl)-second-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl } phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[2-methyl isophthalic acid-phenyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-ethanoyl-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-1-cyclohexyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[2-methyl isophthalic acid-(4-trifluoromethyl-phenyl)-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-2-hydroxy-2-methyl-third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-cyanic acid-phenyl)-2-hydroxy-2-methyl-third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-cyanic acid-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-oil of Niobe;
3-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-cyanic acid-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
6-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-pyridine-2-formic acid;
6-{3-[1-(4-cyanic acid-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-pyridine-2-formic acid;
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-cyanic acid-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-fluoro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
6-{3-[1-(4-fluoro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-pyridine-2-formic acid;
3-{3-[2-methyl isophthalic acid-pyridin-3-yl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-1-cyclohexyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[2-methyl isophthalic acid-(4-trifluoromethyl-phenyl)-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[2-methyl isophthalic acid-thiene-3-yl-)-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{5-chloro-3-[2-methyl isophthalic acid-(4-trifluoromethyl-phenyl)-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-ethanoyl-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
N-(3-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-benzoyl-)-Toluidrin;
N-(3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-benzoyl-)-Toluidrin; With
N-(3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl--third-(Z)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-benzoyl-)-Toluidrin.
20. according to any one compound in the claim 1 to 19, said compound is selected from:
3-{3-[1-(4-chloro-phenyl)-1-phenyl-first-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
3-{3-[1-(4-cyanic acid-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-phenylformic acid;
6-{3-[1-(4-chloro-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-pyridine-2-formic acid; With
6-{3-[1-(4-cyanic acid-phenyl)-2-methyl-third-(E)-fork]-2-oxo-2,3-dihydro-indoles-1-ylmethyl }-pyridine-2-formic acid.
21. one kind is used for preparing according to any one the method for formula (I) compound of claim 1 to 20,
Said method one of comprises the following steps:
(a) according to the compound of formula (A)
At R 7Reaction under-X and copper catalyst exist;
(b) according to the compound of formula (B)
Figure FDA0000145086790000112
At R 8Reaction under-I and palladium catalyst exist;
(c) according to the compound of formula (C)
Reaction in the presence of boron tribromide;
(d) according to the compound of formula (D)
Figure FDA0000145086790000121
At R 6Reaction under-ZnBr and nickel catalyzator exist;
(e) according to the compound of formula (E)
Figure FDA0000145086790000122
Reaction in the presence of alkali;
(f) according to the compound of formula (F)
Figure FDA0000145086790000123
At R 8-B (OH) 2With the reaction under the palladium catalyst existence;
(g) according to the compound of formula (G)
Figure FDA0000145086790000124
At MeSO 2NH 2With the reaction under the coupling agent existence;
R wherein 1To R 7Such as in the claim 1 to 18 any one definition, wherein Ar is a phenyl, substituted phenyl, pyridyl or thiazolyl; Wherein substituted phenyl is by 1 or 2 substituted phenyl of substituting group, and said substituting group is independently selected from alkyl, hydroxyl, alkoxyl group; Carboxyl, alkoxy carbonyl alkyl, alkyl amino-carbonyl, carboxyl alkoxyl group; Alkoxy carbonyl, alkoxy carbonyl alkoxyl group and alkyl sulfonyl amino carbonyl, wherein R 10By 1 to 3 substituted phenyl of substituting group, said substituting group is independently selected from alkyl, alkoxyl group, halogen, cyanic acid, haloalkyl, alkylthio, amino-sulfonyl, alkyl sulphonyl, halogenated alkoxy and alkyl-carbonyl, wherein R 9Be alkyl, R wherein 11Be alkyl, and wherein X is a chlorine or bromine.
22. according to any one compound in the claim 1 to 20, said compound is as therapeutic active substance.
23. a pharmaceutical composition, said pharmaceutical composition comprise according in the claim 1 to 20 any one compound with the treatment inert support.
24. according to the application that the compound of any one in the claim 1 to 20 is used to prepare medicine, said medicine is used for treatment or prevents obesity, dyslipidemia, hyperglycemia, 1 type or diabetes B.
25. according to the preparation of the method for claim 21 according to any one compound in the claim 1 to 20.
26. one kind is used for treatment or prevents obesity, dyslipidemia, and hyperglycemia, the method for 1 type or diabetes B, said method comprise the compound as in claim 1 to 20, defining in any one of effective dosage.
27. aforesaid the present invention.
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