Act on the pyridine derivative compound of prolyl hydroxylaseTechnical field
The present invention relates to the pyrrole suitable for the related symptom of the mediation for the treatment of hypoxia inducible factor and/or hematopoietinPyridine derivative compound.
Background technology
Hypoxia inducible factor (hypoxia inducible factor, HIF) be one kind be widely present in mammal andTranscription regulaton factor in human body cell.HIF is to collectively constitute heterodimer by HIF- α and HIF- β, both belong to base-Helix-loop-helix (bHLH)-PAS protein families.Mainly there are 3 family members：HIF-1, HIF-2 and HIF-3, but in cellIn almost only exist HIF-1 and HIF-2.HIF has different α subunits (HIF-1 α, HIF-2 α and HIF-3 α), identical β subunits.HIF- α are a kind of functional subunits, and stability, Subcellular Localization and the transcription effect of its protein are influenceed by oxygen level, andHIF- β are the structural type subunits expressed in nucleus, and its activity is not by Effect of hypoxia.
HIF-1 α and HIF-2 α have a similar two level protein structure domain, including bHLH domains, PAS domains, oxygen according toRely degraded (oxygen dependent degradation, ODD) domain and transcription activating domain (transcriptionActivation domain, TAD) (N-TAD and C-TAD), both have 42% structural homology；HIF-3 α two level eggWhite structure is similar to the above two, does not include the transcription activating domain (C-TAD) of C-terminal simply, the structure homology for having 37% with HIF-1 αProperty.
HIF-1 α are influenceed closely by oxygen concentration level.Under the conditions of normal oxygen, PHD hydroxylating HIF- α subunits, by hydroxylThe HIF- α subunits of change are then degraded by proteasome.HIF-1 α half-life period probably only 5min, it is difficult to detect HIF-1 α；LowUnder the conditions of oxygen, HIF-1 α degradeds are obstructed, and in the increase of intracytoplasmic concentration, and nucleus is arrived in indexing, and HIF- is combined to form with HIF- β1.The gene about 150, including hematopoietin regulated and controled by HIF having confirmed at present(erythropoietin, EPO), VEGF (vascular endothelialgrowth factor,VEGF), Heme oxygeanse-1 (heme oxygenase 1, HO-1), nitric oxide synthase type(induciblenitric oxide synthase, iNOS), Glut1 (glucose transporters1, GluT-1), insulin-like growth factor-2 (insulin-like growth factor 2, IGF-2), Endothelin receptor A, turn ironAlbumen etc..
The content of the invention
The invention provides the micromolecular compound that can suppress HIF prolyl hydroxylases (PHD) activity, its mechanism of actionTo cause HIF-a content to raise so as to increase EPO generation and secretion by suppressing PHD enzymatic activitys, promote erythrocyte maturationWith improve blood oxygen carrying capability, for treating and preventing anemia and ischemic disease.The compounds of this invention structure such as formula (I)
Wherein：
R1 is hydrogen or hydroxyl；
R2 be independently selected from：Hydrogen, halogeno-group, C1-4 alkyl, phenyl ,-O- phenyl ,-O- benzyls ,-O-C1-4 alkyl, appointSelection of land is by the alkyl-substituted phenyl of-C1-4, the benzyl optionally substituted by-C1-4.
R1 is hydrogen, and R2 is selected from：Hydrogen, chlorine, phenyl, phenoxy group, benzyloxy, ethyoxyl, methoxyl group, ethyl, methyl；R1 is hydroxylBase, R2 are selected from：Hydrogen, chlorine, phenyl, phenoxy group, benzyloxy, ethyoxyl, methoxyl group, ethyl, methyl.
Specific exemplary compounds are as follows：
([3,3 '-bipyridyl] -6- carbonyls) glycine
(6 '-chloro- [3,3 '-bipyridyl] -6- carbonyls) glycine
(6 '-phenyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
(6 '-benzyloxy-[3,3 '-bipyridyl] -6- carbonyls) glycine
(6 '-ethyoxyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
(6 '-methoxyl group-[3,3 '-bipyridyl] -6- carbonyls) glycine
(6 '-ethyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
(6 '-methyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
(5 '-chloro- [3,3 '-bipyridyl] -6- carbonyls) glycine
(5 '-phenyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
(5 '-phenoxy group-[3,3 '-bipyridyl] -6- carbonyls) glycine
(5 '-benzyloxy-[3,3 '-bipyridyl] -6- carbonyls) glycine
(5 '-ethyoxyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
(5 '-methoxyl group-[3,3 '-bipyridyl] -6- carbonyls) glycine
(5 '-ethyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
(5 '-methyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
(2 '-chloro- [3,3 '-bipyridyl] -6- carbonyls) glycine
(2 '-phenyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
(2 '-benzyloxy-[3,3 '-bipyridyl] -6- carbonyls) glycine
(2 '-ethyoxyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
(2 '-methoxyl group-[3,3 '-bipyridyl] -6- carbonyls) glycine
(2 '-ethyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
(2 '-methyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
(5- hydroxyls-[3,3 '-bipyridyl] -6- carbonyls) glycine
(6 '-chloro- 5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(6 '-phenyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(6 '-benzyloxy -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(6 '-ethyoxyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(6 '-methoxyl group -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(6 '-ethyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(6 '-methyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(5 '-chloro- 5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(5 '-phenyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(5 '-phenoxy group -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(5 '-benzyloxy -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(5 '-ethyoxyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(5 '-methoxyl group -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(5 '-ethyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(5 '-methyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(2 '-chloro- 5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(2 '-phenyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(2 '-benzyloxy -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(2 '-ethyoxyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(2 '-methoxyl group -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(2 '-ethyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
(2 '-methyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
The invention provides a kind of preparation method of formula (I) compound, synthetic route are as follows：
In synthetic route, R1 and R2 definition are identical with the definition in formula above (I), and R3 is methyl or ethyl；
This method includes:
Step 1：Formula (II) and formula (III) carry out amide condensed obtaining formula (IV)；Wherein formula (III) be glycine methyl ester orHydrochloride, glycine ethyl ester or hydrochloride；
Step 2：Formula (IV) and formula (V) carry out Suzuki coupling reactions and obtain formula (VI)；The catalyst wherein used is palladiumMetal salt；
Step 3：Formula (VI) hydrolyzes obtain formula (I) in the basic conditions, wherein the alkali used is sodium hydroxide, potassium hydroxideOr lithium hydroxide；
Wherein step 1, when R1 is hydroxyl, condensing agent HATU, HBTU or PyBOP, preferably HBTU；Palladium in step 2Metal salt preferably [double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride；Wherein step 3, organic solvent are methanol, ethanol, fourHydrogen furans or its mixing.
Here is the part pharmacodynamics and Biological Detection result of the compounds of this invention
Document discloses the non-limitative example of the measure that can be used for detection favorable activity of report：Oehme, F., et al.,Anal.Biochem.330：74-80(2004)；M, et al., J.Bio.Chem 278 (33)：30772-30780(2005)；Hyunju, C., et al., Biochem.Biophys.Res.Comm.330 (2005) 275-280；And Hewitson,K.S., et al., Methods in Enzymology, (Oxygen Biology and Hypoxia)；ElsevierPublisher (2007), P25-42 (ISSN：0076-6879).
The bioactivity of the compounds of this invention refers to following assay methods and assessed：
The measure buffer solution of test compounds and 20uL of the 1uL in DMSO is added into each hole of 96- orifice plates(50mM Tris pH 7.4/0.01% Tween-20s/1mg/ml bovine serum albumin(BSA)s/10uM ferrous sulfate/1mM ascorbic acidSodium/20ug/ml catalyzing enzymes), measure buffer solution contains the Sf9 cells in baculoviral-infection of 0.15ug/ml FIAG- marksThe middle total length PHD2 for expressing and purifying.At room temperature after pre-incubation 30min, by adding 14ul substrates (0.2uM 2- ketone penta 2The final concentrate (concentrations) of hydrochlorate and 0.5um HIF-1a peptide biotinyls-DLDLEMLAPYIPMDDDFQL)Trigger enzyme reaction.At room temperature after 2 hours, by 1mM orthophenanthrolines, 0.1mM EDTA, 0.5nm anti-(His)6The streptavidin of LANCE reagents (Perkin-Elmer Life Sciences), 100nM AF647- marksAnd 2ug/ml (His) (Invitrogen)6- VHL compounds (S.Tan (2001) Protein Expr.Purif.21,224-234) 25uL is added in final concentrate to be quenched/detect mixture terminating reaction and produce information.Minute differentiates 665nmWith the ratio of fluorescence signal under 620nm, the percentage for not suppressing control sample for calculating relative parallel test suppresses.
Table 1 lists the PHD2 binding activity of the compounds of this invention disclosed in embodiment 1-20, with IC50Nm is represented.
+=≤ 10IC50(nM)
++=>10 to≤100IC50(nM)
Embodiment
Embodiment 1
([3,3 '-bipyridyl] -6- carbonyls) glycine
Step A：The preparation of the bromo- pyridine glycine methyl esters of 5-
By 5- bromo-2-pyridyls formic acid (4.04g, 20.0mmol), triethylamine 9.1ml, HOBt (3.26g.24.0mmol) and100ml dichloromethane is added in 500ml reactors, and EDCI (4.59g, 24.0mmol), stirring are added after stirring 15min30min, glycine methyl ester hydrochloride (2.75g, 22.0mmol) is added, continues to stir, reacted at room temperature to complete, use respectively100ml saturated sodium bicarbonates, 100ml washings.100ml saturated aqueous common salts wash successively.Organic layer anhydrous sodium sulfate drying, decompressionAfter distillation, crude product silica gel column chromatography separating purification (petrol ether/ethyl acetate=10:1-3:1) target product 4.25g is obtained,Yield 77.8%,1H-NMR(300MHz,DMSO-d6) δ ppm 8.75-8.83 (m, 2H), 8.59 (s, 1H), 8.39 (dd, 1H),3.90 (s, 2H), 3.71 (s, 3H), EI-MS m/z [m]+：273.
Step B：The preparation of ([3,3 '-bipyridyl] -6- carbonyls) glycine methyl ester
By ([3,3 '-bipyridyl] -6- carbonyls) glycine methyl ester (2.73g, 10mmol), 3- pyridine boronic acids (1.35g,11mmol) it is dissolved in 20ml dioxane/ethanol (1:1) potassium carbonate 3.0g and [1,1'- double (diphenylphosphine) ferrocene], are addedPalladium chloride (0.14g), stirring is heated to reflux to reacting complete, is filtered to remove insoluble matter, filtrate decompression is evaporated, crude product column chromatographyIsolate and purify (petrol ether/ethyl acetate 10:1-3:1) target compound 2.15g, is obtained, yield 79.3%,1H-NMR(300MHz,DMSO-d6) δ ppm 9.30 (m, 2H), 8.75 (dd, 1H), 8.62 (s, 1H), 8.55 (s, 2H), 8.43 (m, 1H),7.61 (t, 1H) 3.89 (s, 2H), 3.65 (s, 3H), EI-MS m/z [m]+：272.1.
Step C：The preparation of ([3,3 '-bipyridyl] -6- carbonyls) glycine
([3,3 '-bipyridyl] -6- carbonyls) glycine methyl ester (2.00g, 7.4mmol) is dissolved in 20ml tetrahydrofurans, adds1N lithium hydroxide 5ml, 50 DEG C of reactions are heated to complete, decompression evaporates solvent, adds 5% hydrochloric acid 10ml, is dispersed with stirring solid,Filter, dry and obtain off-white powder 1.2g, yield 63.1%,1H-NMR(300MHz,DMSO-d6) δ ppm 12.96 (s, 1H),9.28 (d, 2H), 8.73 (m, 1H), 8.59 (s, 1H), 8.53 (s, 2H), 8.41 (m, 1H), 7.55 (t, 1H) 3.75 (s, 2H),EI-MS m/z[m]+：258.1.
Embodiment 2
6 '-chloro- [3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 6- chloro-3-pyridyls boric acid (1.73g, 11mmol) will be used to replace 3- pyridine boronSour (1.35g, 11mmol) is reacted, and obtains white solid object 1.45g,1H-NMR(300MHz,DMSO-d6)δppm12.94 (s, 1H), 9.27 (s, 1H), 9.15 (d, 1H), 8.70 (s, 1H), 8.59 (d, 2H), 8.41 (s, 2H), 7.55 (t, 1H)3.73 (s, 2H), EI-MS m/z [m]+：292.1.
Embodiment 3
(6 '-phenyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 6- phenyl -3- pyridine boronic acids (2.19g, 11mmol) will be used to replace 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g,1H-NMR(300MHz,DMSO-d6)δppm12.95 (s, 1H), 9.27 (s, 1H), 9.01 (d, 1H), 8.68 (s, 1H), 8.56 (d, 2H), 8.35 (m, 2H), 8.05 (d,1H), 7.92 (m, 1H) 7.57 (m, 3H) 3.72 (s, 2H), EI-MS m/z [m]+：334.1.
Embodiment 4
(6 '-benzyloxy-[3,3 '-bipyridyl] -6- carbonyls) glycine
In step B 6- benzyloxy -3- pyridine boronic acids (2.52g, 11mmol) will be used to replace 3- pyridines as described in Example 1Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.64g, H-NMR (300MHz, DMSO-d6)δppm12.95 (s, 1H), 9.27 (s, 1H), 8.64 (s, 1H), 8.56 (s, 2H), 8.11 (m, 2H), 7.48 (m, 2H), 7.41 (t,2H), 7.35 (m, 1H), 6.87 (d, 1H) 4.51 (s, 2H), 3.71 (s, 2H), EI-MS m/z [m]+：364.2.
Embodiment 5
(6 '-ethyoxyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 6- ethyoxyl -3- pyridine boronic acids (1.84g, 11mmol) will be used to replace 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.85g, H-NM (300MHz, DMSO-d6)δppm12.98 (s, 1H), 9.27 (s, 1H), 8.63 (s, 1H), 8.55 (s, 2H), 8.11 (m, 2H), 6.77 (d, 1H), 4.51 (m,2H), 3.72 (s, 2H), 1.35 (s, 3H), EI-MS m/z [m]+：302.1.
Embodiment 6
(6 '-methoxyl group-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 6- methoxyl group -3- pyridine boronic acids (1.68g, 11mmol) will be used to replace 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.90g, H-NM (300MHz, DMSO-d6)δppm12.98 (s, 1H), 9.26 (s, 1H), 8.64 (s, 1H), 8.56 (s, 2H), 8.11 (m, 2H), 6.76 (d, 1H), 3.81 (s,3H), 3.71 (s, 2H), EI-MS m/z [m]+：288.2.
Embodiment 7
(6 '-ethyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 6- ethyl -3- pyridine boronic acids (1.66g, 11mmol) will be used to replace 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.75g, H-NM (300MHz, DMSO-d6)δppm12.98 (s, 1H), 9.25 (s, 1H), 9.01 (s, 1H), 8.64 (s, 1H), 8.54 (s, 2H), 8.05 (d, 1H), 7.46 (d,1H), 3.71 (s, 2H), 3.52 (m, 2H), 1.33 (t, 3H), EI-MS m/z [m]+：286.1.
Embodiment 8
(6 '-methyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 6- methyl -3- pyridine boronic acids (1.51g, 11mmol) will be used to replace 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm12.98 (s, 1H), 9.25 (s, 1H), 9.05 (s, 1H), 8.63 (s, 1H), 8.55 (s, 2H), 8.10 (d, 1H), 7.36 (d,1H), 3.72 (s, 2H), 2.33 (s, 3H), EI-MS m/z [m]+：272.1.
Embodiment 9
5 '-chloro- [3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 5- chloro-3-pyridyls boric acid (1.73g, 11mmol) will be used to replace 3- pyridine boronSour (1.35g, 11mmol) is reacted, and obtains white solid object 1.45g, H-NM (300MHz, DMSO-d6)δppm12.98 (s, 1H), 9.31 (s, 1H), 9.25 (s, 1H), 8.90 (d, 1H), 8.63 (s, 1H), 8.55 (s, 2H), 8.45 (d,1H), 3.72 (s, 2H), EI-MS m/z [m]+：292.1.
Embodiment 10
(5 '-phenyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 5- phenyl -3- pyridine boronic acids (2.19g, 11mmol) will be used to replace 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g, H-NM (300MHz, DMSO-d6)δppm12.98 (s, 1H), 9.36 (d, 2H), 9.25 (s, 1H), 8.65 (s, 1H), 8.55 (s, 2H), 8.45 (d, 1H), 7.53 (m,2H), 7.45 (m, 2H) 7.39 (t, 1H), 3.70 (s, 2H), EI-MS m/z [m]+：334.1.
Embodiment 11
(5 '-phenoxy group-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 5- phenyl -3- pyridine boronic acids (2.19g, 11mmol) will be used to replace 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g, H-NM (300MHz, DMSO-d6)δppm13.01 (s, 1H), 9.25 (s, 1H), 8.98 (s, 1H), 8.65 (s, 1H), 8.55 (s, 2H), 8.40 (d, 1H), 7.75 (s,1H), 7.35 (m, 2H), 7.00 (t, 1H), 6.95 (m, 2H), 3.69 (s, 2H), EI-MS m/z [m]+：350.1.
Embodiment 12
(5 '-benzyloxy-[3,3 '-bipyridyl] -6- carbonyls) glycine
In step B 5- benzyloxy -3- pyridine boronic acids (2.52g, 11mmol) will be used to replace 3- pyridines as described in Example 1Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.64g, H-NM (300MHz, DMSO-d6)δppm12.99 (s, 1H), 9.25 (s, 1H), 9.00 (d, 1H), 8.65 (s, 1H), 8.55 (s, 2H), 8.38 (d, 1H), 7.71 (s,1H), 7.45 (t, 2H), 7.38 (t, 2H), 7.29 (m, 1H), 4.85 (s, 2H), 3.68 (s, 2H), EI-MS m/z [m]+：364.2。
Embodiment 13
(5 '-ethyoxyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 5- ethyoxyl -3- pyridine boronic acids (1.84g, 11mmol) will be used to replace 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.85g, H-NM (300MHz, DMSO-d6)δppm12.98 (s, 1H), 9.25 (s, 1H), 9.00 (d, 1H), 8.64 (s, 1H), 8.56 (s, 2H), 8.40 (d, 1H), 7.69 (s,1H), 4.15 (m, 2H), 3.68 (s, 2H), 1.35 (t, 3H), EI-MS m/z [m]+：302.1.
Embodiment 14
(5 '-methoxyl group-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 5- methoxyl group -3- pyridine boronic acids (1.68g, 11mmol) will be used to replace 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.90g, H-NM (300MHz, DMSO-d6)δppm13.00 (s, 1H), 9.24 (s, 1H), 9.00 (d, 1H), 8.64 (s, 1H), 8.55 (s, 2H), 8.40 (d, 1H), 7.72 (s,1H), 3.85 (s, 3H), 3.68 (s, 2H), EI-MS m/z [m]+：288.2.
Embodiment 15
(5 '-ethyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 5- ethyl -3- pyridine boronic acids (1.66g, 11mmol) will be used to replace 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.75g, H-NM (300MHz, DMSO-d6)δppm13.01 (s, 1H), 9.25 (s, 1H), 9.18 (s, 1H), 8.64 (s, 1H), 8.55 (s, 2H), 8.50 (s, 1H), 8.05 (s,1H), 3.69 (s, 2H), 2.75 (m, 2H) 1.28 (m, 3H), EI-MS m/z [m]+：286.1.
Embodiment 16
(5 '-methyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 5- methyl -3- pyridine boronic acids (1.51g, 11mmol) will be used to replace 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm12.98 (s, 1H), 9.25 (s, 1H), 9.20 (s, 1H), 8.64 (s, 1H), 8.55 (m, 3H), 8.05 (s, 1H), 3.67 (s,2H), 2.55 (s, 3H), EI-MS m/z [m]+：272.1.
Embodiment 17
2 '-chloro- [3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 2- chloro-3-pyridyls boric acid (1.73g, 11mmol) will be used to replace 3- pyridine boronSour (1.35g, 11mmol) is reacted, and obtains white solid object 1.45g, H-NM (300MHz, DMSO-d6)δppm12.98 (s, 1H), 9.26 (s, 1H), 8.63 (s, 1H), 8.56 (m, 2H), 8.45 (m, 2H), 7.85 (m, 1H), 3.67 (s,2H), EI-MS m/z [m]+：292.1.
Embodiment 18
(2 '-phenyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 2- phenyl -3- pyridine boronic acids (2.19g, 11mmol) will be used to replace 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g, H-NM (300MHz, DMSO-d6)δppm12.98 (s, 1H), 9.25 (s, 1H), 8.64 (s, 1H), 8.56 (m, 2H), 8.45 (m, 1H), 8.21 (m, 2H) 7.80 (m,1H), 7.70 (m, 2H), 7.51 (t, 1H), 7.15 (m, 1H), 3.67 (s, 2H), EI-MS m/z [m]+：334.1.
Embodiment 19
(2 '-benzyloxy-[3,3 '-bipyridyl] -6- carbonyls) glycine
In step B 2- benzyloxy -3- pyridine boronic acids (2.52g, 11mmol) will be used to replace 3- pyridines as described in Example 1Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.64g, H-NM (300MHz, DMSO-d6)δppm13.01 (s, 1H), 9.26 (s, 1H), 8.64 (s, 1H), 8.55 (m, 2H), 8.12 (m, 1H), 7.50 (m, 2H), 7.40-7.30(m, 5H), 6.38 (s, 2H), 3.68 (s, 2H), EI-MS m/z [m]+：364.2.
Embodiment 20
(2 '-ethyoxyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 2- ethyoxyl -3- pyridine boronic acids (1.84g, 11mmol) will be used to replace 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.85g, H-NM (300MHz, DMSO-d6)δppm12.99 (s, 1H), 9.26 (s, 1H), 8.63 (s, 1H), 8.55 (m, 2H), 8.08 (m, 1H), 7.30 (m, 1H), 6.38 (m,1H), 4.35 (m, 2H), 3.68 (s, 2H), 1.36 (m, 3H), EI-MS m/z [m]+：302.1.
Embodiment 21
(2 '-methoxyl group-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 2- methoxyl group -3- pyridine boronic acids (1.68g, 11mmol) will be used to replace 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.90g, H-NM (300MHz, DMSO-d6)δppm12.98 (s, 1H), 9.25 (s, 1H), 8.65 (s, 1H), 8.55 (m, 2H), 8.08 (m, 1H), 7.30 (m, 1H), 6.45 (m,1H), 4.05 (s, 3H), 3.65 (s, 2H), EI-MS m/z [m]+：288.2.
Embodiment 22
(2 '-ethyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 2- ethyl -3- pyridine boronic acids (1.66g, 11mmol) will be used to replace 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.75g, H-NM (300MHz, DMSO-d6)δppm12.98 (s, 1H), 9.26 (s, 1H), 8.65 (s, 1H), 8.55 (m, 3H), 8.02 (m, 1H), 7.40 (m, 1H), 3.67 (s,2H), 3.38 (m, 2H), 1.35 (m, 3H), EI-MS m/z [m]+：286.1.
Embodiment 23
(2 '-methyl-[3,3 '-bipyridyl] -6- carbonyls) glycine
As described in Example 1, in step B 2- methyl -3- pyridine boronic acids (1.51g, 11mmol) will be used to replace 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm12.98 (s, 1H), 9.25 (s, 1H), 8.63 (m, 2H), 8.55 (s, 2H), 8.05 (m, 1H), 7.40 (m, 1H), 3.67 (s,2H), 2.89 (s, 3H), EI-MS m/z [m]+：272.1.
Embodiment 24
(5- hydroxyls-[3,3 '-bipyridyl] -6- carbonyls) glycine
Step A：The preparation of the bromo- 3- hydroxyls -2- pyridine carboxylic acids of 5-
The bromo- 3- hydroxyls -2- pyridine carboxylic acids methyl esters (5.0g, 21.55mmol) of 5-, methanol 100ml and 6N sodium hydroxide is moltenLiquid 20ml is added in 500ml reaction bulbs, heating response 2 hours, methanol is evaporated, and adjusts PH to acidity, 100ml ethyl acetate pointExtract twice, merge organic phase, anhydrous sodium sulfate drying, be evaporated, obtain white solid object 4.2g, yield 89.3%, H-NM(300MHz,DMSO-d6) δ ppm 14.85 (s, 1H), 12.28 (s, 1H), 8.63 (m, 1H), 8.05 (s, 1H), EI-MS m/z[m]+：217.9.
Step B：The bromo- 3- hydroxyls -2- pyridine glycine methyl esters of 5-
By the bromo- 3- hydroxyls -2- pyridine carboxylic acids (3.00g, 22.94mmol) of 5-, glycine methyl ester hydrochloride (3.44g,27.53mmol) it is added to DMF 30ml in reactor, is separately added into triethylamine (11.5ml) and HBTU(10.5g, 27.53mmol).Reaction solution is stirred at room temperature overnight, is quenched with water, adds saline solution 50ml, and use 100mlEthyl acetate extracts at twice, merges organic layer, and anhydrous sodium sulfate drying filters, and filtrate decompression is evaporated to obtain white solid meshMark thing 3.05g, yield 76.6%, H-NM (300MHz, DMSO-d6) δ ppm 14.89 (s, 1H), 8.63 (m, 1H), 8.45 (s,1H), 8.08 (s, 1H) 3.79 (s, 2H), 3.58 (s, 3H), EI-MS m/z [m]+：289.1.Step C：(5- hydroxyls-[3,3 '-Bipyridyl] -6- carbonyls) glycine methyl ester
By the bromo- 3- hydroxyls -2- pyridine glycines methyl esters (2.89g, 10mmol) of 5- and 3- pyridine boronic acids (1.35g,11mmol) it is dissolved in 20ml dioxane/ethanol (1:1) potassium carbonate 3.0g and [1,1'- double (diphenylphosphine) ferrocene], are addedPalladium chloride (0.14g), stirring is heated to reflux to reacting complete, is filtered to remove insoluble matter, filtrate decompression is evaporated, crude product column chromatographyIsolate and purify (petrol ether/ethyl acetate 1:1-1:3) target compound 2.1g, is obtained, yield 73.2%, H-NM (300MHz,DMSO-d6) δ ppm 14.93 (s, 1H), 9.23 (s, 1H), 9.01 (s, 1H), 8.78 (m, 1H), 8.63 (s, 1H), 8.35 (d,1H), 8.13 (s, 1H), 7.50 (t, 1H), 3.69 (s, 2H), 3.55 (s, 3H), EI-MS m/z [m]+：288.1.
Step D：(5- hydroxyls-[3,3 '-bipyridyl] -6- carbonyls) glycine
(5- hydroxyls-[3,3 '-bipyridyl] -6- carbonyls) glycine methyl ester (2.00g, 6.96mmol) is dissolved in 20ml tetrahydrochysene furansMutter, add 1N lithium hydroxide 5ml, be heated to 50 DEG C of reactions to complete, decompression evaporates solvent, adds 5% hydrochloric acid 10ml, stirring pointSolid is dissipated, is filtered, drying obtains off-white powder 1.25g, yield 65.8%, H-NM (300MHz, DMSO-d6)δppm 14.95(s, 1H), 13.00 (s, 1H), 9.25 (s, 1H), 9.00 (s, 1H), 8.75 (m, 1H), 8.63 (s, 1H), 8.35 (d, 1H),8.13 (s, 1H), 7.53 (t, 1H), 3.72 (s, 2H), EI-MS m/z [m]+：274.0.
Embodiment 25
(6 '-chloro- 5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 6- chloro-3-pyridyls boric acid (1.73,11mmol) in step C is replaced into 3- pyridine basinsBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.75g, H-NM (300MHz, DMSO-d6)δppm14.95 (s, 1H), 12.98 (s, 1H), 9.15 (s, 1H), 9.01 (s, 1H), 8.63 (s, 1H), 8.35 (m, 1H), 8.16 (d,1H), 7.52 (d, 1H), 3.69 (s, 2H), EI-MS m/z [m]+：308.1.
Embodiment 26
(6 '-phenyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 6- phenyl -3- pyridine boronic acids (2.19g, 11mmol) in step C are replaced into 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.53g, H-NM (300MHz, DMSO-d6)δppm14.95 (s, 1H), 12.99 (s, 1H), 8.95 (s, 1H), 8.91 (s, 1H), 8.63 (s, 1H), 8.35 (m, 2H), 8.17 (d,1H), 8.02 (d, 1H), 7.76 (m, 1H), 7.50 (m, 2H), 7.45 (m, 1H), 3.69 (s, 2H), EI-MS m/z [m]+：350.1。
Embodiment 27
(6 '-benzyloxy -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 6- benzyloxy -3- pyridine boronic acids (2.52,11mmol) in step C are replaced into 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 2.0g, H-NM (300MHz, DMSO-d6)δppm14.95 (s, 1H), 12.99 (s, 1H), 8.98 (s, 1H), 8.63 (s, 1H), 8.19 (d, 1H), 8.05 (m, 2H), 7.76 (m,1H), 7.50 (m, 2H), 7.42 (t, 2H), 7.30 (m, 1H), 6.78 (d, 1H), 5.10 (s, 1H), 3.68 (s, 2H), EI-MSm/z[m]+：380.1.
Embodiment 28
(6 '-ethyoxyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 6- ethyoxyl -3- pyridine boronic acids (1.84g, 11mmol) in step C are replaced into 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g, H-NM (300MHz, DMSO-d6)δppm14.98 (s, 1H), 13.03 (s, 1H), 8.98 (s, 1H), 8.65 (s, 1H), 8.18 (d, 1H), 8.05 (m, 2H), 6.78 (d,1H), 4.50 (s, 2H), 3.68 (s, 2H), 1.35 (m, 3H), EI-MS m/z [m]+：318.1.
Embodiment 29
(6 '-methoxyl group -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 6- methoxyl group -3- pyridine boronic acids (1.68g, 11mmol) in step C are replaced into 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.60g, H-NM (300MHz, DMSO-d6)δppm14.99 (s, 1H), 13.00 (s, 1H), 8.99 (s, 1H), 8.65 (s, 1H), 8.17 (d, 1H), 8.06 (m, 2H), 6.75 (d,1H), 3.75 (s, 3H), 3.68 (s, 2H), EI-MS m/z [m]+：304.1.
Embodiment 30
(6 '-ethyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 6- ethyl -3- pyridine boronic acids (1.66g, 11mmol) in step C are replaced into 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm14.98 (s, 1H), 13.00 (s, 1H), 8.99 (m, 2H), 8.63 (s, 1H), 8.18 (d, 1H), 8.06 (m, 1H), 7.35 (d,1H), 3.68 (s, 2H), 3.45 (m, 2H), 1.35 (m, 3H), EI-MS m/z [m]+：302.1.
Embodiment 31
(6 '-methyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 6- methyl -3- pyridine boronic acids (1.37g, 11mmol) in step C are replaced into 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm14.99 (s, 1H), 13.01 (s, 1H), 9.01 (m, 2H), 8.63 (s, 1H), 8.18 (s, 1H), 8.06 (m, 1H), 7.35 (d,1H), 3.68 (s, 2H), 2.48 (s, 3H), EI-MS m/z [m]+：302.1.
Embodiment 32
5 '-chloro- 5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 5- chloro-3-pyridyls boric acid (1.73,11mmol) in step C is replaced into 3- pyridine basinsBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.75g, H-NM (300MHz, DMSO-d6)δppm14.98 (s, 1H), 12.98 (s, 1H), 9.25 (s, 1H), 9.01 (m, 2H) 8.87 (s, 1H), 8.63 (s, 1H), 8.30 (s,1H), 3.68 (s, 2H), EI-MS m/z [m]+：308.1.
Embodiment 33
(5 '-phenyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 5- phenyl -3- pyridine boronic acids (2.19g, 11mmol) in step C are replaced into 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.53g, H-NM (300MHz, DMSO-d6)δppm14.99 (s, 1H), 13.01 (s, 1H), 9.31 (d, 2H), 9.01 (s, 1H), 8.63 (s, 1H), 8.37 (s, 1H), 8.20 (m,1H), 7.48 (m, 2H), 7.42 (m, 2H), 7.36 (m, 1H), 3.68 (s, 2H), EI-MS m/z [m]+：350.1.
Embodiment 34
(5 '-phenoxy group -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 5- phenoxy group -3- pyridine boronic acids (2.19g, 11mmol) in step C are replaced into 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.53g, H-NM (300MHz, DMSO-d6)δppm14.98 (s, 1H), 12.98 (s, 1H), 9.01 (m, 2H), 8.63 (s, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.69 (s,1H), 7.30 (m, 2H), 7.00 (m, 1H), 6.89 (m, 2H), 3.67 (s, 2H), EI-MS m/z [m]+：366.1.
Embodiment 35
(5 '-benzyloxy -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 5- benzyloxy -3- pyridine boronic acids (2.52,11mmol) in step C are replaced into 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 2.0g, H-NM (300MHz, DMSO-d6)δppm14.98 (s, 1H), 12.98 (s, 1H), 9.01 (m, 2H), 8.63 (s, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.45 (m,2H), 7.38 (m, 2H), 7.31 (m, 1H), 5.20 (s, 2H), 3.67 (s, 2H), EI-MS m/z [m]+：366.1 EI-MS m/z[m]+：380.1.
Embodiment 36
(5 '-ethyoxyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 5- ethyoxyl -3- pyridine boronic acids (1.84g, 11mmol) in step C are replaced into 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g, H-NM (300MHz, DMSO-d6)δppm15.03 (s, 1H), 13.02 (s, 1H), 9.01 (m, 2H), 8.63 (s, 1H), 8.39 (d, 1H), 8.20 (d, 1H), 7.75 (m,1H), 4.10 (dd, 2H), 3.67 (s, 2H), 1.35 (t, 3H), EI-MS m/z [m]+：318.1.
Embodiment 37
(5 '-methoxyl group -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 5- methoxyl group -3- pyridine boronic acids (1.68g, 11mmol) in step C are replaced into 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.60g, H-NM (300MHz, DMSO-d6)δppm15.02 (s, 1H), 13.00 (s, 1H), 9.00 (m, 2H), 8.63 (s, 1H), 8.39 (d, 1H), 8.20 (d, 1H), 7.72 (m,1H), 3.85 (s, 3H), 3.67 (s, 2H), EI-MS m/z [m]+：304.1.
Embodiment 38
(5 '-ethyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 5- ethyl -3- pyridine boronic acids (1.66g, 11mmol) in step C are replaced into 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm15.00 (s, 1H), 12.99 (s, 1H), 9.21 (d, 1H), 9.00 (s, 1H), 8.63 (s, 1H), 8.50 (s, 1H), 8.20 (d,1H), 8.00 (d, 1H), 3.67 (s, 2H), 2.75 (m, 2H), 1.34 (t, 3H), EI-MS m/z [m]+：302.1.
Embodiment 39
(5 '-methyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 5- methyl -3- pyridine boronic acids (1.37g, 11mmol) in step C are replaced into 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm15.00 (s, 1H), 13.00 (s, 1H), 9.21 (d, 1H), 9.00 (s, 1H), 8.66 (s, 1H), 8.53 (s, 1H), 8.20 (d,1H), 8.01 (d, 1H), 3.67 (s, 2H), 2.45 (s, 3H), EI-MS m/z [m]+：302.1.
Embodiment 40
2 '-chloro- 5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 2- chloro-3-pyridyls boric acid (1.73,11mmol) in step C is replaced into 3- pyridine basinsBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.75g, H-NM (300MHz, DMSO-d6)δppm14.99 (s, 1H), 12.98 (s, 1H), 9.00 (s, 1H), 8.65 (s, 1H) 8.50 (m, 1H), 8.39 (m, 1H), 8.20 (d,1H), 7.85 (m, 1H), 3.68 (s, 2H), EI-MS m/z [m]+：308.1.
Embodiment 41
(2 '-phenyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 2- phenyl -3- pyridine boronic acids (2.19g, 11mmol) in step C are replaced into 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.53g, H-NM (300MHz, DMSO-d6)δppm15.01 (s, 1H), 13.01 (s, 1H), 9.01 (d, 1H), 8.65 (s, 1H), 8.47 (m, 1H), 8.20 (m, 3H), 7.83 (d,1H), 7.68 (m, 2H), 7.49 (m, 1H), 7.15 (m, 1H), 3.68 (s, 2H), EI-MS m/z [m]+：350.1.
Embodiment 42
(2 '-benzyloxy -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 2- benzyloxy -3- pyridine boronic acids (2.52,11mmol) in step C are replaced into 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 2.0g, H-NM (300MHz, DMSO-d6)δppm15.03 (s, 1H), 13.02 (s, 1H), 8.98 (m, 1H), 8.65 (s, 1H), 8.18 (s, 1H), 8.10 (m, 1H), 7.49 (m,2H), 7.41 (m, 2H), 7.30 (m, 2H), 6.58 (m, 1H), 5.21 (s, 2H), 3.67 (s, 2H), EI-MS m/z [m]+：380.1。
Embodiment 43
(2 '-ethyoxyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 2- ethyoxyl -3- pyridine boronic acids (1.84g, 11mmol) in step C are replaced into 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g, H-NM (300MHz, DMSO-d6)δppm14.98 (s, 1H), 12.99 (s, 1H), 8.99 (m, 1H), 8.63 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 7.35 (m,1H), 6.56 (m, 1H), 4.38 (m, 2H), 3.67 (s, 2H), 1.35 (m, 3H), EI-MS m/z [m]+：318.1.
Embodiment 44
(2 '-methoxyl group -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 2- methoxyl group -3- pyridine boronic acids (1.68g, 11mmol) in step C are replaced into 3- pyrrolesPyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.60g, H-NM (300MHz, DMSO-d6)δppm15.01 (s, 1H), 13.01 (s, 1H), 9.01 (m, 1H), 8.63 (s, 1H), 8.56 (m, 1H) 8.19 (d, 1H), 8.10 (d,1H), 7.32 (m, 1H), 4.05 (s, 3H), 3.67 (s, 2H), EI-MS m/z [m]+：304.1.
Embodiment 45
(2 '-ethyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 2- ethyl -3- pyridine boronic acids (1.66g, 11mmol) in step C are replaced into 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm15.00 (s, 1H), 12.99 (s, 1H), 9.01 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.20 (d, 1H), 8.01 (d,1H), 7.40 (s, 1H), 3.67 (s, 2H), 3.35 (m, 2H), 1.34 (t, 3H), EI-MS m/z [m]+：302.1.
Embodiment 46
(2 '-methyl -5- hydroxyls-[2,2 '-bipyridyl] -6- carbonyls) glycine
By the method for embodiment 24, the 2- methyl -3- pyridine boronic acids (1.37g, 11mmol) in step C are replaced into 3- pyridinesBoric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm15.01 (s, 1H), 12.99 (s, 1H), 9.01 (d, 1H), 8.63 (m, 2H), 8.20 (d, 1H), 8.01 (d, 1H), 7.40 (m,1H), 3.67 (s, 2H), 2.89 (s, 3H), EI-MS m/z [m]+：302.1.