WO2017059623A1 - 炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 - Google Patents

炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 Download PDF

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WO2017059623A1
WO2017059623A1 PCT/CN2015/095728 CN2015095728W WO2017059623A1 WO 2017059623 A1 WO2017059623 A1 WO 2017059623A1 CN 2015095728 W CN2015095728 W CN 2015095728W WO 2017059623 A1 WO2017059623 A1 WO 2017059623A1
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hydroxy
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propyne
pharmaceutically acceptable
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French (fr)
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张晓进
尤启冬
雷永华
胡天寒
吴杏森
孙昊鹏
郭小可
徐晓莉
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China Pharmaceutical University
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China Pharmaceutical University
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Priority to JP2018515119A priority Critical patent/JP6635562B2/ja
Priority to SI201531228T priority patent/SI3360862T1/sl
Priority to HK18107005.8A priority patent/HK1247613B/zh
Priority to LTEP15905721.5T priority patent/LT3360862T/lt
Priority to HRP20200907TT priority patent/HRP20200907T1/hr
Priority to KR1020187012413A priority patent/KR20180063229A/ko
Priority to PL15905721T priority patent/PL3360862T3/pl
Priority to CN201580079971.2A priority patent/CN107848976B/zh
Priority to RU2018113258A priority patent/RU2692494C1/ru
Priority to BR112018005969-2A priority patent/BR112018005969A2/zh
Priority to AU2015411258A priority patent/AU2015411258B2/en
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Priority to EP15905721.5A priority patent/EP3360862B1/en
Priority to MX2018003832A priority patent/MX379007B/es
Priority to ES15905721T priority patent/ES2794002T3/es
Priority to UAA201804628A priority patent/UA120407C2/uk
Priority to DK15905721.5T priority patent/DK3360862T3/da
Priority to US15/765,387 priority patent/US10889546B2/en
Priority to CA3000040A priority patent/CA3000040A1/en
Publication of WO2017059623A1 publication Critical patent/WO2017059623A1/zh
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Priority to US17/018,221 priority patent/US20200407319A1/en
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    • 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
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the field of medicinal chemistry. Specifically, it relates to a class of alkynyl pyridine prolyl hydroxylase inhibitors. These compounds can enhance the production and secretion of erythropoietin, which can promote the production of red blood cells, and can be used for treating or preventing anemia such as chronic kidney disease anemia and ischemic diseases such as ischemic stroke, myocardial ischemia, etc. Related diseases.
  • Anemia generally refers to any abnormality in hemoglobin or red blood cells that cause a decrease in oxygen levels in the blood. Anemia can also occur in association with chronic diseases such as chronic infections, neoplastic diseases, and chronic inflammation including subsequent inflammatory inhibition of bone marrow.
  • Chronic disease anemia is one of the most common syndromes in the medical field, such as chronic kidney disease anemia.
  • the main cause of anemia in chronic kidney disease is insufficient secretion of erythropoietin (EPO) (Nephrol Dial Transplant 17 (2002) 2-7). Insufficient secretion of EPO can block the production of red blood cells, leading to anemia.
  • EPO erythropoietin
  • the expression and secretion of EPO is regulated by the transcription factor hypoxia inducible factor (HIF).
  • the HIF protein with complete transcriptional function is composed of two subunits, HIF- ⁇ and HIF- ⁇ .
  • the HIF- ⁇ subunit is regulated by prolyl hydroxylase (PHD), and the PHD enzyme can hydroxylate HIF- ⁇ thus promotes its degradation.
  • prolyl hydroxylase 2 PHD2
  • PHD2 Journal of Medicinal Chemistry 56 (2013) 9369-9402
  • proline hydroxylase can increase the level of HIF- ⁇ , increase the production of EPO, thereby promoting the maturation of red blood cells and improving the ability of blood to transport oxygen, and improving anemia or ischemia symptoms.
  • the present invention provides a small molecule compound capable of inhibiting the activity of proline hydroxylase (PHD), which increases the content of HIF- ⁇ by inhibiting PHD enzyme, thereby increasing the production and secretion of EPO, promoting red blood cell maturation and improving blood transport.
  • PHD proline hydroxylase
  • the ability of oxygen to treat and prevent anemia and ischemic diseases such as chronic kidney disease anemia, myocardial ischemia, cerebral ischemia, stroke, etc.
  • the compounds of the invention are structured as follows:
  • X represents NH, NCH 3 or CH 2 ;
  • Y represents hydrogen, hydroxy, methoxy or ethoxy;
  • L represents -CH 2 -, -CH 2 O- or
  • R 6 represents hydrogen, C 1 -C 4 alkyl or phenyl;
  • n represents 0 or 1;
  • R 1 represents a C 1 -C 4 alkyl group, a phenyl group, a substituted phenyl group, a 5- to 6-membered aromatic heterocyclic ring containing oxygen or nitrogen, a substituted 5- or 6-membered aromatic heterocyclic ring containing oxygen or nitrogen, said substituent Is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, halogen, cyano, a phenyl group or a 5- to 6-membered aromatic heterocyclic ring containing oxygen or nitrogen, wherein R 7 represents a C 1 -C 4 alkyl group; and R 8 and R 9 each independently represent hydrogen or a C 1 -C 4 alkyl group, or R 8 And R 9 is bonded to form a nitrogen-containing heterocyclic ring of 3 to 7 members;
  • R 2 represents hydrogen, halogen or methyl
  • R 3 and R 4 each independently represent hydrogen, methyl or ethyl
  • R 5 represents a hydroxyl group, a C 1 -C 4 alkoxy group or —NR 10 R 11 ;
  • R 10 and R 11 each independently represent hydrogen, methyl or ethyl.
  • X preferably represents NH.
  • L preferably represents -CH 2 -, -CH 2 O- or
  • R 6 preferably represents hydrogen, methyl, tert-butyl or phenyl.
  • R 1 preferably represents a substituted benzene ring, and the substituent is methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, tert-butoxy, cyclopropoxy, phenyl, cyano, halogen , fluoromethyl, trifluoromethyl, imidazolyl, acetylamino, cyclopropylformamido or
  • R 8 and R 9 each independently represent hydrogen, methyl, butyl or t-butyl, or both are bonded to form a cyclopropylamino group, a tetrahydropyrrolyl group or an N-methylhomopiperazinyl group.
  • R 1 also preferably represents a cyclopropyl, tert-butyl, phenyl, naphthyl, quinolyl or benzofuranyl group.
  • R 3 or R 4 preferably represents hydrogen.
  • R 5 preferably represents -NH 2 , -NHCH 3 , hydroxy, methoxy, isopropoxy, cyclopropoxy or cyclopropyl methoxy.
  • the present invention includes both the pharmaceutically acceptable salt of the compound (I) and the solvate thereof, all having the same pharmacological effects as the compound (I).
  • the present invention discloses a pharmaceutical composition
  • a pharmaceutical composition comprising Compound (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents and excipients.
  • the present invention also provides the use of a compound of the formula (I) and/or a pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for treating the enzyme-mediated disease by inhibiting a prolyl hydroxylase, the disease As anemia, it can be treated by inhibiting prolyl hydroxylase.
  • the compound of the present invention is used in a clinical dose of 0.01 mg to 1000 mg/day, and may be deviated from this range depending on the severity of the condition or the dosage form.
  • a compound according to formula I may contain an acidic functional group sufficient to form a salt.
  • Representative salts include pharmaceutically acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum and zinc salts; pharmaceutically acceptable metal cations such as sodium, potassium, lithium, calcium, Carbonate and hydrogencarbonate of magnesium, aluminum and zinc; pharmaceutically acceptable organic primary, secondary and tertiary amines, including fatty amines, aromatic amines, fatty diamines and hydroxyalkylamines, such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanol.
  • the invention also provides a preparation method of the compound of the formula (I), comprising the following steps:
  • R 1 , R 2 , R 3 , R 4 , X, Y, n, and L are as defined above.
  • the intermediate VI can be synthesized by the following formula.
  • VEGF Vascular endothelial growth factor
  • EPO vascular endothelial growth factor
  • FG-4592 is a PHD2 inhibitor for the treatment of anemia which has now entered clinical stage III, and FG-4592 is used as a positive control compound in the present invention.
  • the compound of the present invention has a strong inhibitory activity of prolyl hydroxylase 2.
  • the patent US 2007/0299086 A1 discloses a series of prolyl hydroxylase inhibitors, wherein the structure of the compound with better activity is:
  • the compound of the present invention is characterized in that the 5-position of the pyridine nucleus contains an alkynyl group directly bonded to the pyridine ring, and the introduction of the alkynyl group at the site can greatly enhance the inhibitory activity of the compound on the prolyl hydroxylase.
  • the prolyl hydroxylase 2 (PHD2) subtype regulates HIF content, so we also determined the PHD3 inhibitory activity of representative compounds. as follows:
  • % inhibition rate 100 * (1- (measured value - blank) / (negative value - blank))
  • the compounds of the present invention have strong inhibitory activities of prolyl hydroxylase 2, 3, wherein the activity of the partial compounds is significantly better than that of the positive drug FG-4592.
  • Hep3B cells human hepatoma cells
  • the compounds of the present invention have an apparent ability to increase the levels of VEGF and EPO in the cells, and exhibit a good cell-level activity.
  • Table 4 is an experimental result showing whether some of the compounds of the present invention have an effect on the level of cellular HIF- ⁇ .
  • the compounds of the invention significantly increase the expression of VEGF, EPO at the animal level, indicating the effectiveness of the compounds of the invention at the animal level.
  • the alkynylpyridine compounds of the present invention have good biological activities at the molecular level, at the cellular level, and at the animal level.
  • the compound of the present invention can raise the level of erythropoietin (EPO) in the blood at the animal level, thereby promoting the production of red blood cells, and can be used for treating or preventing chronic disease-related anemia, ischemic diseases, and hematopoietic system-related diseases.
  • EPO erythropoietin
  • Figure 1 shows the results of immunoblot assays at the cellular level of some compounds (Hep3B cells: human hepatoma cells; compound concentration 50 ⁇ M, 250 ⁇ M, administration for 24 hours)
  • Figure 2 shows the elevated levels of VEGF and EPO in compounds 14, 15, 47, and FG-4592 after 24 h of concentration at 50 ⁇ M.
  • Experiment model: mouse C57Bl/6 male 8-9 weeks
  • the compound III 3-hydroxy-5-bromopyridinecarboxylic acid (3.47 g, 16 mmol) was dissolved in 150 mL of dichloromethane, 7.3 mL of triethylamine and HOBt (3.26 g, 24 mmol) were added, and after stirring for 10 min, EDCI (4.59 g, 24 mmol), stirred for 10 min, added glycine methyl ester hydrochloride (2.4 g, 19.2 mmol). The reaction was carried out at room temperature and stirred for 6 h. Saturated sodium bicarbonate (100 mL), washed with water (2 ⁇ 100 mL) and brine (2 ⁇ 100 mL) were successively washed.
  • Methyl 2-(3-hydroxy-5-propynyl)pyridinecaridoacetate (100.0 mg, 0.4 mmol) was dissolved in 10 mL of tetrahydrofuran, 1 mL of 1 M lithium hydroxide was added, and heated to 30 ° C for 3 h, the reaction was complete. . After the completion of the reaction, the tetrahydrofuran in the reaction mixture was removed by pressure distillation, and 3 mmol of dilute hydrochloric acid was added under ice-cooling, and a white solid was taken out, and then filtered and dried to give a white product, 61.0 mg, yield 65.2%. Mp179.1-181.3 °C.
  • Example 2 In the same manner as in Example 1, the glycine methyl ester hydrochloride was replaced with alanine methyl ester hydrochloride, and the propane was replaced with p-cyclopropylphenylacetylene (156.2 mg, 1.1 mmol) to give a white solid product 77 mg. The rate was 22.0%; mp202.5-204.7 °C.
  • Example 2 In the procedure of Example 1, the glycine methyl ester hydrochloride was replaced with butyrate methyl ester hydrochloride, and the propyne was replaced with p-chlorophenylacetylene (149.6 mg, 1.1 mmol) to give a pale yellow solid product 145 mg. 40.5%. Mp177.6-179.9 °C.
  • the compound 3-hydroxy-5-bromopyridine (348 mg, 2 mmol) was dissolved in 40 mL of dichloromethane, and dimethyl succinate chloride (400 mg, 4 mmol), 100 mg of aluminum trichloride was added in an ice bath, and reacted at room temperature for 2 hours. . After completion of the reaction, water and 3 M hydrochloric acid were added to separate the layers, and then washed with (2 ⁇ 100 mL) and saturated brine (1 ⁇ 100 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. 156.6-158.2mp °C.
  • Methyl 2-(3-hydroxy-5-propynyl)pyridinecaridoacetate (70.0 mg, 0.2 mmol) was dissolved in 10 mL of tetrahydrofuran, 1 mL of 1 M lithium hydroxide was added, and heated to 30 ° C for 3 h, the reaction was complete. . After the completion of the reaction, the tetrahydrofuran in the reaction mixture was removed by pressure distillation, and 3 mmol of dilute hydrochloric acid was added under ice-cooling, and a white solid was taken up, and then filtered and dried to give a white product 41.0 mg, yield 56.9%. Mp185.7-187.8 °C.
  • the preparation method was the same as in Example 1, using N-methylglycine methyl ester hydrochloride (333.2 mg, 2.4 mmol), p-methylphenylacetylene (255.2 mg, 2.2 mmol), 5,6-dibromo-3-hydroxypyridine.
  • N-methylglycine methyl ester hydrochloride 333.2 mg, 2.4 mmol
  • p-methylphenylacetylene 255.2 mg, 2.2 mmol
  • 5,6-dibromo-3-hydroxypyridine formic acid (592mg, 2mmol) was substituted for glycine methyl ester hydrochloride, propyne, 5-bromo-3-hydroxypicolinic acid, and obtained as a pale yellow solid after hydrolysis, 121.0mg, three-step yield 15.1%.mp227.1-229.4 °C.
  • the preparation method was the same as that in Example 6.
  • the propyne was replaced with p-butylaminophenyl phenylacetylene (205.7 mg, 1.1 mmol), and the glycine methyl ester hydrochloride was replaced with glycine methyl propyl ester to obtain 75.4 mg of a brown solid product. 12.3%. Mp178.5-180.2 °C.
  • the preparation method was the same as that in Example 6.
  • the propyne was replaced with p-butylcarbamoylphenylacetylene (205.7 mg, 1.1 mmol), and the glycine methyl ester hydrochloride was replaced with isopropyl glycinate to obtain a brown solid product of 81.4 mg.
  • the rate is 18.6%. Mp187.2-189.5 °C.
  • the preparation method was the same as that in Example 6.
  • the propyne was replaced with p-propylpropionylaminophenylacetylene (203.5 mg, 1.1 mmol), and the glycine methyl ester hydrochloride was replaced with N-ethylglycinamide to obtain a brown solid product (71.4 mg).
  • the three-step reaction yield was 18.3%. Mp195.2-197.7 °C.

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Abstract

本发明涉及药物化学领域。具体涉及一类炔基吡啶类脯氨酰羟化酶抑制剂(I)。实验表明该类化合物具有良好的脯氨酰羟化酶抑制活性，可以在细胞或动物模型上增强促红细胞生成素的生成与分泌，从而可以促进红细胞的生成，可应用于治疗或预防贫血症如慢性肾病贫血以及缺血性疾病如缺血性脑卒中、心肌缺血等相关疾病。本发明还公开了该类化合物的制备方法。

Description

炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 技术领域
本发明涉及药物化学领域。具体涉及一类炔基吡啶类脯氨酰羟化酶抑制剂。该类化合物可增强促红细胞生成素及的生成与分泌，从而可以促进红细胞的生成，可应用于治疗或预防贫血症如慢性肾病贫血以及缺血性疾病如缺血性脑卒中、心肌缺血等相关疾病。
背景技术
贫血一般是指导致血液中氧水平降低的血红蛋白或红细胞的任何异常。贫血也可以与慢性感染、肿瘤疾病、慢性炎症包括接下来发生骨髓的炎症性抑制的病变等慢性疾病相关而发生。慢性疾病性贫血是医学领域中最常见的综合征之一，例如慢性肾病贫血。慢性肾病贫血形成的主要原因是促红细胞生成素(erythropoietin,EPO)分泌不足(Nephrol Dial Transplant 17(2002)2-7)。EPO分泌不足会阻碍红细胞的生成，从而导致贫血的发生。EPO的表达与分泌受转录因子低氧诱导因子(hypoxia inducible factor,HIF)的调控。具有完整转录功能的HIF蛋白由HIF-α及HIF-β两个亚基组成，其中HIF-α亚基受脯氨酰羟化酶(prolyl hydroxylase,PHD)的调控，PHD酶可以羟基化HIF-α从而促使其降解。在人体中，脯氨酰羟化酶2(PHD2)(Journal of Medicinal Chemistry 56(2013)9369-9402)是调控HIF水平的最主要亚型。当抑制体内脯氨酸羟化酶(PHD)的活性时，可以稳定体内HIF-α亚基，从而使其进入细胞核同细胞核内HIF-β亚基相结合，形成稳定的HIF二聚体，进一步引起下游基因的表达，从而促进EPO的表达与分泌。因此抑制脯氨酸羟化酶的活性可以提高HIF-α的水平，增加EPO的生成，从而促进红细胞成熟及提升血液输送氧气的能力，改善贫血或缺血症状。
发明内容
本发明提供了一种可以抑制脯氨酸羟化酶(PHD)活性的小分子化合物，其通过抑制PHD酶提高HIF-α的含量，从而增加EPO的生成与分泌，促进红细胞成熟及提升血液输送氧气的能力，用于治疗和预防贫血症以及缺血性疾病，如慢性肾病贫血、心肌缺血、脑缺血、中风等。本发明化合物结构如下：
Figure PCTCN2015095728-appb-000001
其中X代表NH、NCH3或CH2；Y代表氢、羟基、甲氧基或乙氧基；L代表–CH2–、–CH2O–或
Figure PCTCN2015095728-appb-000002
R6代表氢、C1-C4烷基或苯基；n代表0或1；
R1代表C1-C4烷基、苯基、取代苯基、含氧或氮的5～6员芳杂环、取代的含氧或氮的5～6员芳杂环，所述取代基是C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、卤素、氰基、
Figure PCTCN2015095728-appb-000003
Figure PCTCN2015095728-appb-000004
苯基或含氧或氮的5～6员芳杂环，其中R7代表C1-C4烷基；R8、R9各自独立地代表氢或C1-C4烷基，或者R8、R9连接形成3～7员含氮杂环；
R2代表氢、卤素或甲基；R3、R4各自独立地代表氢、甲基或乙基；
R5代表羟基、C1-C4烷氧基或–NR10R11；R10、R11各自独立地代表氢、甲基或乙基。
X优选代表NH。L优选代表–CH2–、–CH2O–或
Figure PCTCN2015095728-appb-000005
R6优选代表氢、甲基、叔丁基或苯基。R1优选代表取代苯环，取代基是甲基、乙基、异丙基、叔丁基、环丙基、甲氧基、叔丁氧基、环丙氧基、苯基、氰基、卤素、氟甲基、三氟甲基、咪唑基、乙酰氨基、环丙基甲酰氨基或
Figure PCTCN2015095728-appb-000006
其中R8、R9各自独立地代表氢、甲基、丁基或叔丁基，或两者连接形成环丙氨基、四氢吡咯基或N-甲基高哌嗪基。
R1还优选代表环丙基、叔丁基、苯基、萘基、喹啉基或苯并呋喃基。
R3或R4优选代表氢。R5优选代表-NH2、-NHCH3、羟基、甲氧基、异丙氧基、环丙氧基或环丙基甲氧基。
本发明同时包括化合物(I)的药学上可接受的盐，及其溶剂化物，都与化合物(I)有同样的药理功效。
本发明公开了一种药物组合物，其包含化合物(I)或其可药用盐，或溶剂合物，以及一种或多种可药用载体、稀释剂和赋形剂。
本发明还提供式(I)化合物和/或其可药用盐或溶剂合物在制备用于通过抑制脯氨酰羟化酶来治疗该酶介导的疾病的药物中的用途，所述疾病如贫血症，其可通过抑制脯氨酰羟化酶来治疗。
本发明的化合物临床所用剂量为0.01mg～1000mg/天，也可以根据病情的轻重或剂型的不同偏离此范围。
在某些实施方案中，根据式I的化合物可含有足以形成盐的酸性官能团。代表性的盐包括可药用金属盐如钠、钾、锂、钙、镁、铝和锌盐；可药用金属阳离子如钠、钾、锂、钙、 镁、铝和锌的碳酸盐和碳酸氢盐；可药用有机伯胺、仲胺和叔胺，包括脂肪胺、芳香胺、脂肪二胺和羟基烷基胺，如甲胺、乙胺、2-羟基乙基胺、二乙胺、三乙胺、乙二胺、乙醇胺、二乙醇。
同时本发明还提供了式(I)相关化合物的制备方法，包括以下步骤：
Figure PCTCN2015095728-appb-000007
其中R1、R2、R3、R4、X、Y、n、L定义同前。
其中中间体VI可通过下式进行合成得到，
Figure PCTCN2015095728-appb-000008
下面是本发明化合物的部分药效学实验数据：
血管内皮生长因子(vascular endothelial growth factor,VEGF)和EPO为体内HIF升高后的两个标志物(Journal of Medicinal Chemistry 55(2012)2945-2959)，当PHD活性受到抑制后，体内HIF含量升高，其会进入细胞核诱导下游相关基因表达，使体内EPO、VEGF等蛋白表达含量升高，通过检测VEGF和EPO的表达来验证化合物在细胞水平是否具有抑制PHD活性，提高HIF的能力。同时FG-4592(专利WO 2013013609A1)是一个目前已经进入临床III期的用于治疗贫血的PHD2抑制剂，本发明中FG-4592作为阳性对照化合物。
表1本发明中部分化合物的脯氨酰羟化酶抑制活性及其相关生物学活性
Figure PCTCN2015095728-appb-000009
Figure PCTCN2015095728-appb-000010
Figure PCTCN2015095728-appb-000011
aND为未进行测试；b化合物的结构见具体实施例；cFG-4592的结构：
Figure PCTCN2015095728-appb-000012
由表1可见，本发明的化合物具有较强的脯氨酰羟化酶2的抑制活性。
此外，专利US2007/0299086 A1公开了一系列脯氨酰羟化酶抑制剂，其中活性较好的化合物结构：
Figure PCTCN2015095728-appb-000013
本发明化合物的特征在于吡啶母核5位含有炔基直接与吡啶环相连，并且该位点炔基的引入，可以大幅度提升化合物对脯氨酰羟化酶的抑制活性。为了对比本发明化合物与US2007/0299086 A1化合物的活性，我们合成了US2007/0299086 A1专利中的部分化合物(合成方法见Tetrahedron Lett.,2015,56(35),5017–5019.)，并采用本发明中相同的活性测试方法、同一批次进行脯氨酰羟化酶抑制活性测定。本发明中部分化合物与US2007/0299086专利中化合物的对比结果如下：
表2本发明中部分化合物与专利US2007/0299086中化合物的对比情况
Figure PCTCN2015095728-appb-000014
Figure PCTCN2015095728-appb-000015
由表2化合物的数据对比可以看出，在其他基团基本相同的情况下，本发明中炔基的引入，可以显著提升化合物对脯氨酰羟化酶2的抑制活性。
荧光偏振法(Biochemical and Biophysical Research Communications 337(2005)275–280)，加药过后1h，使用荧光偏振仪器进行数据读取，以溶剂为对照，使用下面公式计算化合物对脯氨酰羟化酶的抑制剂率，同时使进行IC50的计算，结果见表1、3。
除了脯氨酰羟化酶2(PHD2)亚型之外，脯氨酰羟化酶3(PHD3)亚型可以调控HIF的含量，因此我们也测定了代表性化合物的PHD3抑制活性，其测试结果如下：
表3本发明部分化合物对脯氨酰羟化酶3的抑制活性
Figure PCTCN2015095728-appb-000016
其中计算公式如下：％抑制率＝100*(1-(实测数值-空白)/(阴性数值-空白))
由表1、3可见，本发明的化合物具有较强的脯氨酰羟化酶2、3的抑制活性，其中分部分化合物活性明显优于阳性药FG-4592。
以下是本发明部分化合物的细胞水平VEGF和细胞水平EPO活性的实验，方法参照(Bioorganic&Medicinal Chemistry Letters 23(2013)5953-5957)，给药24h后分别采用VEGF、EPO试剂盒进行检测结果如表1所示。
Hep3B细胞：人肝癌细胞
由表1可见，本发明的化合物具有明显的提高细胞内VEGF，EPO水平的能力，表现出较好的细胞水平活性。
同时本发明的部分化合物也进行了细胞水平的免疫印迹试验(Western-blot)，表4为本发明部分化合物是否对细胞HIF-α水平具有提高作用的实验结果
表4本发明部分化合物是否能够提高细胞HIF-α水平
Figure PCTCN2015095728-appb-000017
同时部分化合物的细胞水平的免疫印迹试验(Western-blot)结果见图1.
以下是本发明部分化合物的动物水平VEGF和细胞水平EPO活性的实验，方法参照(Journal of Medicinal Chemistry 55(2012)2945-2959)，给药4h时之后分别采用VEGF、EPO试剂盒进行检测结果如下图2所示。
由图2可见，本发明的化合物在动物水平可以明显提高VEGF、EPO的表达，说明本发明化合物在动物水平的有效性。
本发明的炔基吡啶类化合物无论在分子水平、细胞水平以及动物水平都具有良好的生物学活性。本发明的化合物可以在动物水平提升血液中红细胞生成素(EPO)的水平，进而促进红细胞的生成，可用于治疗或预防慢性疾病性相关的贫血、缺血性疾病及造血系统相关疾病。
附图说明
图1是部分化合物细胞水平的免疫印迹试验结果(Hep3B细胞：人肝癌细胞；化合物浓度50μM、250μM，给药24小时)
图2是化合物14、15、47、FG-4592在50μM浓度给药24h后细胞VEGF、EPO的提高水平 实验(模型：小鼠C57Bl/6雄性8-9周)
具体实施方式
实施例1
Figure PCTCN2015095728-appb-000018
2-(3-羟基-5-丙炔基)吡啶甲酰氨基乙酸
1)2-(3-羟基-5-溴吡啶)甲酰氨基乙酸甲酯的制备
将化合物III 3-羟基-5-溴吡啶甲酸(3.47g，16mmol)溶于150mL二氯甲烷中，加入三乙胺7.3mL及HOBt(3.26g，24mmol)，搅拌10min后加入EDCI(4.59g，24mmol)，搅拌10min，加入甘氨酸甲酯盐酸盐(2.4g，19.2mmol)。室温反应，搅拌6h。分别用饱和碳酸氢钠(100mL)，水洗(2×100mL)，饱和食盐水(2×100mL)依次洗涤。无水硫酸钠干燥，减压蒸馏后，粗品用硅胶柱层析分离纯化(石油醚：乙酸乙酯＝3：1)，得白色固体化合物1.88g，率65.3％。m.p.143.6-145.7℃.1H-NMR(300MHz,CDCl3)δ11.90(s,1H),8.16(s,1H),7.54(d,J＝1.83Hz,1H),7.28(d,J＝1.86Hz,1H),4.25(d,J＝3.3Hz,2H,),3.83(s,3H)；EI-MS m/z:288/290[M]+.
2)2-(3-羟基-5-丙炔基)吡啶甲酰氨基乙酸甲酯的制备
将化合物2-(3-羟基-5-溴吡啶)甲酰氨基乙酸甲酯(288mg，1mmol)、丙炔(44mg，1.1mmol)溶于6mL DMF中，加入6mL N,N-二异丙基乙胺，40mg碘化亚铜，40mg二氯(二三苯基膦)钯，常规加热至80℃6h，或者微波加热至80℃反应15min，反应基本完全。反应结束后，加入二氯甲烷100mL，3mmol盐酸60mL，分液后用水(2×100mL)，饱和食盐水(2×100mL)依次洗涤。无水硫酸钠干燥，减压蒸馏后，粗品用硅胶柱层析分离纯化(石油醚：乙酸乙酯＝6：1)，得白色固体化合物124.5mg，收率50.2％。m.p.119.2-121.5℃。1H-NMR(300MHz,CDCl3)δ8.91(s,1H),8.76(d,J＝1.2Hz,1H),8.20(s,1H),7.69(d,J＝1.2Hz,1H),3.92(s,2H),3.64(s,3H),1.85(s,3H)；EI-MS m/z:248[M]+.
3)标题化合物2-(3-羟基-5-丙炔基)吡啶甲酰氨基乙酸的制备
将2-(3-羟基-5-丙炔基)吡啶甲酰氨基乙酸甲酯(100.0mg，0.4mmol)溶于10mL四氢呋喃中，加入1M氢氧化锂3mL，加热至30℃反应3h，反应完全。反应结束后，加压蒸馏除去反应液中的四氢呋喃，冰浴条件下加入3mmol稀盐酸，有白色固体吸出，抽滤干燥后得白色产物61.0mg，收率65.2％。m.p.179.1-181.3℃。1H-NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.76 (d,J＝1.2Hz,1H),8.20(s,1H),7.70(d,J＝1.3Hz,1H),3.60(s,2H),1.85(s,3H)；EI-MS m/z:234[M]+.
实施例2
Figure PCTCN2015095728-appb-000019
2-(3-羟基-5-异丙基乙炔基)吡啶甲酰氨基乙酸
按实施例1的方法，用异丙基乙炔(74.8mg，1.1mmol)替换丙炔，得白色固体产物112.0mg，两部收率42.7％。m.p.155.5-157.8℃。1H-NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.79(d,J＝1.2Hz,1H),8.20(s,1H),7.70(d,J＝1.2Hz,1H),3.60(s,2H),2.89-2.85(m,1H),1.26(d,J＝6.8Hz,6H)；EI-MS m/z:262[M]+.
实施例3
Figure PCTCN2015095728-appb-000020
2-(3-羟基-5-叔丁基乙炔基)吡啶甲酰氨基乙酸
按实施例1的方法，用叔丁基乙炔(90.2mg，1.1mmol)替换丙炔，得白色固体化合物98.0mg，两步收率35.5％。m.p.165.2-167.8℃。1H NMR(300MHz,DMSO-d6)δ8.78(d,J＝1.2Hz,1H),8.20(s,1H),7.69(d,J＝1.2Hz,1H),3.60(s,2H),1.27(s,9H)；EI-MS m/z:276[M]+.
实施例4
Figure PCTCN2015095728-appb-000021
2-(3-羟基-5-环丙乙炔基)吡啶甲酰氨基乙酸
按实施例1的方法，用环丙基乙炔(72.6mg，1.1mmol)替换丙炔，得白色固体化合物得白色固体化合物79.1mg，两部收率30.42％。m.p.154.2-155.4℃。1H NMR(300MHz,DMSO-d6)δ8.68(d,J＝1.3Hz,1H),8.20(s,1H),7.63(d,J＝1.3Hz,1H),3.60(s,2H),1.41-1.32(m,1H),0.63–0.44(m,2H),0.45–0.25(m,2H)；EI-MS m/z:261[M]+.
实施例5
Figure PCTCN2015095728-appb-000022
2-(3-羟基-5-苯基乙炔基)吡啶甲酰氨基乙酸
按实施例1的方法，用苯乙炔(112.2mg，1.1mmol))替换丙炔，得白色固体化合物得白色固体化合物102.2mg，两步收率34.4％。m.p.172.1-173.9℃。1HNMR(300MHz,DMSO-d6)δ8.75(d,J＝1.2Hz,1H),8.20(s,1H),7.68(d,J＝1.3Hz,1H),7.60–7.49(m,2H),7.48–7.27(m,3H),3.89(s,2H)；EI-MS m/z:296[M]+.
实施例6
Figure PCTCN2015095728-appb-000023
2-(3-羟基-5-苯基乙炔基)吡啶甲酰氨基乙酸甲酯
将化合物2-(3-羟基-5-溴吡啶)甲酰氨基乙酸甲酯(288mg，1mmol)、苯基乙炔(110.2mg，1.1mmol)溶于6mL DMF中，加入6mL N,N-二异丙基乙胺，40mg碘化亚铜，40mg二氯(二三苯基膦)钯，常规加热至80℃6h，或者微波加热至80℃反应15min，反应基本完全。反应结束后，加入二氯甲烷100mL，3mmol盐酸60mL，分液后用水(2×100mL)，饱和食盐水(2×100mL)依次洗涤。无水硫酸钠干燥，减压蒸馏后，粗品用硅胶柱层析分离纯化(石油醚：乙酸乙酯＝6：1)，得白色固体化合物140.0mg，收率45.2％。m.p.109.7-111.9℃。1HNMR(300MHz,DMSO-d6)δ8.77(d,J＝1.2Hz,1H),8.20(s,1H),7.69(d,J＝1.2Hz,1H),7.60–7.49(m,2H),7.48–7.27(m,3H),3.92(s,2H),3.64(s,3H)；EI-MS m/z:310[M]+.
实施例7
Figure PCTCN2015095728-appb-000024
2-(3-羟基-5-对甲苯基乙炔基-6-甲基)吡啶甲酰氨基乙酸
按实施例1的方法，用3-羟基-5-溴-6-甲基吡啶甲酸(372mg，2mmol)替换3-羟基-5-溴吡啶甲酸，对甲基苯乙炔(127.6mg，1.1mmol)替换丙炔，得到白色固体产物120.3mg，三步收率18.5％。m.p.223.3-225.6℃。1H NMR(300MHz,DMSO-d6)δ8.20(s,1H),7.67(s,1H),7.51–7.40(m,2H),7.01-7.17(m,1.1Hz,2H),3.88(s,2H),2.73(s,3H),2.34(t,J＝1.1Hz,3H)；EI-MS m/z:324[M]+.
实施例8
Figure PCTCN2015095728-appb-000025
2-(3-羟基-5-对甲氧基苯基乙炔基-6-氯)吡啶甲酰氨基乙酸
按实施例1的方法，用3-羟基-5-溴-6-氯吡啶甲酸(412mg，2mmol)替换3-羟基-5-溴吡啶甲酸，对甲氧基苯乙炔(145.2mg，1.1mmol)替换丙炔，得到淡黄色固体产物127.0mg，三步收率17.6％。m.p.232.2-2.34.3℃。1H NMR(300MHz,DMSO-d6)δ8.20(s,1H),7.85(s,1H),7.51–7.40(m,2H),7.00–6.89(m,2H),3.80(s,3H),3.60(s,2H)；EI-MS m/z:360[M]+.
实施例9
Figure PCTCN2015095728-appb-000026
2-(3-羟基-5-对环丙基苯基乙炔基吡啶)甲酰氨基丙酸
按实施例1的方法，用丙氨酸甲酯盐酸盐替换甘氨酸甲酯盐酸盐，用对环丙基苯乙炔(156.2mg，1.1mmol)替换丙炔得到白色固体产物77mg，两步收率22.0％；m.p.202.5-204.7℃。1H NMR(300MHz,DMSO-d6)δ8.85(d,J＝1.2Hz,1H),7.74(d,J＝1.2Hz,1H),7.57–7.46(m,2H),7.20–7.04(m,3H),4.31-4.40(m,＝1H),1.94–1.77(m,1H),1.42(d,J＝6.8Hz,3H),1.21–1.06(m,2H),0.82-0.90(m,2H)；EI-MS m/z:350[M]+.
实施例10
Figure PCTCN2015095728-appb-000027
2-(3-羟基-5-对氟苯基乙炔基吡啶)甲酰氨基丁酸
按实施例1的方法，用丁氨酸甲酯盐酸盐替换甘氨酸甲酯盐酸盐，用对氯苯乙炔(149.6mg，1.1mmol)替换丙炔得到淡黄色固体产物145mg，两步收率40.5％。m.p.177.6-179.9℃。1H NMR(300MHz,DMSO-d6)δ8.77(d,J＝1.2Hz,1H),7.69(d,J＝1.3Hz,1H),7.58–7.48(m,2H),7.46–7.35(m,2H),7.08(s,1H),4.60(d,J＝1.4Hz,1H),2.11–1.82(m,2H),1.02(t,J＝6.0Hz,3H).EI-MS m/z:342[M]+.
实施例11
Figure PCTCN2015095728-appb-000028
2-(3-羟基-5-对氟苯基乙炔基吡啶)甲酰氨基丁酸
按实施例1的方法，用异丁氨酸甲酯盐酸盐替换甘氨酸甲酯盐酸盐，用对氟苯乙炔(149.6mg，1.1mmol)替换丙炔得到淡黄色固体产物115mg，两步收率32.12％。m.p.175.4-177.5℃。1H NMR(300MHz,DMSO-d6)δ8.94(s,1H),8.75(d,J＝1.2Hz,1H),7.67(d,J＝1.3Hz,1H),7.58–7.47(m,2H),7.45–7.35(m,2H),1.55(s,6H).EI-MS m/z:342[M]+.
实施例12
Figure PCTCN2015095728-appb-000029
4-(3-羟基5-(4-乙基苯基炔基))吡啶-4-氧代丁酸
(1)4-(3-羟基-5-溴吡啶-2基)-4-氧代丁酸甲酯的制备
将化合物3-羟基-5-溴吡啶(348mg，2mmol)溶于40mL二氯甲烷，冰浴条件下加入丁二酸单甲酯酰氯(400mg，4mmol)，三氯化铝100mg，常温反应2小时。反应结束后，加入水，3M盐酸，分液后，以此用(2×100mL)，饱和食盐水(1×100mL)依次洗涤。无水硫酸钠干燥，减压蒸馏后，粗品用硅胶柱层析分离纯化(石油醚：乙酸乙酯＝5：1)，得白色固体化合物196.5mg，收率34..1％。156.6-158.2m.p.℃。1H NMR(300MHz,CDCl3)δ8.64(d,J＝1.3Hz,1H),7.77(d,J＝1.3Hz,1H),3.63(s,3H),3.05(t,J＝7.1Hz,2H),2.78(t,J＝7.0Hz,2H).EI-MS m/z:287[M]+.
(2)4-(3-羟基-5-对乙基苯基炔基吡啶-2基)-4-氧代丁酸甲酯的制备
将化合物4-(3-羟基-5-溴吡啶-2基)-4-氧代丁酸甲酯(190mg，0.66mmol)、对乙基苯乙炔(94mg，0.72mmol)溶于6mL DMF中，加入6mL N,N-二异丙基乙胺，40mg碘化亚铜，40mg二氯(二三苯基膦)钯，常规加热至80℃6h，或者微波加热至80℃反应15min，反应基本完全。反应结束后，加入二氯甲烷100mL，3mmol盐酸60mL，分液后用水(2×100mL)，饱和食盐水(2×100mL)依次洗涤。无水硫酸钠干燥，减压蒸馏后，粗品用硅胶柱层析分离纯化(石油醚：乙酸乙酯＝6：1)，得白色固体化合物84.5mg，收率38.1％。m.p.109.5-112.1℃。1H NMR(300MHz,CDCl3)δ8.76(d,J＝1.2Hz,1H),7.63(d,J＝1.3Hz,1H),7.57–7.46(m,2H),7.20-7.06(m,2H),3.63(s,3H),2.84–2.64(m,4H),2.58(t,J＝5.7Hz,2H),1.19(t,J＝6.6Hz,3H).EI-MS m/z:337[M]+.
(3)标题化合物4-(3-羟基5-(4-乙基苯基炔基))吡啶-4-氧代丁酸的制备
将2-(3-羟基-5-丙炔基)吡啶甲酰氨基乙酸甲酯(70.0mg，0.2mmol)溶于10mL四氢呋喃中，加入1M氢氧化锂3mL，加热至30℃反应3h，反应完全。反应结束后，加压蒸馏除去反应液中的四氢呋喃，冰浴条件下加入3mmol稀盐酸，有白色固体吸出，抽滤干燥后得白色产 物41.0mg，收率56.9％。m.p.185.7-187.8℃。1H NMR(300MHz,DMSO-d6)δ8.77(d,J＝1.2Hz,1H),7.64(d,J＝1.2Hz,1H),7.57–7.46(m,2H),7.20-7.17(m,2H),2.87(t,J＝5.4Hz,2H),2.78–2.62(m,4H),1.19(t,J＝6.6Hz,3H).EI-MS m/z:358[M]+.
实施例13
Figure PCTCN2015095728-appb-000030
N-(6-溴-5-对甲基苯基乙炔-3-羟基-2-吡啶)甲酰基-N-甲基甘氨酸
制备方法同实施例1，用N-甲基甘氨酸甲酯盐酸盐(333.2mg，2.4mmol)，对甲基苯乙炔(255.2mg，2.2mmol)，5,6-二溴-3-羟基吡啶甲酸(592mg，2mmol)分别替代甘氨酸甲酯盐酸盐，丙炔，5-溴-3-羟基吡啶甲酸，水解后得淡黄色固体，121.0mg，三步收率15.1％.m.p.227.1-229.4℃。1H NMR(300MHz,DMSO-d6)δ7.79(s,1H),7.55–7.44(m,2H),7.12-7.09(m,2H),3.90(s,2H),3.05(s,3H),2.34(s,2H),2.34(d,J＝2.3Hz,1H).EI-MS m/z:402/404[M]+.
实施例14
Figure PCTCN2015095728-appb-000031
2-(3-羟基-5-间甲基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1，用间甲基苯乙炔(127.6mg，1.1mmol)替换丙炔，得白色固体产物106.0mg，三步反应收率34.2％。m.p.229.2-231.3℃。1H NMR(300MHz,DMSO-d6)δ8.75(d,J＝1.3Hz,1H),8.20(s,1H),7.67(d,J＝1.2Hz,1H),7.54–7.43(m,2H),7.15–7.05(m,2H),3.60(s,2H),2.34(d,J＝1.1Hz,3H).EI-MS m/z:310[M]+.
实施例15
Figure PCTCN2015095728-appb-000032
2-(3-羟基-5-对氟苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1，用对氟苯基乙炔(132.0mg，1.1mmol)替换丙炔，得白色固体产物112.4mg，三步反应收率36.1％。m.p.187.8-200.7℃。1H NMR(300MHz,DMSO-d6)δ8.75(d,J＝1.3Hz,1H),8.20(s,1H),7.69–7.52(m,3H),7.13–6.99(m,2H),3.60(s,2H).EI-MS m/z:314[M]+.
实施例16
Figure PCTCN2015095728-appb-000033
2-(3-羟基-5-对甲氧基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1，用对甲氧基苯乙炔(145.2mg，1.1mmol)替换丙炔，得白色固体产物142.4mg，三步反应收率43.5％。m.p.219.2-221.3℃。1H NMR(300MHz,DMSO-d6)δ8.73(d,J＝1.2Hz,1H),8.20(s,1H),7.67(d,J＝1.2Hz,1H),7.50–7.39(m,2H),7.00–6.89(m,2H),3.80(s,3H),3.60(s,2H).EI-MS m/z:326[M]+.
实施例17
Figure PCTCN2015095728-appb-000034
2-(3-羟基-5-间甲氧基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1，用间甲氧基苯乙炔(145.2mg，1.1mmol)替换丙炔，得淡黄色固体产物92.4mg，三步反应收率28.3％。m.p.220.2-222.5℃。1H NMR(300MHz,DMSO-d6)δ8.77(d,J＝1.3Hz,1H),8.20(s,1H),7.67(d,J＝1.2Hz,1H),7.29(t,J＝7.4Hz,1H),7.24–7.08(m,2H),6.95-6.91(m,1H),3.81(s,3H),3.60(s,2H).EI-MS m/z:326[M]+.
实施例18
Figure PCTCN2015095728-appb-000035
2-(3-羟基-5-(联苯-4-基乙炔基))吡啶甲酰氨基乙酸
制备方法同实施例1，用联苯基乙炔(195.8mg，1.1mmol)替换丙炔，得棕色固体产物82.2mg，三步反应收率22.1％。m.p.242.5-244.3℃。1H NMR(300MHz,DMSO-d6)δ8.87(d,J＝1.2Hz,1H),8.20(s,1H),7.81–7.69(m,3H),7.67–7.53(m,4H),7.51–7.37(m,2H),7.39–7.26(m,1H),3.60(s,2H).EI-MS m/z:372[M]+.
实施例19
Figure PCTCN2015095728-appb-000036
2-(3-羟基-5-对氰基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1，用对氰基苯乙炔(139.7mg，1.1mmol)替换丙炔，得白色固体产物65.7mg，三步反应收率20.4％。m.p.195.2-197.7℃。1H NMR(300MHz,DMSO-d6)δ8.75(d,J＝1.3Hz,1H),8.20(s,1H),7.81–7.64(m,3H),7.63–7.52(m,2H),3.60(s,2H).EI-MS m/z:321[M]+.
实施例20
Figure PCTCN2015095728-appb-000037
2-(3-羟基-5-邻氰基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1，用邻氰基苯乙炔(139.7mg，1.1mmol)替换丙炔，得白色固体产物55.2mg，三步反应收率17.2％。m.p.182.2-184.8℃。1H NMR(300MHz,DMSO-d6)δ8.87(d,J＝1.3Hz,1H),8.20(s,1H),7.76(dd,J＝7.4,2.1Hz,1H),7.67-7.65(m,2H),7.60-7.55(m,1H),7.51-7.47(m,1H),3.60(s,2H).EI-MS m/z:321[M]+.
实施例21
Figure PCTCN2015095728-appb-000038
2-(3-羟基-5-对三氟甲基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1，用对三氟甲基苯乙炔(187.0mg，1.1mmol)替换丙炔，得乳白色固体产物105.2mg，三步反应收率28.8％。m.p.201.5-2.3.8℃。1H NMR(300MHz,DMSO-d6)δ8.78(d,J＝1.2Hz,1H),8.20(s,1H),7.70(d,J＝1.2Hz,1H),7.63–7.47(m,4H),3.60(s,2H).EI-MS m/z:364[M]+.
实施例22
Figure PCTCN2015095728-appb-000039
2-(3-羟基-5-对乙酰氨基苯基乙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1，用对乙酰氨基苯乙炔(174.0mg，1.1mmol)替换丙炔，得白色固体产物75.9mg，三步反应收率21.5％。m.p.251.2-253.7℃。1H NMR(300MHz,DMSO-d6)δ8.77(d,J＝1.3Hz,1H),8.20(s,1H),7.85–7.63(m,5H),3.60(s,2H),2.10(s,3H).EI-MS m/z:353[M]+.
实施例23
Figure PCTCN2015095728-appb-000040
2-(3-羟基-5-对二甲氨基甲酰基苯基乙炔基)吡啶甲酰氨基乙酰胺
制备方法同实施例1，用对二甲氨基甲酰基苯乙炔(190.3mg，1.1mmol)替换丙炔，用甘氨酰胺(110mg，1.5mmol)替换甘氨酸甲酯盐酸盐，得白色固体产物95.9mg，三步反应收率26.2％。m.p.229.1-231.5℃。1H NMR(300MHz,CDCl3)δ8.78(d,J＝1.3Hz,1H),8.20(s,1H),7.77–7.59(m,5H),6.49(s,2H),3.84(s,2H),3.03(s,6H).EI-MS m/z:366[M]+.
实施例24
Figure PCTCN2015095728-appb-000041
2-(3-羟基-5-对丁酰胺氨基苯基乙炔基)吡啶甲酰氨基乙酸环丙甲酯
制备方法同实施例6，用对丁酰胺基苯乙炔(205.7mg，1.1mmol)替换丙炔，用甘氨酸环丙甲酯替换甘氨酸甲酯盐酸盐得棕色固体产物75.4mg，三步反应收率12.3％。m.p.178.5-180.2℃。1H NMR(300MHz,CDCl3)δ8.87(d,J＝1.2Hz,1H),7.85–7.65(m,6H),4.00(d,J＝7.0Hz,2H),3.92(s,2H),2.42(t,J＝8.0Hz,2H),1.76-1.66(m,2H),1.50–1.17(m,3H),0.95(t,J＝7.9Hz,3H),0.61–0.48(m,2H),0.29-0.23(m,2H).EI-MS m/z:449[M]+.
实施例25
Figure PCTCN2015095728-appb-000042
2-(3-羟基-5-对丁氨甲酰基苯基乙炔基)吡啶甲酰氨基乙酸异丙酯
制备方法同实施例6，用对丁氨甲酰基苯乙炔(205.7mg，1.1mmol)替换丙炔，用甘氨酸异丙酯替换甘氨酸甲酯盐酸盐，得棕色固体产物81.4mg，三步反应收率18.6％。m.p.187.2-189.5℃。1H NMR(300MHz,CDCl3)δ8.81(s,1H),8.20(s,1H),7.85–7.73(m,3H),7.71–7.61(m,2H),5.88(s,1H),5.02-4.93(m,1H),3.92(s,2H),3.31(t,J＝7.5Hz,2H),1.59-1.56(m,J＝7.8Hz,2H),1.39–1.25(m,2H),1.16(d,J＝6.8Hz,6H),0.88(t,J＝7.9Hz,3H).EI-MS m/z:437[M]+.
实施例26
Figure PCTCN2015095728-appb-000043
N-乙基-(2-(3-羟基-5-对环丙甲酰氨基苯基乙炔基)吡啶甲酰氨基)乙酰胺
制备方法同实施例6，用对环丙甲酰氨基苯乙炔(203.5mg，1.1mmol)替换丙炔，用N-乙基甘氨酰胺替换甘氨酸甲酯盐酸盐，得棕色固体产物71.4mg，三步反应收率18.3％。m.p.195.2-197.7℃。1H NMR(300MHz,CDCl3)δ9.50(s,1H),9.23(s,1H),8.83(d,J＝1.3Hz,1H),8.20(s,1H),7.83–7.64(m,5H),3.85(s,2H),3.21(q,J＝6.3Hz,2H),1.73-1.64(m,1H),1.22(t,J＝6.3Hz,3H),1.11–0.90(m,4H).EI-MS m/z:406[M]+.
实施例27
Figure PCTCN2015095728-appb-000044
N-甲基-(2-(3-羟基-5-(3-苯氧基丙炔-1-基)吡啶甲酰氨基)乙酰胺
制备方法同实施例6，用3-苯氧基丙炔(145.2mg，1.1mmol)替换丙炔，用N-甲基甘氨酰胺替换甘氨酸甲酯盐酸盐，得棕色固体产物91.2mg，三步反应收率26.9％。m.p.192.2-194.4℃。1H NMR(300MHz,CDCl3)δ8.67(d,J＝1.2Hz,1H),8.20(s,1H),7.66(d,J＝1.2Hz,1H),7.37–7.23(m,2H),6.94-6.85(m,3H),6.09(s,1H),4.68(s,2H),3.85(s,2H),2.82(s,3H).EI-MS m/z:339[M]+.
实施例28
Figure PCTCN2015095728-appb-000045
2-(3-羟基-5-(3-对氯苯氧基丙炔-1-基))吡啶甲酰氨基乙酰胺
制备方法同实施例1，用3-(对氯苯氧基)丙炔(182.6mg，1.1mmol)替换丙炔，干氨酰胺替换甘氨酸甲酯盐酸盐，得到棕色产物54.0mg，三步收率15.1％。m.p.152.2-154.6℃。1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.64(d,J＝1.3Hz,1H),7.68(d,J＝1.3Hz,1H),7.36–7.26(m,2H),7.12(s,2H),6.99–6.89(m,2H),4.73(s,2H),3.85(s,2H).EI-MS m/z:359[M]+.
实施例29
Figure PCTCN2015095728-appb-000046
2-(3-羟基-5-(3-对乙基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸甲酯
制备方法同实施例6，用3-(对乙基苯氧基)丙炔(160.6mg，1.1mmol)替换丙炔，得白色固体产物105.0mg，收率28.5％。m.p.112.2-114.3℃。1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.67(d,J＝1.3Hz,1H),7.69(d,J＝1.3Hz,1H),7.19-7.13(m,2H),6.92–6.82(m,2H),4.68(s,2H),3.86(s,2H),3.63(s,3H),2.73-2.70(m,J＝6.6,1.1Hz,2H),1.19(t,J＝6.6Hz,3H).EI-MS m/z:368[M]+.
实施例30
Figure PCTCN2015095728-appb-000047
2-(3-羟基-5-(3-对氰基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸异丙酯
制备方法同实施例6，用3-(对氰基苯氧基)丙炔(172.7mg，1.1mmol)替换丙炔，甘氨酸异丙酯替换甘氨酸甲酯盐酸盐，得白色固体产物126.0mg，收率32.1％。m.p.120.2-123.1℃。1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.62(d,J＝1.2Hz,1H),7.79–7.66(m,3H),7.20–7.09(m,2H),4.91-4.87(m,J＝6.8Hz,1H),4.68(s,2H),3.86(s,2H),1.14(d,J＝6.8Hz,6H).EI-MS m/z:393[M]+.
实施例31
Figure PCTCN2015095728-appb-000048
2-(3-羟基-5-(3-对氟苯氧基丙炔-1-基))吡啶甲酰氨基乙酸环丙酯
制备方法同实施例6，用3-(对氟基苯氧基)丙炔(165.0mg，1.1mmol)替换丙炔，甘氨酸环丙酯替换甘氨酸甲酯盐酸盐，得白色固体产物117.0mg，收率30.4％。m.p.107.2-109.9℃。1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.76(d,J＝1.3Hz,1H),7.78(d,J＝1.3Hz,1H),7.26–7.12(m,2H),7.09–6.96(m,2H),4.68(s,2H),3.86(s,2H),3.33(p,J＝7.0Hz,1H),0.47-0.45(m,2H),0.43–0.18(m,2H).EI-MS m/z:384[M]+.
实施例32
Figure PCTCN2015095728-appb-000049
N,N’-二甲基-(2-(3-羟基-5-(3-对氯苯氧基丙炔-1-基))吡啶甲酰氨基)乙酰胺
制备方法同实施例1，用3-(对氯基苯氧基)丙炔(182.6mg，1.1mmol)替换丙炔，N,N’-二甲基氨酰胺替换甘氨酸甲酯盐酸盐，得白色固体产物97.0mg，收率24.2％。m.p.177.2-179.9℃。1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.67(d,J＝1.3Hz,1H),7.68(d,J＝1.2Hz,1H),7.36–7.26(m,2H),7.00–6.89(m,2H),4.68(s,2H),3.85(s,2H),2.87(s,6H).EI-MS m/z:387[M]+.
实施例33
Figure PCTCN2015095728-appb-000050
2-(3-羟基-5-(3-苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-苯氧基丙炔(145.2mg，1.1mmol)替换丙炔，得到白色固体产物77.1mg，两步收率23.6％。m.p.112.2-114.6℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J＝1.2Hz,1H),8.20(s,1H),7.65(d,J＝1.3Hz,1H),7.37–7.23(m,2H),6.94-6.85(m,3H),4.68(s,2H),3.60(s,2H).EI-MS m/z:326[M]+.
实施例34
Figure PCTCN2015095728-appb-000051
2-(3-羟基-5-(3-对甲苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-(对甲基苯氧基)丙炔(160.6mg，1.1mmol)替换丙炔，得到白色固体产物89.2mg，两步收率24.7％。m.p.162.2-164.3℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J＝1.3Hz,1H),8.20(s,1H),7.64(d,J＝1.2Hz,1H),7.08-7.04(m,2H),6.83–6.72(m,2H),4.68(s,2H),3.60(s,2H),2.31(s,2H),2.31(d,J＝2.2Hz,1H).EI-MS m/z:340[M]+.
实施例35
Figure PCTCN2015095728-appb-000052
2-(3-羟基-5-(3-邻甲基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-(邻甲基苯氧基)丙炔(160.6mg，1.1mmol)替换丙炔，得到白色固体产物99.4mg，两步收率29.1％。m.p.154.3-156.7℃。1H NMR(300MHz,DMSO-d6)δ8.73(d,J＝1.3Hz,1H),8.20(s,1H),7.64(d,J＝1.3Hz,1H),7.19–7.03(m,2H),6.94-6.85(m,1H),6.69-6.65(m,1H),4.68(s,2H),3.60(s,2H),2.22(d,J＝1.0Hz,3H).EI-MS m/z:340[M]+.
实施例36
Figure PCTCN2015095728-appb-000053
2-(3-羟基-5-(3-对乙基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-(对乙基苯氧基)丙炔(176.0mg，1.1mmol)替换丙炔，得到白色固体产物110.3mg，两步收率31.1％。m.p.172.4-174.7℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J＝1.2Hz,1H),8.20(s,1H),7.65(d,J＝1.2Hz,1H),7.14-7.10(m,2H),6.85–6.75(m,2H),4.68(s,2H),3.60(s,2H),2.73-2.69(m,J＝6.6,1.1Hz,2H),1.19(t,J＝6.6Hz,3H).EI-MS m/z:354[M]+.
实施例37
Figure PCTCN2015095728-appb-000054
2-(3-羟基-5-(3-对叔丁基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-(对叔丁基苯氧基)丙炔(206.8mg，1.1mmol)替换丙炔，得到白色固体产物110.3mg，两步收率31.1％。m.p.180.1-182.5℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J＝1.3Hz,1H),8.20(s,1H),7.64(d,J＝1.2Hz,1H),7.37–7.26(m,2H),6.82–6.72(m,2H),4.68(s,2H),3.60(s,2H),1.28(s,9H).EI-MS m/z:382[M]+.
实施例38
Figure PCTCN2015095728-appb-000055
2-(3-羟基-5-(3-(2,3-二甲基苯基)氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用对3-(2,3-二甲基苯基)氧基丙炔(176.0mg，1.1mmol)替换丙炔，得到白色固体产物60.3mg，两步收率16.9％。m.p.182.2-184.3℃。1H NMR(300MHz,DMSO-d6) δ8.69(d,J＝1.3Hz,1H),8.20(s,1H),7.65(d,J＝1.2Hz,1H),7.06(t,J＝7.5Hz,1H),6.76–6.63(m,2H),4.68(s,2H),3.60(s,2H),2.25–2.13(m,6H).EI-MS m/z:354[M]+.
实施例39
Figure PCTCN2015095728-appb-000056
2-(3-羟基-5-(3-对甲氧基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-对甲氧基苯氧基丙炔(180.0mg，1.1mmol)替换丙炔，得到白色固体产物80.1mg，两步收率22.4％。m.p.223.3-225.6℃。1H NMR(300MHz,DMSO-d6)δ8.73(d,J＝1.3Hz,1H),8.20(s,1H),7.65(d,J＝1.2Hz,1H),6.79(s,4H),4.68(s,2H),3.80(s,3H),3.60(s,2H).EI-MS m/z:356[M]+.
实施例40
Figure PCTCN2015095728-appb-000057
2-(3-羟基-5-(3-间叔丁基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-间叔丁氧苯氧基丙炔(224.4mg，1.1mmol)替换丙炔，得到白色固体产物85.5mg，两步收率21.5％。m.p.237.2-239.4℃。1H NMR(300MHz,DMSO-d6)δ8.68(d,J＝1.2Hz,1H),8.20(s,1H),7.62(d,J＝1.2Hz,1H),7.24(t,J＝7.5Hz,1H),6.69-6.67(m,J＝5.7,1.9Hz,2H),6.48(t,J＝2.0Hz,1H),4.68(s,2H),3.60(s,2H),1.41(s,9H).EI-MS m/z:398[M]+.
实施例41
Figure PCTCN2015095728-appb-000058
2-(3-羟基-5-(3-间环丙氧基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-间环丙氧基苯氧基丙炔(206.8mg，1.1mmol)替换丙炔，得到白色固体产物95.0mg，两步收率24.9％。m.p.212.3-214.7℃。1H NMR(300MHz,DMSO-d6)δ8.80(d,J＝1.3Hz,1H),8.20(s,1H),7.78(d,J＝1.2Hz,1H),7.25(t,J＝7.5Hz,1H),6.69-6.67(m, 2H),6.48(t,J＝2.1Hz,1H),4.68(s,2H),3.60(s,2H),3.17-3.14(m,1H),0.74–0.57(m,2H),0.52–0.32(m,2H).EI-MS m/z:382[M]+.
实施例42
Figure PCTCN2015095728-appb-000059
2-(3-羟基-5-(3-对三氟甲基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-对三氟甲基苯氧基丙炔(220.0mg，1.1mmol)替换丙炔，得到白色固体产物79.0mg，两步收率20.3％。m.p.197.2-199.5℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J＝1.2Hz,1H),8.20(s,1H),7.66(d,J＝1.2Hz,1H),7.56–7.47(m,2H),6.92–6.82(m,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:394[M]+.
实施例43
Figure PCTCN2015095728-appb-000060
2-(3-羟基-5-3-(5-氟甲基呋喃-2-基氧基)-1-丙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1，用3-(5-氟甲基呋喃2-基氧基)丙炔(180.0mg，1.1mmol)替换丙炔，得到白色固体产物95.0mg，两步收率26.5％。m.p.187.2-189.3℃。1H NMR(300MHz,DMSO-d6)δ8.71(d,J＝1.2Hz,1H),8.20(s,1H),7.63(d,J＝1.2Hz,1H),7.35-7.31(m,1H),6.90–6.79(m,1H),5.43(t,J＝1.1Hz,1H),5.27(t,J＝1.1Hz,1H),4.68(s,2H),3.60(s,2H).EI-MS m/z:348[M]+.
实施例44
Figure PCTCN2015095728-appb-000061
2-(3-羟基-5-(3-对氯苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-对氯苯氧基丙炔(182.6mg，1.1mmol)替换丙炔，得到白色固体产物95.0mg，两步收率26.5％。m.p.132.7-134.7℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J＝1.2Hz,1H),8.20(s,1H),7.65(d,J＝1.3Hz,1H),7.33–7.22(m,2H),6.84–6.73(m,2H),4.80(s,2H),3.88(s,2H).EI-MS m/z:360[M]+.
实施例45
Figure PCTCN2015095728-appb-000062
2-(3-羟基-5-(3-邻氯苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-邻氯苯氧基丙炔(182.6mg，1.1mmol)替换丙炔，得到白色固体产物84.0mg，两步收率23.6％。m.p.127.1-129.4℃。1H NMR(300MHz,DMSO-d6)δ8.74(d,J＝1.2Hz,1H),8.20(s,1H),7.64(d,J＝1.3Hz,1H),7.31(dd,J＝7.5,2.0Hz,1H),7.16-7.10(m,1H),6.98-6.92(m,1H),6.83(dd,J＝7.5,2.1Hz,1H),4.68(s,2H),3.60(s,2H).EI-MS m/z:360[M]+.
实施例46
Figure PCTCN2015095728-appb-000063
2-(3-羟基-5-(3-间氯苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-间氯苯氧基丙炔(182.6mg，1.1mmol)替换丙炔，得到白色固体产物74.0mg，两步收率20.5％。m.p.110.2-112.6℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J＝1.2Hz,1H),8.20(s,1H),7.64(d,J＝1.2Hz,1H),7.24(t,J＝7.5Hz,1H),7.09-7.05(m,1H),6.94–6.76(m,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:360[M]+.
实施例47
Figure PCTCN2015095728-appb-000064
2-(3-羟基-5-(3-对氟苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-对氟苯氧基丙炔(165.0mg，1.1mmol)替换丙炔，得到白色固体产物88.0mg，两步收率25.5％。m.p.171.2-173.7℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J＝1.2Hz,1H),8.20(s,1H),7.64(d,J＝1.3Hz,1H),7.09–6.96(m,2H),6.88–6.75(m,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:344[M]+.
实施例48
Figure PCTCN2015095728-appb-000065
2-(3-羟基-5-(3-间溴苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-间溴苯氧基丙炔(165.0mg，1.1mmol)替换丙炔，得到白色固体产物88.0mg，两步收率25.5％。m.p.132.1-134.5℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J＝1.2Hz,1H),8.20(s,1H),7.64(d,J＝1.3Hz,1H),7.37-7.33(m,1H),7.15(t,J＝7.5Hz,1H),7.01–6.84(m,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:404[M]+.
实施例49
Figure PCTCN2015095728-appb-000066
2-(3-羟基-5-(3-间氰基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-间氰基苯氧基丙炔(127.7mg，1.1mmol)替换丙炔，得到白色固体产物68.0mg，两步收率19.4％。m.p.181.2-183.4℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J＝1.3Hz,1H),8.20(s,1H),7.75–7.61(m,3H),7.19–7.09(m,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:351[M]+.
实施例50
Figure PCTCN2015095728-appb-000067
2-(3-羟基-5-(3-对乙酰氨基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-对乙酰胺基苯氧基丙炔(207.9mg，1.1mmol)替换丙炔，得到黄色固体产物77.0mg，两步收率20.1％。m.p.117.1-119.3℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J＝1.3Hz,1H),8.20(s,1H),7.65(d,J＝1.2Hz,1H),7.57(s,1H),7.48–7.37(m,2H),6.88–6.78(m,2H),4.68(s,2H),3.60(s,2H),2.10(s,3H).EI-MS m/z:383[M]+.
实施例51
Figure PCTCN2015095728-appb-000068
2-(3-羟基-5-(3-对叔丁氨基甲酰基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-(对叔丁基氨甲酰基苯氧基)丙炔(254.1mg，1.1mmol)替换丙炔，得到棕色固体产物77.0mg，两步收率20.1％。m.p.141.2-143.5℃。1H NMR(300MHz,DMSO-d6)δ8.73(d,J＝1.3Hz,1H),8.20(s,1H),7.73–7.62(m,3H),6.97–6.86(m,2H),5.99(s,1H),4.68(s,2H),3.60(s,2H),1.47(s,9H).EI-MS m/z:425[M]+.
实施例52
Figure PCTCN2015095728-appb-000069
2-(3-羟基-5-(3-对氨基甲酰基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-对氨基甲酰基苯氧基丙炔(190.3mg，1.1mmol)替换丙炔，得到棕色固体产物76.0mg，两步收率20.6％。m.p.122.1-124.7℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J＝1.2Hz,1H),8.20(s,1H),7.69–7.56(m,3H),6.97–6.86(m,2H),6.15(s,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:369[M]+.
实施例53
Figure PCTCN2015095728-appb-000070
2-(3-羟基-5-(3-(N-甲基-N-叔丁基氨甲酰基)吡啶-3-基氧基)丙炔-1-基)吡啶甲酰氨基乙酸
制备方法同实施例1，用3-((N-甲基-N-叔丁基氨甲酰基)吡啶-3-基氧基)丙炔(269.5mg，1.1mmol)替换丙炔，得到白色固体产物106.0mg，两步收率24.1％。m.p.137.1-139.3℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J＝1.2Hz,1H),8.20(s,1H),7.63–7.52(m,2H),7.06–6.95(m,2H),4.68(s,2H),3.60(s,2H),2.99(s,3H),1.21(s,9H).EI-MS m/z:440[M]+.
实施例54
Figure PCTCN2015095728-appb-000071
2-(3-羟基-5-(3-对环戊氨基甲酰基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-(对环戊氨基甲酰基苯氧基)丙炔(251.9mg，1.1mmol)替换丙炔，得到白色固体产物56.0mg，两步收率13.2％。m.p.154.1-156.8℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J＝1.3Hz,1H),8.20(s,1H),7.64(d,J＝1.2Hz,1H),7.55–7.44(m,2H),6.95–6.84(m,2H),4.68(s,2H),3.60(s,2H),3.56–3.42(m,4H),2.03–1.87(m,4H).EI-MSm/z:423[M]+.
实施例55
Figure PCTCN2015095728-appb-000072
2-(3-羟基-5-(3-对环丙氨基甲酰基苯氧基丙炔-1-基)-6-氯)吡啶甲酰氨基乙酸
制备方法同实施例1，用3-羟基-5-溴-6-氯吡啶2-甲酸替换2-羟基-5-溴吡啶-2-甲酸，用3-(对环丙氨基甲酰基苯氧基)丙炔(251.9mg，1.1mmol)替换丙炔，得到白色固体产物76.0mg，三步收率17.7％。m.p.147.2-149.2℃。1H NMR(300MHz,DMSO-d6)δ8.20(s,1H),7.92–7.77(m,3H),7.23–7.12(m,2H),4.68(s,2H),3.60(s,2H),1.61(s,4H).EI-MS m/z:429[M]+.
实施例56
Figure PCTCN2015095728-appb-000073
2-(3-羟基-5-(3-对(甲基高哌嗪基甲酰基)苯氧基丙炔-1-基)-苯氧基-1-丙炔基)吡啶甲酰氨基乙酸
制备方法同实施例1，用3-((甲基高哌嗪基)甲酰基苯氧基)丙炔(299.2mg，1.1mmol)替换丙炔，得到白色固体产物86.0mg，两步收率18.4％。m.p.168.9-172.1℃。1H NMR(300MHz,DMSO-d6)δ8.73(d,J＝1.2Hz,1H),8.20(s,1H),7.66(d,J＝1.3Hz,1H),7.55–7.45(m,2H),6.95–6.85(m,2H),4.68(s,2H),3.60(s,2H),3.60-3.27(m,4H),2.90(t,J＝5.9Hz,2H),2.66(t,J＝6.4Hz,2H),2.27(s,3H),1.73-1.65(m,2H).EI-MS m/z:466[M]+.
实施例57
Figure PCTCN2015095728-appb-000074
2-(3-羟基-5-(3-对苯基苯氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-对苯基苯氧基丙炔(228.8mg，1.1mmol)替换丙炔，得到白色固体产物95.0mg，两步收率23.6％。m.p.201.5-203.7℃。1H NMR(300MHz,DMSO-d6)δ8.69(d,J＝1.3Hz,1H),8.20(s,1H),7.73(d,J＝1.3Hz,1H),7.64–7.53(m,2H),7.55–7.38(m,4H),7.36-7.30(m,1H),7.12–7.01(m,2H),4.68(s,2H),3.60(s,2H).EI-MS m/z:402[M]+.
实施例58
Figure PCTCN2015095728-appb-000075
2-(3-羟基-5-(3-(萘-2-氧基)丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-(萘-2-氧基)丙炔(200.2mg，1.1mmol)替换丙炔，得到白色固体产物45.0mg，两步收率11.9％。m.p.211.5-213.7℃。1H NMR(300MHz,DMSO-d6)δ8.80(d,J＝1.2Hz,1H),8.20(s,1H),7.76(d,J＝1.3Hz,1H),7.72–7.62(m,2H),7.56(dt,J＝7.3,1.6Hz,1H),7.41-7.36(m,2H),7.14(dd,J＝7.9,1.5Hz,1H),6.97(t,J＝1.7Hz,1H),4.91(s,2H),3.89(s,2H).EI-MS m/z:376[M]+.
实施例59
Figure PCTCN2015095728-appb-000076
2-(3-羟基-5-(3-(喹啉-5-氧基)丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-(喹啉-5-氧基)丙炔(201.3mg，1.1mmol)替换丙炔，得到棕色固体产物65.0mg，两步收率17.2％。m.p.223.1-225.6℃。1H NMR(300MHz,DMSO-d6)δ8.83–8.71(m,2H),8.44(dd,J＝7.4,1.5Hz,1H),8.20(s,1H),7.80–7.67(m,2H),7.53-7.49(m,2H),6.70-6.68(m,1H),4.68(s,2H),3.60(s,2H).EI-MS m/z:377[M]+.
实施例60
Figure PCTCN2015095728-appb-000077
2-(3-羟基-5-(3-(苯并呋喃-7-氧基)丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-(苯并呋喃-7-氧基)丙炔(201.3mg，1.1mmol)替换丙炔，得到棕色固体产物75.0mg，两步收率20.4％。m.p.196.1-198.7℃。1H NMR(300MHz,DMSO-d6)δ8.70 (d,J＝1.2Hz,1H),8.20(s,1H),7.66(d,J＝1.3Hz,1H),7.52(d,J＝7.5Hz,1H),7.23–7.06(m,2H),6.99(dd,J＝7.3,1.8Hz,1H),6.72(dd,J＝7.5,1.5Hz,1H),4.68(s,2H),3.60(s,2H).EI-MS m/z:366[M]+.
实施例61
Figure PCTCN2015095728-appb-000078
2-(3-羟基-5-(3-(2,3-二氯苯基)氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-(2,3-二氯苯基)氧基丙炔(218.9mg，1.1mmol)替换丙炔，得到白色固体产物62.0mg，两步收率15.7％。m.p.152.2-154.6℃。1H NMR(300MHz,DMSO-d6)δ8.74(d,J＝1.3Hz,1H),8.20(s,1H),7.64(d,J＝1.3Hz,1H),7.28(dd,J＝7.5,2.1Hz,1H),7.17(t,J＝7.5Hz,1H),6.71(dd,J＝7.4,2.0Hz,1H),4.68(s,2H),3.60(s,2H).EI-MS m/z:394[M]+.
实施例62
Figure PCTCN2015095728-appb-000079
2-(3-羟基-5-(3-(3,4-二氯苯基)氧基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-(3,5-二氯苯基)氧基丙炔(218.9mg，1.1mmol)替换丙炔，得到白色固体产物74.0mg，两步收率18.7％。m.p.157.5-159.4℃。1H NMR(300MHz,DMSO-d6)δ8.68(d,J＝1.2Hz,1H),8.20(s,1H),7.66(d,J＝1.2Hz,1H),7.42(d,J＝2.0Hz,1H),7.26(dd,J＝7.5,2.0Hz,1H),6.97(d,J＝7.5Hz,1H),4.68(s,2H),3.60(s,2H).EI-MS m/z:394[M]+.
实施例63
Figure PCTCN2015095728-appb-000080
2-(3-羟基-5-(3-对环丙基苯氧基丙炔-1-基)-6-甲基)吡啶甲酰氨基乙酸
按实施例1的方法，用3-羟基-5-溴-6-甲基吡啶甲酸(372mg，2mmol)替换3-羟基-5-溴吡啶甲酸，3-对环丙基苯氧基丙炔替换丙炔(189.2，1.1mmol)，得到谈黄色固体产物82mg，收率21.5％。m.p.177.5-179.4℃。1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),7.77(s,1H),7.17– 7.06(m,2H),6.93–6.82(m,2H),4.68(s,2H),3.60(s,2H),2.76(s,3H),1.18–1.03(m,2H),0.90–0.72(m,2H).EI-MS m/z:380[M]+.
实施例64
Figure PCTCN2015095728-appb-000081
2-(3-羟基-5-(3-苯氨基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-苯氨基丙炔(144.1mg，1.1mmol)替换丙炔，得到白色固体产物64.0mg，两步收率20.0％。m.p.131.1-133.5℃。1H NMR(300MHz,DMSO-d6)δ8.75(d,J＝1.3Hz,1H),8.20(s,1H),7.63(d,J＝1.2Hz,1H),7.11–6.97(m,2H),6.74-6.69(m,1H),6.64–6.52(m,2H),4.29(s,1H),3.80(s,2H),3.60(s,2H).EI-MS m/z:325[M]+.
实施例65
Figure PCTCN2015095728-appb-000082
2-(3-羟基-5-((3-对氯苯氨基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-对氯苯氨基丙炔(181.1mg，1.1mmol)替换丙炔，得到白色固体产物78.0mg，两步收率21.7％。m.p.137.2-139.3℃。1H NMR(300MHz,DMSO-d6)δ8.73(d,J＝1.3Hz,1H),8.20(s,1H),7.71(d,J＝1.2Hz,1H),7.07–6.96(m,2H),6.56–6.45(m,2H),4.13(s,1H),3.80(s,2H),3.60(s,2H).EI-MS m/z:359[M]+.
实施例66
Figure PCTCN2015095728-appb-000083
2-(3-羟基-5-(3-对乙基苯氨基丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-对乙基苯氨基丙炔(174.9mg，1.1mmol)替换丙炔，得到白色固体产物68.0mg，两步收率19.2％。m.p.145.1-147.3℃。1H NMR(300MHz,DMSO-d6)δ8.70(d,J＝1.3Hz,1H),8.20(s,1H),7.64(d,J＝1.2Hz,1H),6.99-6.90(m,2H),6.63–6.53(m,2H),4.11(s,1H),3.80(s,2H),3.60(s,2H),2.64-2.5(m,2H),1.19(t,J＝6.6Hz,3H).EI-MS m/z:353[M]+.
实施例67
Figure PCTCN2015095728-appb-000084
2-(3-羟基-5-(3-((N-甲基-N-对咪唑-2基苯基)氨基)丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-((N-甲基-N-对咪唑-2基苯基)氨基)丙炔(131.2mg，1.1mmol)替换丙炔，得到白色固体产物68.0mg，两步收率16.7％。m.p.199.1-201.7℃。1H NMR(300MHz,DMSO-d6)δ8.49(d,J＝1.3Hz,1H),8.20(s,1H),7.91(s,1H),7.65–7.53(m,3H),7.41(s,1H),6.97–6.86(m,2H),4.09(s,2H),3.60(s,2H),2.97(s,3H).EI-MS m/z:405[M]+.
实施例68
Figure PCTCN2015095728-appb-000085
2-(3-羟基-5-(3-((N-苯基-N-3,4-二氟苯基)氨基)丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-((N-苯基-N-3,4-二氟苯基)氨基)丙炔(267.3mg，1.1mmol)替换丙炔，得到白色固体产物72.0mg，两步收率16.4％。m.p.205.2-207.3℃。1H NMR(300MHz,DMSO-d6)δ8.80(d,J＝1.2Hz,1H),8.20(s,1H),7.63(d,J＝1.3Hz,1H),7.30–7.17(m,4H),7.11–6.96(m,1H),6.93-6.90(m,1H),6.79-6.76(m,1H),6.66-6.56(m,1H),3.80(s,2H),3.60(s,2H).EI-MS m/z:437[M]+.
实施例69
Figure PCTCN2015095728-appb-000086
2-(3-羟基-5-(3-((N-叔丁基-N-3-甲基-4-乙氧基苯基)氨基)丙炔-1-基))吡啶甲酰氨基乙酸
制备方法同实施例1，用3-((N-叔丁基-N-3-甲基-4-乙氧基苯基)氨基)丙炔(269.5mg，1.1mmol)替换丙炔，得到白色固体产物82.0mg，两步收率18.6％。m.p.210.2-212.6℃。1H NMR(300MHz,DMSO-d6)δ8.62(d,J＝1.3Hz,1H),8.20(s,1H),7.37(d,J＝1.2Hz,1H),6.99-6.96(m,1H),6.54(s,1H),6.58–6.48(m,1H),4.09(s,3H),4.07(s,1H),3.60(s,2H),2.23(d,J＝1.0Hz,3H),1.43(t,J＝5.9Hz,3H),1.22(s,10H).EI-MS m/z:439[M]+.

Claims (10)

  1. 通式(I)的化合物或其药学上可接受的盐：
    Figure PCTCN2015095728-appb-100001
    其中X代表NH、NCH3或CH2；
    Y代表氢、羟基、甲氧基或乙氧基；
    L代表–CH2–、–CH2O–或
    Figure PCTCN2015095728-appb-100002
    R6代表氢、C1-C4烷基或苯基；
    n代表0或1；
    R1代表C1-C4烷基、苯基、取代苯基、含氧或氮的5～6员芳杂环、取代的含氧或氮的5～6员芳杂环，所述取代基是C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、卤素、氰基、
    Figure PCTCN2015095728-appb-100003
    Figure PCTCN2015095728-appb-100004
    苯基或含氧或氮的5～6员芳杂环，其中R7代表C1-C4烷基；R8、R9各自独立地代表氢或C1-C4烷基，或者R8、R9连接形成3～7员含氮杂环；
    R2代表氢、卤素或甲基；
    R3、R4各自独立地代表氢、甲基或乙基；
    R5代表羟基、C1-C4烷氧基或–NR10R11；R10、R11各自独立地代表氢、甲基或乙基。
  2. 权利要求1的化合物或其药学上可接受的盐，其中X代表NH。
  3. 权利要求1的化合物或其药学上可接受的盐，其中L代表–CH2–、–CH2O–或
    Figure PCTCN2015095728-appb-100005
    R6代表氢、甲基、叔丁基或苯基。
  4. 权利要求1的化合物或其药学上可接受的盐，其中R1代表取代苯环，取代基是甲基、乙基、异丙基、叔丁基、环丙基、甲氧基、叔丁氧基、环丙氧基、苯基、氰基、卤素、氟甲基、三氟甲基、咪唑基、乙酰氨基、环丙基甲酰氨基或
    Figure PCTCN2015095728-appb-100006
    其中R8、R9各自独立地代表氢、甲基、丁基或叔丁基，或两者连接形成环丙氨基、四氢吡咯基或N-甲基高哌嗪基。
  5. 权利要求1的化合物或其药学上可接受的盐，其中R1代表环丙基、叔丁基、苯基、萘基、喹啉基或苯并呋喃基。
  6. 权利要求1的化合物或其药学上可接受的盐，其中R3或R4代表氢。
  7. 权利要求1的化合物或其药学上可接受的盐，其中R5代表-NH2、-NHCH3、羟基、甲氧基、 异丙氧基、环丙氧基或环丙基甲氧基。
  8. 一种药物组合物，其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
  9. 权利要求1的化合物或其药学上可接受的盐用于制备治疗贫血症或缺血性疾病的药物的用途。
  10. 权利要求9的用途，其中缺血性疾病是缺血性脑卒中或心肌缺血相关疾病。
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WO2020177681A1 (zh) 2019-03-04 2020-09-10 江苏恒瑞医药股份有限公司 一种脯氨酰羟化酶抑制剂的药物组合物及其制备方法
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