CN109879804B - 5-heterocyclic substituted pyridine-2-formyl glycine compound, preparation method and medical application thereof - Google Patents
5-heterocyclic substituted pyridine-2-formyl glycine compound, preparation method and medical application thereof Download PDFInfo
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- CN109879804B CN109879804B CN201910088775.1A CN201910088775A CN109879804B CN 109879804 B CN109879804 B CN 109879804B CN 201910088775 A CN201910088775 A CN 201910088775A CN 109879804 B CN109879804 B CN 109879804B
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- formyl
- compound
- tetrahydrofuran
- hydroxypyridine
- ring
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
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Images
Abstract
The present invention relates to the field of pharmaceutical chemistry. In particular to a 5-heterocyclic ring substituted pyridine-2-formyl glycine compound (I), a pharmaceutical composition containing the compound and a preparation method thereof, and pharmacodynamic tests prove that the compound has prolyl hydroxylase inhibitionThe preparation has therapeutic effect on anemia and ischemia.
Description
Technical Field
The present invention relates to the field of medicinal chemistry. In particular to a 5-heterocyclic ring substituted pyridine-2-formyl glycine compound, a pharmaceutical composition containing the compound, a preparation method thereof and medical application of the compound as a prolyl hydroxylase inhibitor in aspects of anemia, ischemic diseases and the like.
Background
Anemia is a hematological disorder characterized by a decrease in the blood cell or hemoglobin content of the circulatory system, and anemia can be caused by chronic kidney disease, tumors, inflammation, malnutrition, familial genetic disorders, and a number of drugs. Anemia caused by malnutrition is commonly found in women, children and the elderly, and is generally treated by supplementing iron and vitamins. Thalassemia is the most common familial hereditary anemia and is usually treated by means of blood transfusion or iron chelators (Am J Hematol.88(2013) 409-. The synthesis of Erythropoietin (EPO) is hindered by chronic kidney disease, chemotherapy and inflammatory diseases, wherein EPO analogs or erythropoiesis-stimulating agents (ESAs) are routinely prescribed for the treatment of Chronic Kidney Disease (CKD) anemia. However, clinical studies show that ESA has disadvantages of low reactivity or drug resistance on the one hand and risk of causing cardiovascular disease or accelerating the progression of malignant tumors on the other hand (j.med.chem.61(2018) 6964-6982). The low reactivity of ESAs is associated with a variety of factors, such as iron deficiency, chronic hyperparathyroidism, low serum albumin levels, elevated aluminum levels, malnutrition, dialysis under suboptimal conditions, drug therapy (angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statins), and the like. Iron deficiency is the most common cause of ESA hyporesponsiveness in maintenance hemodialysis patients (Blood purification.33 (2012) 238-244). Although intravenous administration of iron agents can increase ESA reactivity, the attendant risk of infection is inevitable. Therefore, there is a need to develop a safe and effective alternative therapy.
EPO is synthesized primarily by the kidney and is one of the most important hormones in the hypoxia response and erythropoiesis. Renal EPO-producing cells (REPC) are present in the renal cortex and the outer medullary sites. EPO binds to EPO receptor (EPOR) on erythroid colony forming units (CFU-E), proerythroid, and promyelocytic, causing EPOR to be phosphorylated by tyrosine kinase JAK2, activating downstream signaling pathways, and thereby inhibiting apoptosis of erythroid progenitors (Blood rev.27(2013) 41-53). The expression level of the cell surface membrane protein CD95 of the erythroid progenitor cells is a key factor for regulating and controlling the apoptosis of the erythroid progenitor cells, and EPO can reduce the expression level of CD95 so as to promote the differentiation and maturation of the erythroid progenitor cells (Nat Rev Nephrol.11(2015) 394-410). Hypoxia Inducible Factor (HIF) is a key transcription factor that induces cellular adaptation under hypoxic partial pressure conditions, with a total of 3 subtypes, of which HIF-1 primarily regulates metabolic responses, while HIF-2 is directly associated with EPO production. HIF-2 consists of two subunits, and cytoplasmic HIF-2. alpha. nuclear entry forms a homodimer with HIF-2. beta. which in turn binds to Hypoxia Response Element (HRE) on DNA, stimulating EPO gene expression (Expert opin ther targets.20(2016) 287-301). The concentration level of HIF is regulated by Prolyl Hydroxylase (PHD), which can hydroxylate HIF and initiate the ubiquitination proteasome pathway, activating E3SCF ubiquitin ligase under the synergistic effect of COP9 signal complex, ubiquitin-like protein NEDD8, degrading HIF (Nat Rev Drug discov.13(2014) 852-869). Under normoxic conditions, PHD is highly active and HIF is not stable. Inhibiting the catalytic activity of PHD can simulate the stress reaction under the anoxic state and promote the generation of red blood cells.
The HIF pathway is involved in iron metabolism in the body while regulating EPO synthesis. HIF-2 can up-regulate the transcription levels of divalent metal ion transporter 1(DMT1) and duodenal cytochrome b (DCYTB), and promote the absorption of iron in the intestinal tract. Meanwhile, the transcription levels of transferrin, transferrin receptor (TFR1), ceruloplasmin, cellular heme oxygenase-1 (HO-1) and Ferroportin (FPN) are improved, and the transport of iron ions is promoted. Erythroblasts stimulated with EPO increase the expression of Erythropoietin (ERFR), thereby inhibiting hepatic hepcidin synthesis and stabilizing the FPN levels (Exp Cell Res.356(2017) 160-165). Therefore, PHD inhibitors achieve the effect of stimulating erythropoiesis by affecting complex signal transduction pathways at the transcriptional level, with fewer side effects than the direct administration of recombinant human EPO or ESA, and without additional supplementation of iron agents (Med Hypotheses.82(2014) 547-550).
Disclosure of Invention
The invention discloses a 5-heterocyclic ring substituted pyridine-2-formylglycine compound with novel structure and prolyl hydroxylase inhibiting effect and a pharmaceutically acceptable salt thereof. The structural formula (I) is as follows:
wherein A represents a five-to seven-membered saturated azamonocyclic ring containing 1 to 2 nitrogen atoms, a spiro ring composed of the above azamonocyclic ring, or a bridged ring composed of the above azamonocyclic ring;
ar represents a monocyclic aryl group consisting of six ring atoms;
l represents a linking chain between A and Ar having a length of 1 to 4 atoms, the linking chain backbone atoms being selected from carbon, nitrogen, oxygen or sulfur atoms and containing at least one carbon atom, wherein the carbon atom on the linking chain may be replaced by a carbonyl group;
r represents one or more substituents optionally substituted on the aromatic ring, the substituents being selected from C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Alkylamino radical, C1-C3Alkanoyl radical, C1-C3Haloalkyl, halogen, cyano, hydroxy or amino.
A preferably represents
L preferably represents
The invention also includes pharmaceutically acceptable salts of the compounds of the general formula I and solvates thereof, which have the same pharmacological effects as the compounds of the general formula I.
There are two forms of pharmaceutically acceptable salts of the compounds of formula I: one is a salt with an acid; the other is a salt with an alkali metal. Acids which form pharmaceutically acceptable salts with the compounds of formula I include inorganic and organic acids. Suitable inorganic acids include: hydrochloric acid, sulfuric acid and phosphoric acid. Suitable organic acids include formic, acetic, propionic, succinic, lactic, tartaric, citric, fumaric, and the like. Alkali metals which form pharmaceutically acceptable salts with the compounds shown in the general formula I comprise lithium, sodium, potassium, magnesium, calcium, aluminum, zinc and the like; the base which forms a pharmaceutically acceptable salt with the compound shown in the general formula I comprises choline, diethanolamine, morpholine and the like.
The invention also discloses a pharmaceutical composition which comprises the general formula I and pharmaceutically acceptable salts or solvates thereof, and one or more pharmaceutically acceptable carriers, diluents and excipients.
The invention also provides the use of a compound of formula i and/or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for inhibiting prolyl hydroxylase, for the treatment of a disease mediated by the enzyme, which therapeutic effect is achieved by the inhibition of prolyl hydroxylase.
The invention also provides the use of a compound of formula I and/or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of anemia or ischemic disease. Wherein the anemia comprises anemia caused by nephritis, kidney injury, rheumatoid arthritis, rheumatic fever, inflammatory bowel disease and tumor chemotherapy. Ischemic diseases include ischemic stroke or myocardial ischemia-related diseases.
The compounds of formula I of the present invention can be prepared by the following process:
wherein A, Ar, L and R are defined as before.
Coupling a raw material II with a nitrogen-containing side chain under the conditions of alkali and a catalyst, wherein the alkali is selected from hexamethyldisilazane lithium amide, cesium carbonate and sodium tert-butoxide, preferably sodium tert-butoxide, and the catalyst can be selected from different combinations of palladium and ligands, preferably palladium acetate and 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine; removing the benzyl protecting group of the intermediate III to obtain an intermediate IV under the action of boron trifluoride diethyl etherate; and finally, carrying out ester hydrolysis on the intermediate IV to obtain the general formula I.
Pharmacodynamic tests prove that the compound has strong prolyl hydroxylase inhibitory activity and can effectively stabilize HIF-alpha so as to achieve the effect of promoting the generation and secretion of EPO.
The pharmacological experiments and results of part of the compounds of the invention are as follows:
first, fluorescence polarization experiment
The prolyl hydroxylase protein and Fluorescein Isothiocyanate (FITC) labeled HIF peptide segment (HIF-1 alpha 556-574) are incubated together with compound solutions with different concentrations, and the ability of competitive combination of the compound and the protein is investigated. The compound can occupy the site of a key cofactor 2-OG, so that HIF can not be combined with protein, and HIF which is not combined with prolyl hydroxylase has high rotation speed and low fluorescence polarization value in solution. According to the characteristic, the prolyl hydroxylase inhibition activity of the compound is indirectly reflected by measuring the fluorescence polarization value of the compound. The compounds were triply diluted to 12 concentration gradients, 20uL was added to a 384 well plate (model Corning #3575), and equal volumes of protein and peptide fragments were added sequentially to give final concentrations of 250nM and 3nM, respectively. And (3) incubating for 1h at 4 ℃ in a shaking table, detecting by adopting a SpectraMax i3x multifunctional enzyme-labeling instrument, wherein the excitation wavelength is 485nm, the emission wavelength is 535nm, and the test result is analyzed by Graphpadprism 6. The results of testing representative compounds are shown in table 1. The blank control used in the test was 20ul HIF peptide +40ul buffer, the negative control was 20ul HIF peptide +20ul protein +20ul buffer, and the positive control was marketed drug FG-4592 (Roxadustat). The buffer solution formula is 10mM hepes,150mM NaCl,10 mu M MnCl2,20μM 2-OG,0.05％Tween-20,pH 7.4。
TABLE 1 prolyl hydroxylase inhibitory Activity of the Compounds of the invention
As shown in Table 1, the compound of the present invention has strong prolyl hydroxylase 2 inhibitory activity, 14 compounds IC50Less than 1 μ M,3 of them having better activity than the positive drug FG-4592.
Second, luciferase reporter gene experiment
HIF-alpha can regulate expression of downstream EPO gene as transcription factor, in order to verify that the compound of the embodiment can stabilize HIF-alpha and stimulate EPO production, the invention designs a dual-luciferase reporter gene experiment regulated by Hypoxia Response Element (HRE). Plasmids with luciferase reporter inserted downstream of HRE were tested. When HIF-alpha exists stably and is incorporated into nucleus, HRE promoter activity can be activated, and the expression of downstream luciferase can be regulated. After adding a luciferin substrate, luminescence can be produced by the expressed luciferase. The intensity of luminescence may indirectly reflect the amount of HIF- α stably present. The results of testing representative compounds are shown in table 2.
TABLE 2 increasing cellular HIF- α levels with compounds of the invention
Third, the immunoblotting experiment (Western blot)
The invention adopts a protein immunoblotting method to detect the expression level of HIF-1 alpha and HIF-2 alpha. We selected example 25 showing better activity in both fluorescence polarization experiments and dual-luciferase reporter gene experiments, and used FG-4592 as a positive control, and administered compounds at two concentrations of 50. mu.M and 250. mu.M using human hepatoma cell Hep3B, and after overnight incubation, the expression levels of HIF-1. alpha. and HIF-2. alpha. were measured. Experimental results as shown in fig. 1, example 25 was able to significantly stabilize HIF- α.
Drawings
FIG. 1 is a graph showing the up-regulation of HIF-1. alpha. and HIF-2. alpha. levels in Hep3B cells by compounds of the invention.
Detailed Description
Example 1
(3-benzyloxy-5- (4- (4-chlorobenzyl) piperazin-1-yl) pyridine-2-formyl) glycine methyl ester
(3-benzyloxy-5-bromopyridine-2-formyl) glycine methyl ester (400mg, 1.05mmol) was dissolved in 10mL of acetone, 1- (4-chlorobenzyl) piperazine (265mg, 1.26mmol) and potassium carbonate (435mg, 3.15mmol) were added, the temperature was raised to 70 ℃ and the reaction was completed under reflux under nitrogen atmosphere for 5 h. After completion of the reaction, potassium carbonate was removed by suction filtration, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol 20:1) to obtain 280mg of a pale yellow oil with a yield of 52.4%. m.p.200.9-202.3 ℃.1H NMR (500MHz, Chloroform-d) δ 8.88(d, J ═ 1.4Hz,1H),8.29(t, J ═ 9.7Hz,1H),7.42(ddq, J ═ 6.9,1.8,1.0Hz,2H), 7.39-7.27 (m,7H),7.03(d, J ═ 1.4Hz,1H),5.22(t, J ═ 1.0Hz,2H),4.16(d, J ═ 9.7Hz,2H), 3.68-3.62 (m,4H),3.33(t, J ═ 7.1Hz,4H),3.01(t, J ═ 7.1Hz,2H),2.92(t, J ═ 7.1, 2H); EI-MS M/z 509[ M + H]+。
(5- (4- (4-chlorobenzyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine methyl ester
(3-benzyloxy-5- (4- (4-chlorobenzyl) piperazin-1-yl) pyridine-2-formyl) glycine methyl ester (280mg, 0.55mmol) was dissolved in 10mL of dichloromethane, boron trifluoride ether solution (1mL, 8.04mmol) was added, heated to 45 ℃ and refluxed under nitrogen for 4h, the reaction was complete. After completion of the reaction, 5mL of a saturated ammonium chloride solution was added thereto, and the mixture was quenched, separated, washed with water (2X 5mL) and saturated brine (1X 5mL), respectively, and dried over anhydrous sodium sulfate to obtain 215mg of a yellow oily substance with a yield of 93.5%. m.p.172.1-174.5 ℃.1H NMR (500MHz, Chloroform-d) δ 8.33-8.25 (m,1H),7.78(d, J ═ 1.4Hz,1H), 7.37-7.28 (m,4H),7.01(d, J ═ 1.4Hz,1H),4.13(d, J ═ 9.8Hz,2H),3.71(s,2H),3.60(t, J ═ 0.9Hz,2H),3.35(t, J ═ 7.1Hz,4H),3.05(t, J ═ 7.1Hz,2H),2.90(t, J ═ 7.1Hz, 2H); EI-MS m/z419[M+H]+。
(5- (4- (4-chlorobenzyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (4-chlorobenzyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.24mmol) was dissolved in 2mL tetrahydrofuran, 1mL water, lithium hydroxide monohydrate (60mg, 1.44mmol) was added, and the mixture was stirred at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until light yellow solid is separated out, and the product 64mg is obtained after suction filtration and drying, wherein the yield is 66.3%. m.p.195.7-197.3 ℃.1H NMR(500MHz,Chloroform-d)δ8.85(d,J＝1.4Hz,1H),8.33(t,J＝10.2Hz,1H),7.37–7.28(m,4H),7.03(d,J＝1.4Hz,1H),4.07(d,J＝10.1Hz,2H),3.64(dt,J＝12.4,0.9Hz,1H),3.56(dt,J＝12.5,1.0Hz,1H),3.34(t,J＝7.1Hz,4H),3.05(t,J＝7.1Hz,2H),2.90(t,J＝7.0Hz,2H)；EI-MS m/z 405[M+H]+。
Example 2
(5- (4- (4-Chloroethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (4-chlorophenethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.23mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (58mg, 1.38mmol) was added and stirred at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until yellow solid is separated out, and 72mg of product is obtained after suction filtration and drying, and the yield is 74.4%. m.p.179.9-181.5 ℃.1H NMR(500MHz,Chloroform-d)δ8.32(t,J＝10.3Hz,1H),7.78(d,J＝1.4Hz,1H),7.37–7.31(m,2H),7.19(dt,J＝7.5,1.0Hz,2H),7.01(d,J＝1.4Hz,1H),4.07(d,J＝10.1Hz,2H),3.33(t,J＝7.1Hz,4H),2.85–2.78(m,2H),2.75–2.68(m,6H)；EI-MS m/z 419[M+H]+。
Example 3
(5- (4- (3- (4-chlorophenyl) propyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
(5- (4- (3- (4-chlorophenyl) propyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine methyl ester (100mg, 0.22mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (55mg, 1.32mmol) and room temperature were addedStirring for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until light yellow solid is separated out, and the product is obtained after filtration and drying, wherein the yield is 70.2%. m.p.192.0-194.2 ℃.1H NMR(500MHz,Chloroform-d)δ8.32(t,J＝10.3Hz,1H),7.78(d,J＝1.5Hz,1H),7.30–7.25(m,2H),7.10(dt,J＝7.4,1.0Hz,2H),7.01(d,J＝1.5Hz,1H),4.07(d,J＝10.3Hz,2H),3.33(t,J＝7.1Hz,4H),2.71(t,J＝7.1Hz,6H),2.53(t,J＝7.1Hz,2H),1.84(p,J＝7.1Hz,2H)；EI-MS m/z 433[M+H]+。
Example 4
(5- (4- (2- (4-chlorophenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (2- (4-chlorophenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.22mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (55mg, 1.32mmol) was added, followed by stirring at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until light yellow solid is separated out, and the product 65mg is obtained after suction filtration and drying, and the yield is 67.1%. m.p.158.2-160.6 ° c.1H NMR (500MHz, Chloroform-d) δ 8.32(t, J ═ 10.3Hz,1H),7.78(d, J ═ 1.4Hz,1H), 7.29-7.23 (m,2H),7.01(d, J ═ 1.5Hz,1H), 6.98-6.93 (m,2H), 4.12-4.04 (m,4H),3.33(t, J ═ 7.1Hz,4H),2.80(t, J ═ 7.1Hz,2H),2.75(t, J ═ 7.1Hz, 4H); EI-MS M/z 435[ M + H ]]+。
Example 5
(5- (4- (3- (4-chlorophenoxy) propyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (3- (4-chlorophenoxy) propyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.22mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (55mg, 1.32mmol) was added, followed by stirring at room temperature for 30 min. After the reaction is finished, removing tetrahydrofuran in the reaction liquid by reduced pressure distillation, adding 6mmol/L hydrochloric acid until light yellow solid is separated out, performing suction filtration and drying to obtain a product of 80mg, wherein the yield is 82.5%. m.p.163.5-165.0 ℃.1H NMR (500MHz, Chloroform-d) δ 8.85(d, J ═ 1.4Hz,1H), 8.38-8.31 (m,1H), 7.28-7.23 (m,2H),7.01(d, J ═ 1.4Hz,1H), 6.97-6.92 (m,2H),4.07(d, J ═ 10.2Hz,2H)),4.01(t,J＝7.1Hz,2H),3.31(t,J＝7.0Hz,4H),2.76(t,J＝7.1Hz,2H),2.70(t,J＝7.1Hz,2H),2.65(t,J＝7.0Hz,2H),1.88(p,J＝7.1Hz,2H)；EI-MS m/z 449[M+H]+。
Example 6
(5- (4- (2- ((4-chlorophenyl) amino) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (2- ((4-chlorophenyl) amino) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.22mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (55mg, 1.32mmol) was added, and the mixture was stirred at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until light yellow solid is separated out, and the product 76mg is obtained after suction filtration and drying, and the yield is 78.4%. m.p.208.6-210.4 ℃.1H NMR (500MHz, Chloroform-d) δ 8.32(t, J ═ 10.3Hz,1H),7.78(d, J ═ 1.4Hz,1H), 7.14-7.08 (m,2H),7.01(d, J ═ 1.4Hz,1H), 6.67-6.61 (m,2H),5.92(t, J ═ 5.8Hz,1H),4.07(d, J ═ 10.3Hz,2H),3.56(td, J ═ 7.1,5.6Hz,2H),3.34(t, J ═ 7.1Hz,4H),2.78(t, J ═ 7.1Hz,2H),2.71(t, J ═ 7.1, 4H); EI-MS M/z 434[ M + H [)]+。
Example 7
(5- (4- (3- ((4-chlorophenyl) amino) propyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (3- ((4-chlorophenyl) amino) propyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.22mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (55mg, 1.32mmol) was added, and the mixture was stirred at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until light yellow solid is separated out, and the product 58mg is obtained after suction filtration and drying, wherein the yield is 59.8%. m.p.199.7-201.3 ℃.1H NMR (500MHz, Chloroform-d) δ 8.85(d, J ═ 1.4Hz,1H), 8.38-8.31 (m,1H), 7.17-7.11 (m,2H),7.01(d, J ═ 1.4Hz,1H), 6.69-6.63 (m,2H),6.38(t, J ═ 5.8Hz,1H),4.07(d, J ═ 10.3Hz,2H),3.31(t, J ═ 7.1Hz,4H),3.19(td, J ═ 7.0,5.7Hz,2H),2.72(t, J ═ 7.1Hz,4H),2.54(t, J ═ 7.1, 2H), p.07 (p, 7.1, 2H),2.07(p, H),2.07 (H); EI-MS 448[ M + H]+。
Example 8
(5- (4- (2- ((4-chlorophenyl) thio) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (2- ((4-chlorophenyl) thio) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.22mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (55mg, 1.32mmol) was added, and the mixture was stirred at room temperature for 30 min. After the reaction is finished, removing tetrahydrofuran in the reaction liquid by reduced pressure distillation, adding 6mmol/L hydrochloric acid until grey solid is separated out, performing suction filtration and drying to obtain 77mg of product with the yield of 79.4%. m.p.182.0-184.1 ℃.1H NMR (500MHz, Chloroform-d) δ 8.85(d, J ═ 1.4Hz,1H),8.32(t, J ═ 10.2Hz,1H), 7.36-7.30 (m,2H), 7.30-7.24 (m,2H),7.01(d, J ═ 1.4Hz,1H),4.07(d, J ═ 10.3Hz,2H),3.33(t, J ═ 7.1Hz,4H),3.08(t, J ═ 7.0Hz,2H),2.76(t, J ═ 7.0Hz,4H),2.66(t, J ═ 7.1Hz, 2H); EI-MS 451[ M + H ]]+。
Example 9
(5- (4- (3- ((4-chlorophenyl) thio) propyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (3- ((4-chlorophenyl) thio) propyl) piperazin-1-yl) -3-hydroxypyridine-2-carbonyl) glycinate (100mg, 0.21mmol) was dissolved in 2mL of tetrahydrofuran, 1mL of water, lithium hydroxide monohydrate (53mg, 1.26mmol) was added, and the mixture was stirred at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until gray solid is separated out, and the product 65mg is obtained after suction filtration and drying, and the yield is 66.9%. m.p.171.9-174.0 ℃.1H NMR (500MHz, Chloroform-d) δ 8.87(d, J ═ 1.4Hz,1H),8.32(t, J ═ 9.7Hz,1H), 7.38-7.32 (m,2H), 7.30-7.24 (m,2H),7.00(d, J ═ 1.6Hz,1H),4.15(d, J ═ 9.7Hz,2H),3.66(s,2H),3.31(t, J ═ 7.1Hz,4H),2.93(t, J ═ 7.1Hz,2H),2.70(t, J ═ 7.1Hz,4H),2.60(t, J ═ 7.1Hz,2H),1.73(p, J ℃, (7.1, 2H); EI-MS 465[ M + H]+。
Example 10
(5- (4- (2- ((4-chlorophenyl) sulfonyl) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
(5- (4- (2- ((4-chlorophenyl) sulfonyl) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine methyl ester (100mg, 0.20mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate ((R))50mg, 1.20mmol), stirring at room temperature for 30 min. After the reaction, tetrahydrofuran in the reaction solution was removed by distillation under reduced pressure, 6mmol/L hydrochloric acid was added to precipitate a white solid, which was then filtered off by suction and dried to obtain 81mg of a product with a yield of 83.3%. m.p.158.8-160.3 ℃.1H NMR (500MHz, Chloroform-d) δ 8.87(d, J ═ 1.4Hz,1H),8.34(t, J ═ 10.2Hz,1H), 7.93-7.88 (m,2H), 7.61-7.55 (m,2H),7.00(d, J ═ 1.6Hz,1H),4.07(d, J ═ 10.1Hz,2H),3.52(t, J ═ 7.1Hz,2H),3.30(t, J ═ 7.0Hz,4H),2.92(t, J ═ 7.0Hz,2H),2.78(t, J ═ 7.1Hz, 4H); EI-MS 483[ M + H]+。
Example 11
(5- (4- (3- ((4-chlorophenyl) sulfonyl) propyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (3- ((4-chlorophenyl) sulfonyl) propyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.20mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (50mg, 1.20mmol) was added, and the mixture was stirred at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until white solid is separated out, and 74mg of product is obtained after suction filtration and drying, wherein the yield is 76.1%. m.p.164.2-166.9 ℃.1H NMR (500MHz, Chloroform-d) δ 8.87(d, J ═ 1.4Hz,1H),8.32(t, J ═ 10.2Hz,1H), 7.88-7.82 (m,2H), 7.61-7.55 (m,2H),7.01(d, J ═ 1.4Hz,1H),4.07(d, J ═ 10.3Hz,2H),3.29(dt, J ═ 20.9,7.1Hz,6H),2.72(t, J ═ 7.0Hz,4H),2.62(t, J ═ 7.0Hz,2H),1.96(p, J ═ 7.1Hz, 2H); EI-MS 497[ M + H]+。
Example 12
(5- (4- (4-chlorobenzoyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (4-chlorobenzoyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycinate (100mg, 0.23mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (58mg, 1.38mmol) was added and stirred at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until light yellow solid is separated out, and the product 60mg is obtained after suction filtration and drying, wherein the yield is 62.0%. m.p.155.9-157.4 ℃.1H NMR (500MHz, Chloroform-d) δ 8.32(t, J ═ 10.3Hz,1H),7.78(d, J ═ 1.4Hz,1H), 7.53-7.48 (m,2H), 7.48-7.43 (m,2H),7.01(d, J ═ 1H)1.4Hz,1H),4.07(d,J＝10.1Hz,2H),3.65(t,J＝7.1Hz,4H),3.21(t,J＝7.1Hz,4H)；EI-MS 419[M+H]+。
Example 13
(5- (4- (2- (4-chlorophenyl) acetyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (2- (4-chlorophenyl) acetyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycinate (100mg, 0.22mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (55mg, 1.32mmol) was added, followed by stirring at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until light yellow solid is separated out, and the product is obtained after suction filtration and drying, wherein the yield is 77.4%. m.p.179.1-181.5 ℃.1H NMR (500MHz, Chloroform-d) δ 8.32(t, J ═ 10.3Hz,1H),7.78(d, J ═ 1.4Hz,1H), 7.40-7.34 (m,2H),7.29(dt, J ═ 7.5,1.1Hz,2H),7.01(d, J ═ 1.4Hz,1H),4.07(d, J ═ 10.3Hz,2H),3.67(t, J ═ 1.0Hz,2H),3.58(t, J ═ 7.0Hz,4H),3.29(t, J ═ 7.1Hz,2H),3.16(t, J ═ 7.1Hz, 2H); EI-MS 433[ M + H ]]+。
Example 14
(5- (4- (3- (4-chlorophenyl) propionyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (3- (4-chlorophenyl) propionyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycinate (100mg, 0.22mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (55mg, 1.32mmol) was added, followed by stirring at room temperature for 30 min. After the reaction is finished, removing tetrahydrofuran in the reaction liquid by reduced pressure distillation, adding 6mmol/L hydrochloric acid until light yellow solid is separated out, performing suction filtration and drying to obtain 69mg of product, wherein the yield is 71.1%. m.p.165.5-167.2 ℃.1H NMR (500MHz, Chloroform-d) δ 8.85(d, J ═ 1.4Hz,1H), 8.38-8.31 (m,1H), 7.33-7.28 (m,2H),7.15(dt, J ═ 7.5,1.1Hz,2H),7.01(d, J ═ 1.4Hz,1H),4.07(d, J ═ 10.3Hz,2H),3.69(t, J ═ 7.1Hz,4H),3.31(t, J ═ 7.0Hz,2H),3.16(t, J ═ 7.0Hz,2H),2.91(tt, J ═ 7.1,1.1Hz,2H),2.68(t, J ═ 7.0, 2H); EI-MS447[ M + H ]]+。
Example 15
(5- (3- (2- (4-chlorophenoxy) ethyl) imidazolidin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (3- (2- (4-chlorophenoxy) ethyl) imidazolidin-1-yl) -3-hydroxypyridine-2-formyl) glycine ester (100mg, 0.23mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (58mg, 1.38mmol) was added thereto, followed by stirring at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until light yellow solid is separated out, and 53mg of product is obtained after suction filtration and drying, and the yield is 54.8%. m.p.202.8-204.4 ℃.1H NMR (500MHz, Chloroform-d) δ 8.32(t, J ═ 10.3Hz,1H),7.78(d, J ═ 1.5Hz,1H), 7.29-7.23 (m,2H), 7.03-6.95 (m,3H),4.32(d, J ═ 0.7Hz,2H),4.12(t, J ═ 7.1Hz,2H),4.07(d, J ═ 10.1Hz,2H),3.64(t, J ═ 7.0Hz,1H),3.58(t, J ═ 7.0Hz,1H),2.91(dt, J ═ 23.7,7.1Hz, 4H); EI-MS 421[ M + H]+。
Example 16
(5- (4- (2- (4-chlorophenoxy) ethyl) -1, 4-diazepan-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (2- (4-chlorophenoxy) ethyl) -1, 4-diazepan-1-yl) -3-hydroxypyridine-2-formyl) glycinate (100mg, 0.22mmol) was dissolved in 2mL of tetrahydrofuran, 1mL of water, lithium hydroxide monohydrate (55mg, 1.32mmol) was added, and the mixture was stirred at room temperature for 30 min. After the reaction, tetrahydrofuran in the reaction solution was removed by distillation under reduced pressure, 6mmol/L hydrochloric acid was added to precipitate a pale yellow solid, which was then filtered off and dried to give 61mg of a product with a yield of 62.9%. m.207.6-209.5 ° c.1H NMR (500MHz, Chloroform-d) δ 8.85(d, J ═ 1.4Hz,1H), 8.38-8.31 (m,1H), 7.29-7.23 (m,2H),7.00(d, J ═ 1.6Hz,1H), 6.98-6.93 (m,2H), 4.13-4.04 (m,4H),3.50(dt, J ═ 12.3,7.1Hz,1H), 3.47-3.38 (m,3H),2.82(t, J ═ 7.1Hz,2H),2.62(td, J ═ 7.1,5.5Hz,4H),1.79(p, J ═ 7.2Hz, 2H); EI-MS 449[ M + H ]]+。
Example 17
(5- (4- (2- (4-chlorophenoxy) ethyl) piperidin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (2- (4-chlorophenoxy) ethyl) piperidin-1-yl) -3-hydroxypyridine-2-formyl) glycinate (100mg, 0.22mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (55mg, 1.32mmol) was added thereto, followed by stirring at room temperature for 30 min. After the reaction, the tetrahydrofuran in the reaction solution was removed by distillation under reduced pressure,6mmol/L hydrochloric acid is added until light yellow solid is precipitated, and the product is obtained after suction filtration and drying, wherein the yield is 79.5 percent. m.p.169.2-171.8 ℃.1H NMR (500MHz, Chloroform-d) δ 8.32(t, J ═ 10.2Hz,1H),7.76(d, J ═ 1.5Hz,1H), 7.28-7.23 (m,2H),7.01(d, J ═ 1.6Hz,1H), 7.00-6.94 (m,2H),4.07(d, J ═ 10.2Hz,2H),4.01(t, J ═ 7.1Hz,2H), 3.54-3.44 (m,2H), 3.47-3.37 (m,2H), 1.82-1.66 (m, 8H); EI-MS 434[ M + H]+。
Example 18
(5- (7- (2- (4-chlorophenoxy) ethyl) -2, 7-diazaspiro [4.4] non-2-yl) -3-hydroxypyridine-2-formyl) glycine
(5- (7- (2- (4-chlorophenoxy) ethyl) -2, 7-diazaspiro [4.4]]Methyl nonan-2-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.20mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (50mg, 1.20mmol) was added and stirred at room temperature for 30 min. After the reaction is finished, removing tetrahydrofuran in the reaction liquid by reduced pressure distillation, adding 6mmol/L hydrochloric acid until light yellow solid is separated out, performing suction filtration and drying to obtain a product 57mg, wherein the yield is 58.8%. m.p.184.4-186.0 ℃.1H NMR (500MHz, Chloroform-d) δ 8.85(d, J ═ 1.5Hz,1H),8.34(t, J ═ 10.2Hz,1H), 7.29-7.23 (m,2H),7.00(d, J ═ 1.5Hz,1H), 6.98-6.93 (m,2H), 4.18-4.04 (m,3H), 4.04-3.96 (m,1H), 3.60-3.54 (m,1H), 3.51-3.36 (m,3H),2.97(td, J ═ 7.1,2.1Hz,2H), 2.82-2.76 (m,1H), 2.71-2.60 (m,2H),2.50 (J, 12.12, 1H), 1.83-2H, 2.83 (m, 2H); EI-MS 475[ M + H ]]+。
Example 19
(5- (9- (2- (4-chlorophenoxy) ethyl) -3, 9-diazaspiro [5.5] undecan-3-yl) -3-hydroxypyridine-2-formyl) glycine
(5- (9- (2- (4-chlorophenoxy) ethyl) -3, 9-diazaspiro [5.5]]Undecane-3-yl) -3-hydroxypyridine-2-formyl) glycine methyl ester (100mg, 0.19mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (48mg, 1.14mmol) was added, followed by stirring at room temperature for 30 min. After the reaction is finished, removing tetrahydrofuran in the reaction liquid by reduced pressure distillation, adding 6mmol/L hydrochloric acid until light yellow solid is separated out, performing suction filtration and drying to obtain 55mg of a product, wherein the yield is 56.5%. m.p.196.1-198.3 ℃.1H NMR (500MHz, Chloroform-d) δ 8.87(d, J ═ 1.4Hz,1H),8.34(t, J ═ 10.2Hz,1H), 7.34.29–7.23(m,2H),7.01(d,J＝1.6Hz,1H),7.00–6.94(m,2H),4.15–4.07(m,3H),4.06(s,1H),3.52(t,J＝7.1Hz,4H),2.97(t,J＝7.1Hz,2H),2.55(t,J＝7.1Hz,4H),1.78(t,J＝7.1Hz,4H),1.64(t,J＝7.1Hz,4H)；EI-MS 503[M+H]+。
Example 20
(5- (5- (2- (4-chlorophenoxy) ethyl) -2, 5-diazabicyclo [2.2.1] hept-2-yl) -3-hydroxypyridine-2-formyl) glycine
(5- (5- (2- (4-chlorophenoxy) ethyl) -2, 5-diazabicyclo [ 2.2.1)]Hept-2-yl) -3-hydroxypyridine-2-formyl) glycine methyl ester (100mg, 0.22mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (55mg, 1.32mmol) was added, followed by stirring at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until brown solid is separated out, and the product 70mg is obtained after suction filtration and drying, and the yield is 72.2%. m.p.212.5-214.8 ℃.1H NMR (500MHz, Chloroform-d) δ 8.83(d, J ═ 1.5Hz,1H),8.35(t, J ═ 10.2Hz,1H), 7.29-7.23 (m,2H),7.04(d, J ═ 1.5Hz,1H), 6.98-6.93 (m,2H), 4.18-4.09 (m,2H),4.06(dt, J ═ 12.5,7.1Hz,1H),4.00(dd, J ═ 12.4,10.2Hz,1H),3.83(p, J ═ 7.0Hz,1H),3.33(dd, J ═ 12.4,7.0Hz,1H),3.24(dd, J ═ 9.9, J ═ 7.0Hz,1H),3.33(dd, J ═ 12.4,7.0, 1H),3.24(dd, J ═ 12.9, 9.9, 2H), 1.81, 2H, 1H, 12.2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2, 1, 2H, 2, 1H, 2H, 1H, 7, 1H, 2, 1H, 2, 1H, 2, 1H, 2, 1,2, 1H, 2, 1H, 2, 1,7, 1,2, 1H, 1H, 7, 2,7, 1H, 2, 1,2, 1; EI-MS447[ M + H ]]+。
Example 21
(5- (5- (2- (4-chlorophenoxy) ethyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) -3-hydroxypyridine-2-carbonyl) glycine
(5- (5- (2- (4-chlorophenoxy) ethyl) -2, 5-diazabicyclo [ 2.2.2)]Oct-2-yl) -3-hydroxypyridine-2-formyl) glycine methyl ester (100mg, 0.21mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (53mg, 1.26mmol) was added, followed by stirring at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until brown solid is separated out, and the product 65mg is obtained after suction filtration and drying, and the yield is 67.0%. m.p.206.8-208.3 ℃.1H NMR (500MHz, Chloroform-d) δ 8.88(d, J ═ 1.5Hz,1H),8.34(t, J ═ 10.2Hz,1H), 7.29-7.23 (m,2H),7.04(d, J ═ 1.5Hz,1H), 6.98-6.93 (m,2H), 4.18-4.08 (m,2H),4.07(dt, J ═ 1H), n12.5,7.1Hz,1H),4.00(dd,J＝12.4,10.2Hz,1H),3.78(p,J＝7.0Hz,1H),3.37–3.15(m,4H),3.09–2.98(m,2H),3.00–2.92(m,1H),1.98–1.74(m,5H)；EI-MS 461[M+H]+。
Example 22
(5- (4- (2-phenoxyethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (2-phenoxyethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.24mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (60mg, 1.44mmol) was added and stirred at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until white solid is separated out, and the product is obtained after suction filtration and drying, wherein the yield is 85mg and 88.0%. m.p.167.7-169.2 ℃.1H NMR (500MHz, Chloroform-d) δ 8.32(t, J ═ 10.3Hz,1H),7.78(d, J ═ 1.4Hz,1H), 7.32-7.24 (m,2H),7.03(d, J ═ 1.4Hz,1H),6.94(tt, J ═ 7.5,1.5Hz,1H), 6.93-6.87 (m,2H), 4.10-4.04 (m,4H),3.33(t, J ═ 7.1Hz,4H),2.79(dd, J ═ 14.0,7.1Hz,5H),2.76(s, 1H); EI-MS 401[ M + H ]]+。
Example 23
(5- (4- (2- (p-tolyloxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (2- (p-tolyloxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.23mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (58mg, 1.38mmol) was added, and the mixture was stirred at room temperature for 30 min. After the reaction is finished, removing tetrahydrofuran in the reaction solution by reduced pressure distillation, adding 6mmol/L hydrochloric acid until white solid is separated out, performing suction filtration and drying to obtain 80mg of product, wherein the yield is 82.7%. m.p.163.1-165.8 ℃.1H NMR (500MHz, Chloroform-d) δ 8.32(t, J ═ 10.3Hz,1H),7.78(d, J ═ 1.5Hz,1H), 7.06-6.99 (m,3H), 6.87-6.81 (m,2H), 4.11-4.04 (m,4H),3.34(t, J ═ 7.0Hz,4H), 2.83-2.76 (m,5H),2.76(s,1H),2.30(d, J ═ 0.9Hz, 3H); EI-MS 415[ M + H]+。
Example 24
(5- (4- (2- (4-methoxyphenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
(5- (4- (2- (4-methoxy) phenyl)Phenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine methyl ester (100mg, 0.22mmol) was dissolved in 2mL tetrahydrofuran, and 1mL water, lithium hydroxide monohydrate (55mg, 1.32mmol) was added and stirred at room temperature for 30 min. After the reaction, tetrahydrofuran in the reaction solution was removed by distillation under reduced pressure, 6mmol/L hydrochloric acid was added to precipitate a white solid, which was then filtered off by suction and dried to give 77mg of product in 79.5% yield. m.p.172.6-174.9℃,1H NMR (500MHz, Chloroform-d) δ 8.32(t, J ═ 10.2Hz,1H),7.78(d, J ═ 1.4Hz,1H),7.01(d, J ═ 1.5Hz,1H),6.85(s,4H), 4.12-4.04 (m,4H),3.77(s,2H),3.33(t, J ═ 7.1Hz,4H),2.79(dt, J ═ 13.1,7.1Hz, 6H); EI-MS 431[ M + H ]]+。
Example 25
(5- (4- (2- (4- (trifluoromethyl) phenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (2- (4- (trifluoromethyl) phenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.21mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (53mg, 1.26mmol) was added, and the mixture was stirred at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until light yellow solid is separated out, and the product 64mg is obtained after suction filtration and drying, and the yield is 65.9%. m.p.153.2-155.0 ℃.1H NMR (500MHz, Chloroform-d) δ 8.87(d, J ═ 1.4Hz,1H),8.34(t, J ═ 10.2Hz,1H), 7.63-7.57 (m,2H), 7.02-6.96 (m,3H), 4.10-4.03 (m,4H),3.34(t, J ═ 7.1Hz,4H),2.80(t, J ═ 7.1Hz,2H),2.75(t, J ═ 7.1Hz, 4H); EI-MS 469[ M + H]+。
Example 26
(5- (4- (2- (4-fluorophenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (2- (4-fluorophenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.23mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (58mg, 1.38mmol) was added and stirred at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until yellow solid is separated out, and the product is obtained after suction filtration and drying, wherein the yield is 77.5%. m.p.161.4-163.9 deg.C.1H NMR (500MHz, Chloroform-d) delta 8.32(t, J ═ 10.3Hz,1H),7.78(d,J＝1.4Hz,1H),7.03–6.90(m,5H),4.12–4.04(m,4H),3.34(t,J＝7.0Hz,4H),2.79(dt,J＝12.5,7.1Hz,6H)；EI-MS 419[M+H]+。
Example 27
(5- (4- (2- (4-bromophenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (2- (4-bromophenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.20mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (50mg, 1.20mmol) was added, followed by stirring at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until white solid is separated out, and the product 59mg is obtained after suction filtration and drying, and the yield is 60.7%. m.p.166.6-168.5 ℃.1H NMR (500MHz, Chloroform-d) δ 8.87(d, J ═ 1.4Hz,1H),8.32(t, J ═ 10.2Hz,1H), 7.41-7.35 (m,2H),7.00(d, J ═ 1.6Hz,1H), 6.96-6.90 (m,2H), 4.13-4.05 (m,4H),3.32(t, J ═ 7.0Hz,4H),2.78(dt, J ═ 20.2,7.1Hz, 6H); EI-MS 479[ M + H ]]+。
Example 28
(5- (4- (2- (4-cyanophenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
Methyl (5- (4- (2- (4-cyanophenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine (100mg, 0.23mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (58mg, 1.38mmol) was added, and the mixture was stirred at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until white solid is separated out, and the product 70mg is obtained after suction filtration and drying, and the yield is 72.3%. m.p.158.1-160.3 ℃.1H NMR (500MHz, Chloroform-d) δ 8.32(t, J ═ 10.2Hz,1H),7.78(d, J ═ 1.5Hz,1H), 7.67-7.62 (m,2H), 7.06-6.99 (m,3H), 4.10-4.04 (m,4H),3.33(t, J ═ 7.1Hz,4H),2.79(dt, J ═ 12.7,7.1Hz, 6H); EI-MS426[ M + H ]]+。
Example 29
(5- (4- (2- (4-aminophenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine
(5- (4- (2- (4-Aminophenoxy) ethyl) piperazin-1-yl) -3-hydroxypyridine-2-formyl) glycine methyl ester (100mg, 0.2)3mmol) was dissolved in 2mL tetrahydrofuran, 1mL water, lithium hydroxide monohydrate (58mg, 1.38mmol) was added and stirred at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until light yellow solid is separated out, and the product is obtained after suction filtration and drying, wherein the yield is 64.1%. m.p.179.2-181.7 ℃.1H NMR (500MHz, Chloroform-d) δ 8.32(t, J ═ 10.3Hz,1H),7.78(d, J ═ 1.4Hz,1H),7.01(d, J ═ 1.4Hz,1H), 6.75-6.69 (m,2H), 6.52-6.46 (m,2H),5.10(d, J ═ 5.7Hz,1H),4.92(d, J ═ 5.7Hz,1H), 4.10-4.03 (m,4H),3.34(t, J ═ 7.0Hz,4H),2.79(dt, J ═ 12.2,7.1Hz, 6H); EI-MS 416[ M + H]+。
Example 30
(3-hydroxy-5- (4- (2- (4-hydroxyphenoxy) ethyl) piperazin-1-yl) pyridin-2-formyl) glycine
Methyl (3-hydroxy-5- (4- (2- (4-hydroxyphenoxy) ethyl) piperazin-1-yl) pyridin-2-formyl) glycine (100mg, 0.23mmol) was dissolved in 2mL of tetrahydrofuran, and 1mL of water, lithium hydroxide monohydrate (58mg, 1.38mmol) was added, followed by stirring at room temperature for 30 min. After the reaction is finished, tetrahydrofuran in the reaction liquid is removed through reduced pressure distillation, 6mmol/L hydrochloric acid is added until white solid is separated out, and the product is obtained after suction filtration and drying, wherein the yield is 67mg and is 69.3%. m.p.167.9-169.4 ℃.1H NMR (500MHz, Chloroform-d) δ 8.81(s,1H),8.32(t, J ═ 10.3Hz,1H),7.78(d, J ═ 1.4Hz,1H),7.01(d, J ═ 1.4Hz,1H), 6.87-6.80 (m,4H), 4.12-4.04 (m,4H),3.34(t, J ═ 7.0Hz,4H),2.79(dt, J ═ 12.5,7.1Hz, 6H); EI-MS 417[ M + H ]]+。
Claims (6)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein A represents a five-to seven-membered saturated azamonocyclic ring containing 1 to 2 nitrogen atoms, or a spiro ring composed of the above azamonocyclic ring, or a bridged ring composed of the above azamonocyclic ring, the azamonocyclic ring, spiro ring or bridged ring being
L represents a linking chain between A and Ar, said linking chain being
Ar represents a benzene ring;
r represents one or more substituents optionally substituted on the aromatic ring, the substituents being selected from C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Alkylamino radical, C1-C3Alkanoyl radical, C1-C3Haloalkyl, halogen, cyano, hydroxy or amino.
2. A process for the preparation of a compound of claim 1 comprising the steps of:
wherein A, L, Ar and R are defined as in claim 1.
3. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
4. The use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for prolyl hydroxylase inhibitor.
5. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of anemia, ischemic diseases.
6. The use of claim 5, wherein the anemia is nephritis, kidney injury, rheumatoid arthritis, rheumatic fever, inflammatory bowel disease or anemia arising from tumor chemotherapy; the ischemic disease is ischemic stroke or myocardial ischemia related disease.
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| CN101506149A (en) * | 2006-06-26 | 2009-08-12 | 宝洁公司 | Prolyl hydroxylase inhibitors and methods of use |
| CN107759564A (en) * | 2017-11-28 | 2018-03-06 | 中国药科大学 | Triazole pyridinecarboxylic glycine compounds, its method and medical usage |
| WO2018103600A1 (en) * | 2016-12-06 | 2018-06-14 | 深圳市塔吉瑞生物医药有限公司 | Substituted heteroaryl amide compound and composition comprising same and use thereof |
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| CN101506149A (en) * | 2006-06-26 | 2009-08-12 | 宝洁公司 | Prolyl hydroxylase inhibitors and methods of use |
| WO2018103600A1 (en) * | 2016-12-06 | 2018-06-14 | 深圳市塔吉瑞生物医药有限公司 | Substituted heteroaryl amide compound and composition comprising same and use thereof |
| CN107759564A (en) * | 2017-11-28 | 2018-03-06 | 中国药科大学 | Triazole pyridinecarboxylic glycine compounds, its method and medical usage |
Non-Patent Citations (1)
| Title |
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| An improved and scalable synthesis of N-(5-(4-cyanophenyl)-3-hydroxypicolinoyl)glycine, a promising PHD2 inhibitor for the treatment of anemia;Yonghua Lei et al;《Tetrahedron Letters》;20150709;第56卷;第5017-5019页 * |
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