CN107417605A - Act on the pyridine derivative compound of prolyl hydroxylase - Google Patents
Act on the pyridine derivative compound of prolyl hydroxylase Download PDFInfo
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- CN107417605A CN107417605A CN201710653887.8A CN201710653887A CN107417605A CN 107417605 A CN107417605 A CN 107417605A CN 201710653887 A CN201710653887 A CN 201710653887A CN 107417605 A CN107417605 A CN 107417605A
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- Prior art keywords
- glycine
- bipyridyl
- carbonyls
- hydroxyls
- formula
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- -1 pyridine derivative compound Chemical class 0.000 title claims abstract description 21
- 102000004079 Prolyl Hydroxylases Human genes 0.000 title description 6
- 108010043005 Prolyl Hydroxylases Proteins 0.000 title description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 280
- 239000004471 Glycine Substances 0.000 claims description 140
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 66
- OFDVABAUFQJWEZ-UHFFFAOYSA-N 3-pyridin-3-ylpyridine Chemical group C1=CN=CC(C=2C=NC=CC=2)=C1 OFDVABAUFQJWEZ-UHFFFAOYSA-N 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 claims description 7
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 4
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- DLVNOCMKUDMRFP-UHFFFAOYSA-N 2-chloro-3-pyridin-3-ylpyridine Chemical compound ClC1=NC=CC=C1C1=CC=CN=C1 DLVNOCMKUDMRFP-UHFFFAOYSA-N 0.000 claims description 3
- YCGSHYGAGAYBMU-UHFFFAOYSA-N 2-chloro-5-pyridin-3-ylpyridine Chemical compound C1=NC(Cl)=CC=C1C1=CC=CN=C1 YCGSHYGAGAYBMU-UHFFFAOYSA-N 0.000 claims description 3
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- WDWSGRUKYZNPDY-UHFFFAOYSA-N 2-methyl-5-pyridin-3-ylpyridine Chemical compound C1=NC(C)=CC=C1C1=CC=CN=C1 WDWSGRUKYZNPDY-UHFFFAOYSA-N 0.000 claims description 3
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
Abstract
The present invention relates to the pyridine derivative compound suitable for the related symptom of the mediation for the treatment of hypoxia inducible factor and/or hematopoietin.The pyridine derivative compound of the present invention has following structure：
Description
Technical 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 hematopoietin
Pyridine derivative compound.
Background technology
Hypoxia inducible factor (hypoxia inducible factor, HIF) be one kind be widely present in mammal and
Transcription 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 cell
In 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, and
HIF- 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 to
Rely degraded (oxygen dependent degradation, ODD) domain and transcription activating domain (transcription
Activation domain, TAD) (N-TAD and C-TAD), both have 42% structural homology；HIF-3 α two level egg
White 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 α
Property.
HIF-1 α are influenceed closely by oxygen concentration level.Under the conditions of normal oxygen, PHD hydroxylating HIF- α subunits, by hydroxyl
The 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；Low
Under 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- β
1.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 transporters
1, GluT-1), insulin-like growth factor-2 (insulin-like growth factor 2, IGF-2), Endothelin receptor A, turn iron
Albumen etc..
The content of the invention
The invention provides the micromolecular compound that can suppress HIF prolyl hydroxylases (PHD) activity, its mechanism of action
To cause HIF-a content to raise so as to increase EPO generation and secretion by suppressing PHD enzymatic activitys, promote erythrocyte maturation
With 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, appoint
Selection 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 hydroxyl
Base, 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 or
Hydrochloride, 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 palladium
Metal salt；
Step 3：Formula (VI) hydrolyzes obtain formula (I) in the basic conditions, wherein the alkali used is sodium hydroxide, potassium hydroxide
Or lithium hydroxide；
Wherein step 1, when R1 is hydroxyl, condensing agent HATU, HBTU or PyBOP, preferably HBTU；Palladium in step 2
Metal salt preferably [double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride；Wherein step 3, organic solvent are methanol, ethanol, four
Hydrogen 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)；Elsevier
Publisher (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 acid
Sodium/20ug/ml catalyzing enzymes), measure buffer solution contains the Sf9 cells in baculoviral-infection of 0.15ug/ml FIAG- marks
The middle total length PHD2 for expressing and purifying.At room temperature after pre-incubation 30min, by adding 14ul substrates (0.2uM 2- ketone penta 2
The 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- marks
And 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 665nm
With 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) and
100ml dichloromethane is added in 500ml reactors, and EDCI (4.59g, 24.0mmol), stirring are added after stirring 15min
30min, glycine methyl ester hydrochloride (2.75g, 22.0mmol) is added, continues to stir, reacted at room temperature to complete, use respectively
100ml saturated sodium bicarbonates, 100ml washings.100ml saturated aqueous common salts wash successively.Organic layer anhydrous sodium sulfate drying, decompression
After 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 added
Palladium chloride (0.14g), stirring is heated to reflux to reacting complete, is filtered to remove insoluble matter, filtrate decompression is evaporated, crude product column chromatography
Isolate 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, adds
1N 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 boron
Sour (1.35g, 11mmol) is reacted, and obtains white solid object 1.45g,1H-NMR(300MHz,DMSO-d6)δppm
12.94 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g,1H-NMR(300MHz,DMSO-d6)δppm
12.95 (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 1
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.64g, H-NMR (300MHz, DMSO-d6)δppm
12.95 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.85g, H-NM (300MHz, DMSO-d6)δppm
12.98 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.90g, H-NM (300MHz, DMSO-d6)δppm
12.98 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.75g, H-NM (300MHz, DMSO-d6)δppm
12.98 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm
12.98 (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 boron
Sour (1.35g, 11mmol) is reacted, and obtains white solid object 1.45g, H-NM (300MHz, DMSO-d6)δppm
12.98 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g, H-NM (300MHz, DMSO-d6)δppm
12.98 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g, H-NM (300MHz, DMSO-d6)δppm
13.01 (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 1
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.64g, H-NM (300MHz, DMSO-d6)δppm
12.99 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.85g, H-NM (300MHz, DMSO-d6)δppm
12.98 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.90g, H-NM (300MHz, DMSO-d6)δppm
13.00 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.75g, H-NM (300MHz, DMSO-d6)δppm
13.01 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm
12.98 (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 boron
Sour (1.35g, 11mmol) is reacted, and obtains white solid object 1.45g, H-NM (300MHz, DMSO-d6)δppm
12.98 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g, H-NM (300MHz, DMSO-d6)δppm
12.98 (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 1
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.64g, H-NM (300MHz, DMSO-d6)δppm
13.01 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.85g, H-NM (300MHz, DMSO-d6)δppm
12.99 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.90g, H-NM (300MHz, DMSO-d6)δppm
12.98 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.75g, H-NM (300MHz, DMSO-d6)δppm
12.98 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm
12.98 (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 molten
Liquid 20ml is added in 500ml reaction bulbs, heating response 2 hours, methanol is evaporated, and adjusts PH to acidity, 100ml ethyl acetate point
Extract 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 100ml
Ethyl acetate extracts at twice, merges organic layer, and anhydrous sodium sulfate drying filters, and filtrate decompression is evaporated to obtain white solid mesh
Mark 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 added
Palladium chloride (0.14g), stirring is heated to reflux to reacting complete, is filtered to remove insoluble matter, filtrate decompression is evaporated, crude product column chromatography
Isolate 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 furans
Mutter, add 1N lithium hydroxide 5ml, be heated to 50 DEG C of reactions to complete, decompression evaporates solvent, adds 5% hydrochloric acid 10ml, stirring point
Solid 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 basins
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.75g, H-NM (300MHz, DMSO-d6)δppm
14.95 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.53g, H-NM (300MHz, DMSO-d6)δppm
14.95 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 2.0g, H-NM (300MHz, DMSO-d6)δppm
14.95 (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-MS
m/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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g, H-NM (300MHz, DMSO-d6)δppm
14.98 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.60g, H-NM (300MHz, DMSO-d6)δppm
14.99 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm
14.98 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm
14.99 (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 basins
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.75g, H-NM (300MHz, DMSO-d6)δppm
14.98 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.53g, H-NM (300MHz, DMSO-d6)δppm
14.99 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.53g, H-NM (300MHz, DMSO-d6)δppm
14.98 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 2.0g, H-NM (300MHz, DMSO-d6)δppm
14.98 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g, H-NM (300MHz, DMSO-d6)δppm
15.03 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.60g, H-NM (300MHz, DMSO-d6)δppm
15.02 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm
15.00 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm
15.00 (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 basins
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.75g, H-NM (300MHz, DMSO-d6)δppm
14.99 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.53g, H-NM (300MHz, DMSO-d6)δppm
15.01 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 2.0g, H-NM (300MHz, DMSO-d6)δppm
15.03 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.55g, H-NM (300MHz, DMSO-d6)δppm
14.98 (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- pyrroles
Pyridine boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.60g, H-NM (300MHz, DMSO-d6)δppm
15.01 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm
15.00 (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- pyridines
Boric acid (1.35g, 11mmol) is reacted, and obtains white solid object 1.65g, H-NM (300MHz, DMSO-d6)δppm
15.01 (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.
Claims (9)
1. a kind of compound, it is represented by 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, optionally
By the alkyl-substituted phenyl of-C1-4, the benzyl optionally substituted by-C1-4.
2. compound as claimed in claim 1, wherein R1 are hydrogen, R2 is selected from：Hydrogen, chlorine, phenyl, phenoxy group, benzyloxy, ethoxy
Base, methoxyl group, ethyl, methyl.
3. compound as claimed in claim 1, wherein R1 are hydroxyl, R2 is selected from：Hydrogen, chlorine, phenyl, phenoxy group, benzyloxy, second
Epoxide, methoxyl group, ethyl, methyl.
4. compound as claimed in claim 1, is：
([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.
5. prepare the method for formula (I) compound
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) is glycine methyl ester or hydrochloric acid
Salt, 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 palladium metal
Salt；
Step 3：Formula (VI) hydrolyzes obtain formula (I) in the basic conditions, wherein the alkali used is sodium hydroxide, potassium hydroxide or hydrogen
Lithia.
6. preparing the method for formula (I) compound, wherein step 1 as claimed in claim 5, when R1 is hydroxyl, condensing agent is
HATU, HBTU or PyBOP, preferably HBTU.
7. preparing the method for formula (I) compound as claimed in claim 5, wherein step 2, catalyst are palladium metal salt, preferably
[double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride.
8. preparing the method for formula (I) compound, wherein step 3 as claimed in claim 5, organic solvent is methanol, ethanol, four
Hydrogen furans or its mixing.
9. compound as claimed in claim 1, preparing the purposes in being used to suppress the medicine of HIF hydrogenase activities.
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| CN114315794A (en) * | 2022-01-19 | 2022-04-12 | 中国药科大学 | 5-aliphatic heterocyclic group-3-hydroxypyridine-2-formyl glycine compound, preparation method, pharmaceutical composition and application |
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