US20200407319A1 - Alkynyl pyridine prolyl hydroxylase inhibitor, and preparation method and medical use thereof - Google Patents
Alkynyl pyridine prolyl hydroxylase inhibitor, and preparation method and medical use thereof Download PDFInfo
- Publication number
- US20200407319A1 US20200407319A1 US17/018,221 US202017018221A US2020407319A1 US 20200407319 A1 US20200407319 A1 US 20200407319A1 US 202017018221 A US202017018221 A US 202017018221A US 2020407319 A1 US2020407319 A1 US 2020407319A1
- Authority
- US
- United States
- Prior art keywords
- hydroxy
- mmol
- propyne
- replaced
- mhz
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- -1 Alkynyl pyridine Chemical compound 0.000 title claims abstract description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title abstract description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 title description 63
- 229940078467 Prolyl hydroxylase inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- 238000000034 method Methods 0.000 claims abstract description 31
- 208000007502 anemia Diseases 0.000 claims abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000023589 ischemic disease Diseases 0.000 claims abstract description 9
- 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 6
- 208000032382 Ischaemic stroke Diseases 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 claims 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 2
- 125000004069 aziridinyl group Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims 1
- 102000004079 Prolyl Hydroxylases Human genes 0.000 abstract description 29
- 108010043005 Prolyl Hydroxylases Proteins 0.000 abstract description 29
- 102000003951 Erythropoietin Human genes 0.000 abstract description 22
- 108090000394 Erythropoietin Proteins 0.000 abstract description 22
- 229940105423 erythropoietin Drugs 0.000 abstract description 22
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 abstract description 22
- 230000000694 effects Effects 0.000 abstract description 13
- 230000002401 inhibitory effect Effects 0.000 abstract description 13
- 230000028327 secretion Effects 0.000 abstract description 7
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 230000002265 prevention Effects 0.000 abstract description 4
- 238000010171 animal model Methods 0.000 abstract 1
- 208000020832 chronic kidney disease Diseases 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 147
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 126
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 72
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 71
- 238000005160 1H NMR spectroscopy Methods 0.000 description 67
- 239000012265 solid product Substances 0.000 description 62
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 14
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- 239000007787 solid Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 230000001413 cellular effect Effects 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- KNYSNNRQXSFAGE-UHFFFAOYSA-N 5-bromo-3-hydroxypyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=C(Br)C=C1O KNYSNNRQXSFAGE-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 210000003743 erythrocyte Anatomy 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
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- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 4
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- USRMDNZIKVMDKH-UHFFFAOYSA-N 1-chloro-4-prop-2-ynoxybenzene Chemical compound ClC1=CC=C(OCC#C)C=C1 USRMDNZIKVMDKH-UHFFFAOYSA-N 0.000 description 3
- QXSWHQGIEKUBAS-UHFFFAOYSA-N 1-ethynyl-4-fluorobenzene Chemical group FC1=CC=C(C#C)C=C1 QXSWHQGIEKUBAS-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 3
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 3
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 3
- AIKDJELJHUPYNG-UHFFFAOYSA-N O=C(O)CNC(=O)C1=NC=C(C#CCOC2=CC=C(Cl)C=C2)C=C1O Chemical compound O=C(O)CNC(=O)C1=NC=C(C#CCOC2=CC=C(Cl)C=C2)C=C1O AIKDJELJHUPYNG-UHFFFAOYSA-N 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
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- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
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- LEMXQCYBJJWERN-UHFFFAOYSA-N 2-[[6-bromo-3-hydroxy-5-[2-(4-methylphenyl)ethynyl]pyridine-2-carbonyl]-methylamino]acetic acid Chemical compound BrC1=C(C=C(C(=N1)C(=O)N(CC(=O)O)C)O)C#CC1=CC=C(C=C1)C LEMXQCYBJJWERN-UHFFFAOYSA-N 0.000 description 2
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- 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
- A61P7/06—Antianaemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- 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
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- 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
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- 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 present invention relates to the field of medicinal chemistry. Specifically, the present invention relates to a class of alkynyl pyridines prolyl hydroxylase inhibitors.
- This class of compounds can enhance the production and secretion of erythropoietin, thereby promoting the production of red blood cells, and can be used for the treatment or prevention of anemia, such as anemia in chronic kidney disease, and ischemic diseases, such as ischemic stroke, myocardial ischemia and other related diseases.
- anemia such as anemia in chronic kidney disease
- ischemic diseases such as ischemic stroke, myocardial ischemia and other related diseases.
- Anemia generally refers to any abnormality in hemoglobin or red blood cells that leads to reduced oxygen levels in the blood.
- Anemia can also develop in association with chronic diseases, such as chronic infection, neoplastic diseases, chronic inflammation, including disorders of consequent inflammatory suppression of marrow, etc.
- Anemia of chronic disease for example anemia in chronic kidney disease, is one of the most common syndromes in medicine.
- the main cause of anemia in chronic kidney disease is insufficient secretion of erythropoietin (EPO) ( Nephrol Dial Transplant 17(2002)2-7).
- EPO erythropoietin
- the insufficient secretion of EPO can hinder the production of red blood cells, resulting in the occurrence of anemia.
- the expression and secretion of EPO are regulated by the transcription factor hypoxia inducible factor (HIF).
- HIF hypoxia inducible factor
- the HIF protein with complete transcription function is composed of two subunits HIF- ⁇ and HIF- ⁇ , in which HIF- ⁇ is regulated by prolyl hydroxylase (PHD) that can hydroxylate HIF- ⁇ to promote its degradation.
- prolyl hydroxylase 2 PLD2
- prolyl hydroxylase 2 PLD2
- the HIF- ⁇ subunit can be stabilized in vivo, so that it enters the nucleus, and binds to the HIF- ⁇ subunit in the nucleus to form a stable HIF dimer.
- the dimer further causes the expression of downstream genes, thereby promoting the expression and secretion of EPO. Therefore, the inhibition of activity of prolyl hydroxylase can increase the level of HIF- ⁇ and promote the production of EPO, thereby promoting the maturation of red blood cells, enhancing the capacity of blood in delivering oxygen, and improving anemia or ischemic symptoms.
- the present invention provides a small molecule compound that can inhibit the activity of prolyl hydroxylase (PHD).
- PHD prolyl hydroxylase
- This compound increases the content of HIF- ⁇ by inhibiting PHD, thereby increasing the production and secretion of EPO, promoting the maturation of red blood cells, and enhancing the capacity of blood in delivering oxygen.
- This compound is used for the treatment and prevention of anemia and ischemic diseases, such as anemia in chronic kidney disease, myocardial ischemia, cerebral ischemia, stroke and the like.
- the structure of the compound of the present invention is 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 C 1 -C 4 alkyl, phenyl, substituted phenyl, 5- to 6-membered heteroaryl containing oxygen or nitrogen, substituted 5- to 6-membered heteroaryl containing oxygen or nitrogen, wherein the substituent is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, halogen, cyano,
- R 7 represents C 1 -C 4 alkyl
- R 8 and R 9 each independently represents hydrogen or C 1 -C 4 alkyl, or R 8 and R 9 are attached to form a 3- to 7-membered heterocyclyl containing nitrogen
- R 2 represents hydrogen, halogen or methyl
- R 3 and R 4 each independently represents hydrogen, methyl or ethyl
- R 5 represents hydroxy, C 1 -C 4 alkoxy or —NR 10 R 11
- R 10 and R 11 each independently represents 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 substituted phenyl, wherein the substituent is methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, tert-butoxy, cyclopropoxy, phenyl, cyano, halogen, fluoromethyl, trifluoromethyl, imidazolyl, acetylamino, cyclopropylcarboxamido or
- R 8 and R 9 each independently represents hydrogen, methyl, butyl or tert-butyl, or R 8 and R 9 are attached to form cyclopropylamino, tetrahydropyrrolyl or N-methylhomopiperazinyl.
- R 1 also preferably represents cyclopropyl, tert-butyl, phenyl, naphthyl, quinolyl or benzofuranyl.
- R 3 or R 4 preferably represents hydrogen.
- R 5 preferably represents —NH 2 , —NHCH 3 , hydroxy, methoxy, isopropoxy, cyclopropoxy or cyclopropylmethoxy.
- the present invention also includes a pharmaceutically acceptable salt and a solvate of the compound of formula (I), both of which have the same pharmacological effect as the compound of formula (I).
- the present invention discloses a pharmaceutical composition, comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as well as one or more pharmaceutically acceptable carriers, diluents and excipients.
- the present invention also provides a use of the compound of formula (I) and/or the pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for the treatment of a prolyl hydroxylase-mediated disease by inhibiting prolyl hydroxylase.
- the disease is anemia that can be treated by inhibiting prolyl hydroxylase.
- the clinical dose of the compound of the present invention is 0.01-1000 mg/day, and can also deviate from this range according to the severity of the disease or the dosage form.
- the compound of formula (I) can contain an acidic functional group sufficient to form a salt.
- Representative salts include a pharmaceutically acceptable metal salt such as sodium, potassium, lithium, calcium, magnesium, aluminum and zinc salts; pharmaceutically acceptable carbonate and bicarbonate of metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum and zinc; pharmaceutically acceptable salt of organic primary, secondary and tertiary amine, including fatty amine, aromatic amine, fatty diamine and hydroxyalkylamine, such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, and diethanolamine.
- a pharmaceutically acceptable metal salt such as sodium, potassium, lithium, calcium, magnesium, aluminum and zinc salts
- pharmaceutically acceptable carbonate and bicarbonate of metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum and zinc
- pharmaceutically acceptable salt of organic primary, secondary and tertiary amine including fatty amine, aromatic
- the present invention also provides a method for preparing formula (I)-related compounds, comprising the following steps of
- R 1 , R 2 , R 3 , R 4 , X, Y, n and L are as defined previously.
- the intermediate VI can be synthesized by the following scheme,
- vascular endothelial growth factor (VEGF) and EPO are two markers indicating the increase of HIF in vivo ( Journal of Medicinal Chemistry 55(2012)2945-2959).
- VEGF vascular endothelial growth factor
- EPO vascular endothelial growth factor
- FG-4592 International Patent Application Publication WO 2013013609A1
- FG-4592 is used as a positive control compound.
- Prolyl hydroxylase inhibitory activity and related biological activity of some compounds of the present invention Number Whether it Whether it of can increase can increase example
- the compounds of the present invention have a strong prolyl hydroxylase 2 inhibitory activity.
- patent application US2007/0299086 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 an alkynyl group is connected to the 5-position of the pyridine nucleus directly, and the introduction of the alkynyl group at this position can greatly enhance the inhibitory activity of the compound on prolyl hydroxylase.
- an alkynyl group is connected to the 5-position of the pyridine nucleus directly, and the introduction of the alkynyl group at this position can greatly enhance the inhibitory activity of the compound on prolyl hydroxylase.
- Fluorescence polarization method ( Biochemical and Biophysical Research Communications 337 (2005) 275-280): The data were read using a fluorescence polarization instrument 1 h after adding the drugs, and the solvent was used as a control. The inhibition rate of the compounds on prolyl hydroxylase was calculated using the following formula, and the IC 50 was calculated at the same time. The results are shown in Tables 1 and 3.
- prolyl hydroxylase 2 (PHD2) subtype prolyl hydroxylase 2 (PHD2) subtype
- prolyl hydroxylase 3 (PHD3) subtype can regulate the content of HIF. Therefore, the representative compounds were also tested for their PHD3 inhibitory activity, and the test results are as follows:
- % inhibition rate 100*(1 ⁇ (measured value ⁇ blank)/(negative value ⁇ blank))
- the compounds of the present invention have strong prolyl hydroxylase 2 and 3 inhibitory activity. Among them, the activity of some compounds is significantly better than that of the positive drug FG-4592.
- the test of the activity of some compounds of the present invention on VEGF at the cellular level and EPO at the cellular level is shown as follows. The method is in accordance with Bioorganic & Medicinal Chemistry Letters 23(2013) 5953-5957, and the test was carried out by using VEGF and EPO kit respectively 24 h after administration. The results are shown in Table 1.
- Hep3B Cell Human Hepatoma Cell
- the compounds of the present invention have the ability to significantly increase the levels of VEGF and EPO in cells, and show good activity at the cellular level.
- the test of the activity of some compounds of the present invention on VEGF at the animal level and EPO at the cellular level is shown as follows. The method is in accordance with Journal of Medicinal Chemistry 55(2012) 2945-2959, and the test was carried out by using VEGF and EPO kit respectively 4 h after administration. The results are shown in FIG. 2 below.
- the compounds of the present invention can significantly increase the expression of VEGF and EPO at the animal level, indicating that the compounds of the present invention are effective at the animal level.
- the alkynyl pyridine compounds of the present invention have good biological activity at the molecular, cellular and animal levels.
- the compounds of the present invention can increase the level of erythropoietin (EPO) in blood at the animal level, thereby promoting the production of red blood cells, and can be used for the treatment or prevention of anemia related to chronic diseases, ischemic diseases and hematopoietic system-related diseases.
- EPO erythropoietin
- FIG. 1 is the results of Western-blot test of some compounds at the cellular level (Hep3B cell: human hepatoma cell; the compound concentration: 50 ⁇ M, 250 ⁇ M, 24 hours after administration)
- FIG. 2 is the test of increased level of VEGF and EPO in cells 24 h after the administration of compounds 14, 15, 47 and FG-4592 at a concentration of 50 ⁇ M (model: C57Bl/6 mice, male, 8-9 weeks old)
- Methyl 2-(3-hydroxy-5-propynyl)picolinamido acetate (100.0 mg, 0.4 mmol) was dissolved in 10 mL of tetrahydrofuran, then 3 mL of 1 M lithium hydroxide was added. The mixture was heated to 30° C. for 3 h to complete the reaction. After the completion of the reaction, tetrahydrofuran in the reaction solution was removed by pressurized distillation, then 3 mmol of dilute hydrochloric acid was added in an ice bath to precipitate a white solid. The white solid was filtered and dried to obtain a white product (61.0 mg, yield: 65.2%.). m.p. 179.1-181.3° C.
- Methyl 2-(3-hydroxy-5-bromopyridine)carboxamido acetate (288 mg, 1 mmol) and phenylacetylene (110.2 mg, 1.1 mmol) were dissolved in 6 mL of DMF, then 6 mL of N,N-diisopropylethylamine, 40 mg of cuprous iodide, and 40 mg of dichloro(bis(triphenylphosphine))palladium were added. The mixture was heated to 80° C. by a conventional method for 6 h, or heated to 80° C. by microwave for 15 min, and the reaction was substantially completed.
- 3-Hydroxy-5-bromopyridine (348 mg, 2 mmol) was dissolved in 40 mL of dichloromethane, then methyl succinyl chloride (400 mg, 4 mmol) and 100 mg of aluminum trichloride were added in an ice bath. The reaction was carried out at room temperature for 2 hours. After the completion of the reaction, water and 3 M hydrochloric acid were added. After separation, the solution was washed successively with (2 ⁇ 100 mL) and saturated brine (1 ⁇ 100 mL). The solution was dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Methyl 4-(3-hydroxy-5-bromopyridin-2-yl)-4-oxobutanoate (190 mg, 0.66 mmol) and p-ethylphenylacetylene (94 mg, 0.72 mmol) were dissolved in 6 mL of DMF, then 6 mL of N,N-diisopropylethylamine, 40 mg of cuprous iodide, and 40 mg of dichloro(bis(triphenylphosphine))palladium were added.
- the mixture was heated to 80° C. by a conventional method for 6 h, or heated to 80° C. by microwave for 15 min, and the reaction was substantially completed.
- Methyl 2-(3-hydroxy-5-propynyl)picolinamido acetate (70.0 mg, 0.2 mmol) was dissolved in 10 mL of tetrahydrofuran, then 3 mL of 1 M lithium hydroxide was added. The mixture was heated to 30° C. for 3 h to complete the reaction. After completion of the reaction, tetrahydrofuran in the reaction solution was removed by pressurized distillation, then 3 mmol of dilute hydrochloric acid was added in an ice bath to precipitate a white solid. The white solid was filtered and dried to obtain a white product (41.0 mg, yield: 56.9%.). m.p. 185.7-187.8° C.
- the preparation method is the same as that of Example 6, and propyne was replaced by p-butylcarbamoylphenylacetylene (205.7 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by isopropyl glycinate. Accordingly, a brown solid product was obtained (81.4 mg, yield of three steps: 18.6%). m.p. 187.2-189.5° C.
- the preparation method is the same as that of Example 6, and propyne was replaced by p-cyclopropylcarboxamidophenylacetylene (203.5 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by N-ethylglycinamide. Accordingly, a brown solid product was obtained (71.4 mg, yield of three steps: 18.3%). m.p. 195.2-197.7° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-(p-chlorophenoxy)propyne (182.6 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by glycinamide. Accordingly, a brown product was obtained (54.0 mg, yield of three steps: 15.1%). m.p. 152.2-154.6° C.
- the preparation method is the same as that of Example 6, and propyne was replaced by 3-(p-cyanophenoxy)propyne (172.7 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by isopropyl glycinate. Accordingly, a white solid product was obtained (126.0 mg, yield: 32.1%). m.p. 120.2-123.1° C.
- the preparation method is the same as that of Example 6, and propyne was replaced by 3-(p-fluorophenoxy)propyne (165.0 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by glycine cyclopropyl ester. Accordingly, a white solid product was obtained (117.0 mg, yield: 30.4%). m.p. 107.2-109.9° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-(p-chlorophenoxy)propyne (182.6 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by N,N′-dimethylglycinamide. Accordingly, a white solid product was obtained (97.0 mg, yield: 24.2%). m.p. 177.2-179.9° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-(p-ethylphenoxy)propyne (176.0 mg, 1.1 mmol). Accordingly, a white solid product was obtained (110.3 mg, yield of two steps: 31.1%). m.p. 172.4-174.7° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-m-tert-butoxyphenoxypropyne (224.4 mg, 1.1 mmol). Accordingly, a white solid product was obtained (85.5 mg, yield of two steps: 21.5%). m.p. 237.2-239.4° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-m-cyclopropoxyphenoxypropyne (206.8 mg, 1.1 mmol). Accordingly, a white solid product was obtained (95.0 mg, yield of two steps: 24.9%). m.p. 212.3-214.7° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-(5-fluoromethylfuran-2-yloxy)propyne (180.0 mg, 1.1 mmol). Accordingly, a white solid product was obtained (95.0 mg, yield of two steps: 26.5%). m.p. 187.2-189.3° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-((N-methyl-N-tert-butylcarbamoyl)pyridin-3-yloxy)propyne (269.5 mg, 1.1 mmol). Accordingly, a white solid product was obtained (106.0 mg, yield of two steps: 24.1%). m.p. 137.1-139.3° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-((4-(pyrrolidin-1-carbonyl)phenoxy))propyne (251.9 mg, 1.1 mmol). Accordingly, a white solid product was obtained (56.0 mg, yield of two steps: 13.2%). m.p. 154.1-156.8° C.
- the preparation method is the same as that of Example 1, and 3-hydroxy-5-bromopyridine-2-carboxylic acid was replaced by 3-hydroxy-5-bromo-6-chloropyridine-2-carboxylic acid, and propyne was replaced by 3-((4-(aziridinyl-1-carbonyl))phenoxy)propyne (251.9 mg, 1.1 mmol). Accordingly, a white solid product was obtained (76.0 mg, yield of three steps: 17.7%). m.p. 147.2-149.2° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-((4-(4-methyl-1,4-diazepan-1-carbonyl)phenoxy))propyne (299.2 mg, 1.1 mmol). Accordingly, a white solid product was obtained (86.0 mg, yield of two steps: 18.4%). m.p. 168.9-172.1° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-p-phenylphenoxypropyne (228.8 mg, 1.1 mmol). Accordingly, a white solid product was obtained (95.0 mg, yield of two steps: 23.6%). m.p. 201.5-203.7° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-(naphthalen-2-oxy)propyne (200.2 mg, 1.1 mmol). Accordingly, a white solid product was obtained (45.0 mg, yield of two steps: 11.9%). m.p. 211.5-213.7° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-((N-methyl-N-p-imidazol-2-ylphenyl)amino)propyne (131.2 mg, 1.1 mmol). Accordingly, a white solid product was obtained (68.0 mg, yield of two steps: 16.7%). m.p. 199.1-201.7° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-((N-phenyl-N-3,4-difluorophenyl)amino)propyne (267.3 mg, 1.1 mmol). Accordingly, a white solid product was obtained (72.0 mg, yield of two steps: 16.4%). m.p. 205.2-207.3° C.
- the preparation method is the same as that of Example 1, and propyne was replaced by 3-((N-tert-butyl-N-3-ethoxy-4-methylphenyl)amino)propyne (269.5 mg, 1.1 mmol). Accordingly, a white solid product was obtained (82.0 mg, yield of two steps: 18.6%). m.p. 210.2-212.6° C.
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Abstract
The present invention relates to the field of pharmaceutical chemistry. In particular, the present invention relates to a class of alkynyl pyridine prolyl hydroxylase inhibitors (I). The experiments show that such a compound has good activity of inhibiting prolyl hydroxylase, and can enhance the generation and secretion of erythropoietin in cell or animal models, and thus can promote the generation of red cells, and can be used for the treatment or prevention of anemia, such as chronic kidney disease anemia, and ischemic diseases, including ischemic strokes, myocardial ischemia and other related diseases. The present invention also discloses a method for preparing such a compound.
Description
- This application is a Divisional of U.S. application Ser. No. 15/765,387, filed Apr. 2, 2018, which is a Section 371 of International Application No. PCT/CN2015/095728, filed Nov. 27, 2015, which was published in the Chinese language on Apr. 13, 2017, under International Publication No. WO 2017/059623 A1, which claims priority under 35 U.S.C. § 119(b) to Chinese Application No. 201510648342.9, filed Oct. 9, 2015, the disclosures of which are incorporated herein by reference in their entirety.
- The present invention relates to the field of medicinal chemistry. Specifically, the present invention relates to a class of alkynyl pyridines prolyl hydroxylase inhibitors.
- This class of compounds can enhance the production and secretion of erythropoietin, thereby promoting the production of red blood cells, and can be used for the treatment or prevention of anemia, such as anemia in chronic kidney disease, and ischemic diseases, such as ischemic stroke, myocardial ischemia and other related diseases.
- Anemia generally refers to any abnormality in hemoglobin or red blood cells that leads to reduced oxygen levels in the blood. Anemia can also develop in association with chronic diseases, such as chronic infection, neoplastic diseases, chronic inflammation, including disorders of consequent inflammatory suppression of marrow, etc. Anemia of chronic disease, for example anemia in chronic kidney disease, is one of the most common syndromes in medicine. The main cause of anemia in chronic kidney disease is insufficient secretion of erythropoietin (EPO) (Nephrol Dial Transplant 17(2002)2-7). The insufficient secretion of EPO can hinder the production of red blood cells, resulting in the occurrence of anemia. The expression and secretion of EPO are regulated by the transcription factor hypoxia inducible factor (HIF). The HIF protein with complete transcription function is composed of two subunits HIF-α and HIF-β, in which HIF-α is regulated by prolyl hydroxylase (PHD) that can hydroxylate HIF-α to promote its degradation. Inside the human body, prolyl hydroxylase 2 (PHD2) is the most dominant subtype that regulates HIF levels (Journal of Medicinal Chemistry 56(2013)9369-9402). When the activity of prolyl hydroxylase (PHD) in vivo is inhibited, the HIF-α subunit can be stabilized in vivo, so that it enters the nucleus, and binds to the HIF-β subunit in the nucleus to form a stable HIF dimer. The dimer further causes the expression of downstream genes, thereby promoting the expression and secretion of EPO. Therefore, the inhibition of activity of prolyl hydroxylase can increase the level of HIF-α and promote the production of EPO, thereby promoting the maturation of red blood cells, enhancing the capacity of blood in delivering oxygen, and improving anemia or ischemic symptoms.
- The present invention provides a small molecule compound that can inhibit the activity of prolyl hydroxylase (PHD). This compound increases the content of HIF-α by inhibiting PHD, thereby increasing the production and secretion of EPO, promoting the maturation of red blood cells, and enhancing the capacity of blood in delivering oxygen. This compound is used for the treatment and prevention of anemia and ischemic diseases, such as anemia in chronic kidney disease, myocardial ischemia, cerebral ischemia, stroke and the like. The structure of the compound of the present invention is as follows:
- wherein X represents NH, NCH3 or CH2; Y represents hydrogen, hydroxy, methoxy or ethoxy; L represents —CH2—, —CH2O— or
- R6 represents hydrogen, C1-C4 alkyl or phenyl; n represents 0 or 1;
- R1 represents C1-C4 alkyl, phenyl, substituted phenyl, 5- to 6-membered heteroaryl containing oxygen or nitrogen, substituted 5- to 6-membered heteroaryl containing oxygen or nitrogen, wherein the substituent is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, halogen, cyano,
- phenyl or 5- to 6-membered heteroaryl containing oxygen or nitrogen, wherein R7 represents C1-C4 alkyl; R8 and R9 each independently represents hydrogen or C1-C4 alkyl, or R8 and R9 are attached to form a 3- to 7-membered heterocyclyl containing nitrogen;
R2 represents hydrogen, halogen or methyl; R3 and R4 each independently represents hydrogen, methyl or ethyl; and
R5 represents hydroxy, C1-C4 alkoxy or —NR10R11; R10 and R11 each independently represents hydrogen, methyl or ethyl. - X preferably represents NH. L preferably represents —CH2—, —CH2O— or
- R6 preferably represents hydrogen, methyl, tert-butyl or phenyl. R1 preferably represents substituted phenyl, wherein the substituent is methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, tert-butoxy, cyclopropoxy, phenyl, cyano, halogen, fluoromethyl, trifluoromethyl, imidazolyl, acetylamino, cyclopropylcarboxamido or
- wherein R8 and R9 each independently represents hydrogen, methyl, butyl or tert-butyl, or R8 and R9 are attached to form cyclopropylamino, tetrahydropyrrolyl or N-methylhomopiperazinyl.
- R1 also preferably represents cyclopropyl, tert-butyl, phenyl, naphthyl, quinolyl or benzofuranyl.
- R3 or R4 preferably represents hydrogen. R5 preferably represents —NH2, —NHCH3, hydroxy, methoxy, isopropoxy, cyclopropoxy or cyclopropylmethoxy.
- The present invention also includes a pharmaceutically acceptable salt and a solvate of the compound of formula (I), both of which have the same pharmacological effect as the compound of formula (I).
- The present invention discloses a pharmaceutical composition, comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as well as one or more pharmaceutically acceptable carriers, diluents and excipients.
- The present invention also provides a use of the compound of formula (I) and/or the pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for the treatment of a prolyl hydroxylase-mediated disease by inhibiting prolyl hydroxylase. For example, the disease is anemia that can be treated by inhibiting prolyl hydroxylase.
- The clinical dose of the compound of the present invention is 0.01-1000 mg/day, and can also deviate from this range according to the severity of the disease or the dosage form.
- In certain embodiments, the compound of formula (I) can contain an acidic functional group sufficient to form a salt. Representative salts include a pharmaceutically acceptable metal salt such as sodium, potassium, lithium, calcium, magnesium, aluminum and zinc salts; pharmaceutically acceptable carbonate and bicarbonate of metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum and zinc; pharmaceutically acceptable salt of organic primary, secondary and tertiary amine, including fatty amine, aromatic amine, fatty diamine and hydroxyalkylamine, such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, and diethanolamine.
- The present invention also provides a method for preparing formula (I)-related compounds, comprising the following steps of
- wherein R1, R2, R3, R4, X, Y, n and L are as defined previously.
- The intermediate VI can be synthesized by the following scheme,
- Some of the pharmacodynamic experimental data of the compounds of the present invention are provided below:
- The vascular endothelial growth factor (VEGF) and EPO are two markers indicating the increase of HIF in vivo (Journal of Medicinal Chemistry 55(2012)2945-2959). When the activity of PHD is inhibited, the content of HIF in vivo increases. HIF can enter the nucleus to induce the expression of downstream genes, and the expression levels of EPO, VEGF and the like in vivo increase. The compounds were tested for their ability of inhibiting the activity of PHD and increasing HIF at the cellular level by measuring the expression of VEGF and EPO. At the same time, FG-4592 (International Patent Application Publication WO 2013013609A1) is a PHD2 inhibitor for treating anemia that has currently entered the clinical phase III. In the present invention, FG-4592 is used as a positive control compound.
-
TABLE 1 Prolyl hydroxylase inhibitory activity and related biological activity of some compounds of the present invention Number Whether it Whether it of can increase can increase example Prolyl the expression the expression com- hydroxylase 2of VEGF of EPO in pound (IC50 nM) in cells cells 1 4530 ± 35.2 ND ND 2 1423 ± 43 ND ND 3 1223 ± 56 Yes Yes 4 834.9 ± 3.2 Yes Yes 5 820.5 ± 10.9 Yes Yes 6 5500 ± 43 Yes Yes 7 215.3 ± 21.0 ND Yes 8 550.2 ± 12.1 Yes Yes 9 1045 ± 19.1 Yes Yes 10 2028.0 ± 4.7 ND ND 11 1940 ± 23.1 ND ND 12 2780 ± 44 ND ND 13 2650 ± 38.2 ND ND 14 298.3 ± 13.6 Yes Yes 15 566.7 ± 3.4 Yes Yes 16 563.7 ± 36.3 ND Yes 17 463.5 ± 17.0 Yes Yes 18 8130 ± 40.5 ND ND 19 310 ± 10.5 Yes Yes 20 233.9 ± 13.7 Yes Yes 21 510.4 ± 20.1 ND ND 22 950.5 ± 18.4 Yes Yes 23 1055 ± 40.5 Yes Yes 24 5200 ± 62.2 ND Yes 25 6211 ± 40.0 Yes ND 26 2128 ± 34.0 ND ND 27 1700 ± 87.0 ND ND 28 125.3 ± 15.5 Yes Yes 29 3120 ± 47.0 Yes Yes 30 3756 ± 39.0 Yes Yes 31 6120 ± 17.5 ND ND 32 6100 ± 44.0 ND ND 33 169.5 ± 0.5 Yes Yes 34 110.1 ± 22.0 Yes Yes 35 70.4 ± 0.6 Yes Yes 36 377.9 ± 33.3 Yes Yes 37 390.5 ± 15.5 ND ND 38 79.2 ± 1.9 Yes Yes 39 186.3 ± 3.9 Yes Yes 40 543.6 ± 9.7 Yes Yes 41 489.4 ± 31.0 Yes Yes 42 514.8 ± 6.1 ND ND 43 402.1 ± 2.2 ND ND 44 13.7 ± 1.1 Yes Yes 45 175.1 ± 2.3 Yes Yes 46 101.8 ± 5.0 Yes Yes 47 186.6 ± 8.3 Yes Yes 48 178.2 ± 2.5 Yes Yes 49 652.6 ± 27.1 Yes Yes 50 311.1 ± 5.4 ND ND 51 442.0 ± 6.4 ND ND 52 310.2 ± 5.7 ND Yes 53 519.7 ± 3.9 ND ND 54 210.7 ± 4.4 Yes Yes 55 220.8 ± 2.9 Yes Yes 56 689.9 ± 34.0 ND ND 57 540.0 ± 3.6 Yes Yes 58 605.5 ± 23.1 Yes Yes 59 405.2 ± 10.5 ND ND 60 399.0 ± 3.4 ND ND 61 527.0 ± 6.1 Yes Yes 62 449.7 ± 20.4 Yes Yes 63 759.2 ± 22.1 ND Yes 64 326.5 ± 9.8 Yes Yes 65 290.5 ± 7.5 Yes Yes 66 399.6 ± 1.2 Yes Yes 67 675.4 ± 7.7 ND ND 68 1204 ± 23 ND ND 69 1405 ± 4.1 ND ND FG-4592 599.3 ± 13.0 Yes Yes aND: not determined; bthe structures of compounds are shown in specific examples; cthe structure of FG-4592: - As can be seen from Table 1, the compounds of the present invention have a
strong prolyl hydroxylase 2 inhibitory activity. - In addition, patent application US2007/0299086 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 an alkynyl group is connected to the 5-position of the pyridine nucleus directly, and the introduction of the alkynyl group at this position can greatly enhance the inhibitory activity of the compound on prolyl hydroxylase. In order to compare the activity of the compounds of the present invention with that of the compounds of US2007/0299086 A1, some of the compounds of patent application US2007/0299086 A1 were synthesized (the synthetic method is described in Tetrahedron Lett., 2015, 56(35), 5017-5019). Prolyl hydroxylase inhibitory activity was evaluated according to the same activity test method of the present invention in the same batch. The comparison results of some of the compounds of the present invention with the compounds of patent application US2007/0299086 are shown as follows:
-
TABLE 2 Comparison of some of the compounds of the present invention with the compounds of patent application US2007/0299086 Prolyl Number and structure of example hydroxylase 2 compounds of the present invention (IC50 nM) Example 14 298.3 ± 13.6 Example 19 377.9 ± 33.3 Example 33 169.5 ± 0.5 Example 44 13.7 ± 1.1 Example 66 399.6 ± 1.2 Structure of the compounds Prolyl of patent application hydroxylase US2007/0299086 2 (IC50 nM) Example 14 2224 ± 20.5 Example 19 1497 ± 43.1 Example 33 2028 ± 33.6 Example 44 1385 ± 53.7 Example 66 1497 ± 43.1 - It can be seen from the data comparison of the compounds in Table 2 that the introduction of the alkynyl group in the present invention can significantly enhance the inhibitory activity of the compound on
prolyl hydroxylase 2 when other groups are substantially the same. - Fluorescence polarization method (Biochemical and Biophysical Research Communications 337 (2005) 275-280): The data were read using a fluorescence polarization instrument 1 h after adding the drugs, and the solvent was used as a control. The inhibition rate of the compounds on prolyl hydroxylase was calculated using the following formula, and the IC50 was calculated at the same time. The results are shown in Tables 1 and 3.
- In addition to prolyl hydroxylase 2 (PHD2) subtype, prolyl hydroxylase 3 (PHD3) subtype can regulate the content of HIF. Therefore, the representative compounds were also tested for their PHD3 inhibitory activity, and the test results are as follows:
-
TABLE 3 Inhibitory activity of some compounds of the present invention on prolyl hydroxylase 3Number of example Prolyl hydroxylase 3 (IC50 nM) 2 805.2 ± 21.6 7 711.0 ± 4.8 8 210.2 ± 3.5 9 675.2 ± 7.8 11 645.2 ± 9.0 26 780.2 ± 22.1 28 99.2 ± 10.2 40 221.0 ± 19.2 41 101.2 ± 17.2 59 772.1 ± 30.3 - The formula is as follows: % inhibition rate=100*(1−(measured value−blank)/(negative value−blank))
- As can be seen from Tables 1 and 3, the compounds of the present invention have
strong prolyl hydroxylase - The test of the activity of some compounds of the present invention on VEGF at the cellular level and EPO at the cellular level is shown as follows. The method is in accordance with Bioorganic & Medicinal Chemistry Letters 23(2013) 5953-5957, and the test was carried out by using VEGF and EPO kit respectively 24 h after administration. The results are shown in Table 1.
- Hep3B Cell: Human Hepatoma Cell
- It can be seen from Table 1 that the compounds of the present invention have the ability to significantly increase the levels of VEGF and EPO in cells, and show good activity at the cellular level.
- At the same time, Western-blot test at the cellular level was also carried out for some of the compounds of the present invention. Table 4 shows the experimental results that indicate whether some of the compounds of the present invention have an enhancing effect on the level of HIF-α in cells.
-
TABLE 4 Whether some of the compounds of the present invention can increase the level of HIF-α in cells Whether it can increase the level of Number of example HIF-α in cells 14 Yes 15 Yes 34 Yes 38 Yes 44 Yes 65 Yes - At the same time, the results of Western-blot test of some compounds at the cellular level are shown in
FIG. 1 . - The test of the activity of some compounds of the present invention on VEGF at the animal level and EPO at the cellular level is shown as follows. The method is in accordance with Journal of Medicinal Chemistry 55(2012) 2945-2959, and the test was carried out by using VEGF and EPO kit respectively 4 h after administration. The results are shown in
FIG. 2 below. - As can be seen from
FIG. 2 , the compounds of the present invention can significantly increase the expression of VEGF and EPO at the animal level, indicating that the compounds of the present invention are effective at the animal level. - The alkynyl pyridine compounds of the present invention have good biological activity at the molecular, cellular and animal levels. The compounds of the present invention can increase the level of erythropoietin (EPO) in blood at the animal level, thereby promoting the production of red blood cells, and can be used for the treatment or prevention of anemia related to chronic diseases, ischemic diseases and hematopoietic system-related diseases.
-
FIG. 1 is the results of Western-blot test of some compounds at the cellular level (Hep3B cell: human hepatoma cell; the compound concentration: 50 μM, 250 μM, 24 hours after administration) -
FIG. 2 is the test of increased level of VEGF and EPO in cells 24 h after the administration ofcompounds -
- Compound III 3-hydroxy-5-bromopicolinic acid (3.47 g, 16 mmol) was dissolved in 150 mL of dichloromethane, then 7.3 mL of triethylamine and HOBt (3.26 g, 24 mmol) were added. EDCI (4.59 g, 24 mmol) was added after the mixture was stirred for 10 min. Glycine methyl ester hydrochloride (2.4 g, 19.2 mmol) was added after the mixture was stirred for 10 min. The mixture was stirred for 6 h at room temperature. The mixture was washed successively with saturated sodium bicarbonate (100 mL), water (2×100 mL) and saturated brine (2×100 mL). The mixture was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to obtain a white solid compound (1.88 g, yield: 65.3%). m.p. 143.6-145.7° C. 1H-NMR (300 MHz, CDCl3) δ 11.90 (s, 1H), 8.16 (s, 1H), 7.54 (d, J=1.83 Hz, 1H), 7.28 (d, J=1.86 Hz, 1H), 4.25 (d, J=3.3 Hz, 2H), 3.83 (s, 3H); EI-MS m/z: 288/290[M]+.
- The compound methyl 2-(3-hydroxy-5-bromopyridine)carboxamido acetate (288 mg, 1 mmol) and propyne (44 mg, 1.1 mmol) were dissolved in 6 mL of DMF, then 6 mL of N,N-diisopropylethylamine, 40 mg of cuprous iodide, and 40 mg of dichloro(bis(triphenylphosphine))palladium were added. The mixture was heated to 80° C. by a conventional method for 6 h, or heated to 80° C. by microwave for 15 min, and the reaction was substantially completed. After the completion of the reaction, 100 mL of dichloromethane and 60 mL of hydrochloric acid (3 mmol) were added. After separation, the solution was washed successively with water (2×100 mL) and saturated brine (2×100 mL). The solution was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=6:1) to obtain a white solid compound (124.5 mg, yield: 50.2%). m.p. 119.2-121.5° C. 1H-NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.76 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.69 (d, J=1.2 Hz, 1H), 3.92 (s, 2H), 3.64 (s, 3H), 1.85 (s, 3H); EI-MS m/z: 248[M]+.
- Methyl 2-(3-hydroxy-5-propynyl)picolinamido acetate (100.0 mg, 0.4 mmol) was dissolved in 10 mL of tetrahydrofuran, then 3 mL of 1 M lithium hydroxide was added. The mixture was heated to 30° C. for 3 h to complete the reaction. After the completion of the reaction, tetrahydrofuran in the reaction solution was removed by pressurized distillation, then 3 mmol of dilute hydrochloric acid was added in an ice bath to precipitate a white solid. The white solid was filtered and dried to obtain a white product (61.0 mg, yield: 65.2%.). m.p. 179.1-181.3° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.76 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.70 (d, J=1.3 Hz, 1H), 3.60 (s, 2H), 1.85 (s, 3H); EI-MS m/z: 234[M]+.
-
- In accordance with the method of Example 1, propyne was replaced by isopropylacetylene (74.8 mg, 1.1 mmol). Accordingly, a white solid product was obtained (112.0 mg, yield of two steps: 42.7%). m.p. 155.5-157.8° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.79 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.70 (d, J=1.2 Hz, 1H), 3.60 (s, 2H), 2.89-2.85 (m, 1H), 1.26 (d, J=6.8 Hz, 6H); EI-MS m/z: 262[M]+.
-
- In accordance with the method of Example 1, propyne was replaced by tert-butylacetylene (90.2 mg, 1.1 mmol). Accordingly, a white solid compound was obtained (98.0 mg, yield of two steps: 35.5%). m.p. 165.2-167.8° C. H NMR (300 MHz, DMSO-d6) δ 8.78 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.69 (d, J=1.2 Hz, 1H), 3.60 (s, 2H), 1.27 (s, 9H); EI-MS m/z: 276[M]+.
-
- In accordance with the method of Example 1, propyne was replaced by cyclopropylacetylene (72.6 mg, 1.1 mmol). Accordingly, a white solid compound was obtained (79.1 mg, yield of two steps: 30.42%). m.p. 154.2-155.4° C. H NMR (300 MHz, DMSO-d6) (8.68 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.63 (d, J=1.3 Hz, 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]+.
-
- In accordance with the method of Example 1, propyne was replaced by phenylacetylene (112.2 mg, 1.1 mmol). Accordingly, a white solid compound was obtained (102.2 mg, yield of two steps: 34.4%). m.p. 172.1-173.9° C. 1HNMR (300 MHz, DMSO-d6) δ 8.75 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.68 (d, J=1.3 Hz, 1H), 7.60-7.49 (m, 2H), 7.48-7.27 (m, 3H), 3.89 (s, 2H); EI-MS m/z: 296[M]+.
-
- Methyl 2-(3-hydroxy-5-bromopyridine)carboxamido acetate (288 mg, 1 mmol) and phenylacetylene (110.2 mg, 1.1 mmol) were dissolved in 6 mL of DMF, then 6 mL of N,N-diisopropylethylamine, 40 mg of cuprous iodide, and 40 mg of dichloro(bis(triphenylphosphine))palladium were added. The mixture was heated to 80° C. by a conventional method for 6 h, or heated to 80° C. by microwave for 15 min, and the reaction was substantially completed. After the completion of the reaction, 100 mL of dichloromethane and 60 mL of hydrochloric acid (3 mmol) were added. After separation, the solution was washed successively with water (2×100 mL) and saturated brine (2×100 mL). The solution was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=6:1) to obtain a white solid compound (140.0 mg, yield: 45.2%). m.p. 109.7-111.9° C. 1HNMR (300 MHz, DMSO-d6) δ 8.77 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.69 (d, J=1.2 Hz, 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]+.
-
- In accordance with the method of Example 1, 3-hydroxy-5-bromopicolinic acid was replaced by 3-hydroxy-5-bromo-6-methylpicolinic acid (372 mg, 2 mmol), and propyne was replaced by p-methylphenylacetylene (127.6 mg, 1.1 mmol). Accordingly, a white solid product was obtained (120.3 mg, yield of three steps: 18.5%). m.p. 223.3-225.6° C. 1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.67 (s, 1H), 7.51-7.40 (m, 2H), 7.01-7.17 (m, 1.1 Hz, 2H), 3.88 (s, 2H), 2.73 (s, 3H), 2.34 (t, J=1.1 Hz, 3H); EI-MS m/z: 324[M]+.
-
- In accordance with the method of Example 1, 3-hydroxy-5-bromopicolinic acid was replaced by 3-hydroxy-5-bromo-6-chloropicolinic acid (412 mg, 2 mmol), and propyne was replaced by p-methoxyphenylacetylene (145.2 mg, 1.1 mmol), accordingly, a light yellow solid product was obtained (127.0 mg, yield of three steps: 17.6%). m.p. 232.2-234.3° C. H NMR (300 MHz, DMSO-d6) δ 8.20 (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]+.
-
- In accordance with the method of Example 1, glycine methyl ester hydrochloride was replaced by alanine methyl ester hydrochloride, and propyne was replaced by p-cyclopropylphenylacetylene (156.2 mg, 1.1 mmol). Accordingly, a white solid product was obtained (77 mg, yield of two steps: 22.0%). m.p. 202.5-204.7° C. H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J=1.2 Hz, 1H), 7.74 (d, J=1.2 Hz, 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=6.8 Hz, 3H), 1.21-1.06 (m, 2H), 0.82-0.90 (m, 2H); EI-MS m/z: 350[M]+.
-
- In accordance with the method of Example 1, glycine methyl ester hydrochloride was replaced by methyl aminobutanoate hydrochloride, and propyne was replaced by p-fluorophenylacetylene (149.6 mg, 1.1 mmol), accordingly, a light yellow solid product was obtained (145 mg, yield of two steps: 40.5%). m.p. 177.6-179.9° C. 1H NMR (300 MHz, DMSO-d6) δ 8.77 (d, J=1.2 Hz, 1H), 7.69 (d, J=1.3 Hz, 1H), 7.58-7.48 (m, 2H), 7.46-7.35 (m, 2H), 7.08 (s, 1H), 4.60 (d, J=1.4 Hz, 1H), 2.11-1.82 (m, 2H), 1.02 (t, J=6.0 Hz, 3H). EI-MS m/z: 342[M]+.
-
- In accordance with the method of Example 1, glycine methyl ester hydrochloride was replaced by methyl aminoisobutanoate hydrochloride, and propyne was replaced by p-fluorophenylacetylene (149.6 mg, 1.1 mmol). Accordingly, a light yellow solid product was obtained (115 mg, yield of two steps: 32.12%). m.p. 175.4-177.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.75 (d, J=1.2 Hz, 1H), 7.67 (d, J=1.3 Hz, 1H), 7.58-7.47 (m, 2H), 7.45-7.35 (m, 2H), 1.55 (s, 6H). EI-MS m/z: 342[M]+.
-
- 3-Hydroxy-5-bromopyridine (348 mg, 2 mmol) was dissolved in 40 mL of dichloromethane, then methyl succinyl chloride (400 mg, 4 mmol) and 100 mg of aluminum trichloride were added in an ice bath. The reaction was carried out at room temperature for 2 hours. After the completion of the reaction, water and 3 M hydrochloric acid were added. After separation, the solution was washed successively with (2×100 mL) and saturated brine (1×100 mL). The solution was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain a white solid compound (196.5 mg, yield: 34.1%). m.p. 156.6-158.2° C. 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J=1.3 Hz, 1H), 7.77 (d, J=1.3 Hz, 1H), 3.63 (s, 3H), 3.05 (t, J=7.1 Hz, 2H), 2.78 (t, J=7.0 Hz, 2H). EI-MS m/z: 287[M]+.
- Methyl 4-(3-hydroxy-5-bromopyridin-2-yl)-4-oxobutanoate (190 mg, 0.66 mmol) and p-ethylphenylacetylene (94 mg, 0.72 mmol) were dissolved in 6 mL of DMF, then 6 mL of N,N-diisopropylethylamine, 40 mg of cuprous iodide, and 40 mg of dichloro(bis(triphenylphosphine))palladium were added. The mixture was heated to 80° C. by a conventional method for 6 h, or heated to 80° C. by microwave for 15 min, and the reaction was substantially completed. After the completion of the reaction, 100 mL of dichloromethane and 60 mL of hydrochloric acid (3 mmol) were added. After separation, the solution was washed successively with water (2×100 mL) and saturated brine (2×100 mL). The solution was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=6:1) to obtain a white solid compound (84.5 mg, yield: 38.1%). m.p. 109.5-112.1° C. 1H NMR (300 MHz, CDCl3) δ 8.76 (d, J=1.2 Hz, 1H), 7.63 (d, J=1.3 Hz, 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=5.7 Hz, 2H), 1.19 (t, J=6.6 Hz, 3H). EI-MS m/z: 337[M]+.
- Methyl 2-(3-hydroxy-5-propynyl)picolinamido acetate (70.0 mg, 0.2 mmol) was dissolved in 10 mL of tetrahydrofuran, then 3 mL of 1 M lithium hydroxide was added. The mixture was heated to 30° C. for 3 h to complete the reaction. After completion of the reaction, tetrahydrofuran in the reaction solution was removed by pressurized distillation, then 3 mmol of dilute hydrochloric acid was added in an ice bath to precipitate a white solid. The white solid was filtered and dried to obtain a white product (41.0 mg, yield: 56.9%.). m.p. 185.7-187.8° C. 1H NMR (300 MHz, DMSO-d6) δ 8.77 (d, J=1.2 Hz, 1H), 7.64 (d, J=1.2 Hz, 1H), 7.57-7.46 (m, 2H), 7.20-7.17 (m, 2H), 2.87 (t, J=5.4 Hz, 2H), 2.78-2.62 (m, 4H), 1.19 (t, J=6.6 Hz, 3H). EI-MS m/z: 358[M]+.
-
- In accordance with the method of Example 1, glycine methyl ester hydrochloride, propyne, and 5-bromo-3-hydroxypicolinic acid were respectively replaced by N-methylglycine methyl ester hydrochloride (333.2 mg, 2.4 mmol), p-methylphenylacetylene (255.2 mg, 2.2 mmol), and 5,6-dibromo-3-hydroxypicolinic acid (592 mg, 2 mmol). Accordingly, a light yellow solid product was obtained after hydrolysis (121.0 mg, yield of three steps: 15.1%). m.p. 227.1-229.4° C. H NMR (300 MHz, DMSO-d6) δ 7.79 (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=2.3 Hz, 1H). EI-MS m/z: 402/404[M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by m-methylphenylacetylene (127.6 mg, 1.1 mmol). Accordingly, a white solid product was obtained (106.0 mg, yield of three steps: 34.2%). m.p. 229.2-231.3° C. 1H NMR (300 MHz, DMSO-d6) δ 8.75 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.54-7.43 (m, 2H), 7.15-7.05 (m, 2H), 3.60 (s, 2H), 2.34 (d, J=1.1 Hz, 3H). EI-MS m/z: 310[M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by p-fluorophenylacetylene (132.0 mg, 1.1 mmol). Accordingly, a white solid product was obtained (112.4 mg, yield of three steps: 36.1%). m.p. 187.8-200.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.75 (d, J=1.3 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by p-methoxyphenylacetylene (145.2 mg, 1.1 mmol). Accordingly, a white solid product was obtained (142.4 mg, yield of three steps: 43.5%). m.p. 219.2-221.3° C. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.67 (d, J=1.2 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by m-methoxyphenylacetylene (145.2 mg, 1.1 mmol). Accordingly, a light yellow solid product was obtained (92.4 mg, yield of three steps: 28.3%). m.p. 220.2-222.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.77 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.29 (t, J=7.4 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by biphenylacetylene (195.8 mg, 1.1 mmol). Accordingly, a brown solid product was obtained (82.2 mg, yield of three steps: 22.1%). m.p. 242.5-244.3° C. 1H NMR (300 MHz, DMSO-d6) δ 8.87 (d, J=1.2 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by p-cyanophenylacetylene (139.7 mg, 1.1 mmol). Accordingly, a white solid product was obtained (65.7 mg, yield of three steps: 20.4%). m.p. 195.2-197.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.75 (d, J=1.3 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by o-cyanophenylacetylene (139.7 mg, 1.1 mmol). Accordingly, a white solid product was obtained (55.2 mg, yield of three steps: 17.2%). m.p. 182.2-184.8° C. 1H NMR (300 MHz, DMSO-d6) δ 8.87 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.76 (dd, J=7.4, 2.1 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by p-trifluoromethylphenylacetylene (187.0 mg, 1.1 mmol). Accordingly, an ivory solid product was obtained (105.2 mg, yield of three steps: 28.8%). m.p. 201.5-2.3.8° C. 1H NMR (300 MHz, DMSO-d6) δ 8.78 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.70 (d, J=1.2 Hz, 1H), 7.63-7.47 (m, 4H), 3.60 (s, 2H). EI-MS m/z: 364[M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by p-acetaminophenylacetylene (174.0 mg, 1.1 mmol). Accordingly, a white solid product was obtained (75.9 mg, yield of three steps: 21.5%). m.p. 251.2-253.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.77 (d, J=1.3 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, propyne was replaced by p-dimethylcarbamoylphenylacetylene (190.3 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by glycinamide (110 mg, 1.5 mmol), accordingly, a white solid product was obtained (95.9 mg, yield of three steps: 26.2%). m.p. 229.1-231.5° C. 1H NMR (300 MHz, CDCl3) δ 8.78 (d, J=1.3 Hz, 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]+.
-
- The preparation method is the same as that of Example 6, propyne was replaced by p-pentanamidophenylacetylene (205.7 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by cyclopropylmethyl glycinate, accordingly, a brown solid product was obtained (75.4 mg, yield of three steps: 12.3%). m.p. 178.5-180.2° C. 1H NMR (300 MHz, CDCl3) δ 8.87 (d, J=1.2 Hz, 1H), 7.85-7.65 (m, 6H), 4.00 (d, J=7.0 Hz, 2H), 3.92 (s, 2H), 2.42 (t, J=8.0 Hz, 2H), 1.76-1.66 (m, 2H), 1.50-1.17 (m, 3H), 0.95 (t, J=7.9 Hz, 3H), 0.61-0.48 (m, 2H), 0.29-0.23 (m, 2H). EI-MS m/z: 449[M]+.
-
- The preparation method is the same as that of Example 6, and propyne was replaced by p-butylcarbamoylphenylacetylene (205.7 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by isopropyl glycinate. Accordingly, a brown solid product was obtained (81.4 mg, yield of three steps: 18.6%). m.p. 187.2-189.5° C. 1H NMR (300 MHz, CDCl3) δ 8.81 (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=7.5 Hz, 2H), 1.59-1.56 (m, J=7.8 Hz, 2H), 1.39-1.25 (m, 2H), 1.16 (d, J=6.8 Hz, 6H), 0.88 (t, J=7.9 Hz, 3H). EI-MS m/z: 437[M]+.
-
- The preparation method is the same as that of Example 6, and propyne was replaced by p-cyclopropylcarboxamidophenylacetylene (203.5 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by N-ethylglycinamide. Accordingly, a brown solid product was obtained (71.4 mg, yield of three steps: 18.3%). m.p. 195.2-197.7° C. 1H NMR (300 MHz, CDCl3) δ 9.50 (s, 1H), 9.23 (s, 1H), 8.83 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.83-7.64 (m, 5H), 3.85 (s, 2H), 3.21 (q, J=6.3 Hz, 2H), 1.73-1.64 (m, 1H), 1.22 (t, J=6.3 Hz, 3H), 1.11-0.90 (m, 4H). EI-MS m/z: 406[M]+.
-
- The preparation method is the same as that of Example 6, and propyne was replaced by 3-phenoxypropyne (145.2 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by N-methylglycinamide. Accordingly, a brown solid product was obtained (91.2 mg, yield of three steps: 26.9%). m.p. 192.2-194.4° C. 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.66 (d, J=1.2 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-(p-chlorophenoxy)propyne (182.6 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by glycinamide. Accordingly, a brown product was obtained (54.0 mg, yield of three steps: 15.1%). m.p. 152.2-154.6° C. H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.64 (d, J=1.3 Hz, 1H), 7.68 (d, J=1.3 Hz, 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]+.
-
- The preparation method is the same as that of Example 6, and propyne was replaced by 3-(p-ethylphenoxy)propyne (160.6 mg, 1.1 mmol). Accordingly, a white solid product was obtained (105.0 mg, yield: 28.5%). m.p. 112.2-114.3° C. 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.67 (d, J=1.3 Hz, 1H), 7.69 (d, J=1.3 Hz, 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, 1.1 Hz, 2H), 1.19 (t, J=6.6 Hz, 3H). E-MS m/z: 368[M]+.
-
- The preparation method is the same as that of Example 6, and propyne was replaced by 3-(p-cyanophenoxy)propyne (172.7 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by isopropyl glycinate. Accordingly, a white solid product was obtained (126.0 mg, yield: 32.1%). m.p. 120.2-123.1° C. 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.62 (d, J=1.2 Hz, 1H), 7.79-7.66 (m, 3H), 7.20-7.09 (m, 2H), 4.91-4.87 (m, J=6.8 Hz, 1H), 4.68 (s, 2H), 3.86 (s, 2H), 1.14 (d, J=6.8 Hz, 6H). EI-MS m/z: 393[M]+.
-
- The preparation method is the same as that of Example 6, and propyne was replaced by 3-(p-fluorophenoxy)propyne (165.0 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by glycine cyclopropyl ester. Accordingly, a white solid product was obtained (117.0 mg, yield: 30.4%). m.p. 107.2-109.9° C. 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.76 (d, J=1.3 Hz, 1H), 7.78 (d, J=1.3 Hz, 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=7.0 Hz, 1H), 0.47-0.45 (m, 2H), 0.43-0.18 (m, 2H). EI-MS m/z: 384[M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-(p-chlorophenoxy)propyne (182.6 mg, 1.1 mmol), and glycine methyl ester hydrochloride was replaced by N,N′-dimethylglycinamide. Accordingly, a white solid product was obtained (97.0 mg, yield: 24.2%). m.p. 177.2-179.9° C. 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.67 (d, J=1.3 Hz, 1H), 7.68 (d, J=1.2 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-phenoxypropyne (145.2 mg, 1.1 mmol). Accordingly, a white solid product was obtained (77.1 mg, yield of two steps: 23.6%). m.p. 112.2-114.6° C. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.65 (d, J=1.3 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-(p-methylphenoxy)propyne (160.6 mg, 1.1 mmol). Accordingly, a white solid product was obtained (89.2 mg, yield of two steps: 24.7%). m.p. 162.2-164.3° C. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.64 (d, J=1.2 Hz, 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=2.2 Hz, 1H). EI-MS m/z: 340[M]+.
-
- The preparation method is the same as that of Example 1, propyne was replaced by 3-(o-methylphenoxy)propyne (160.6 mg, 1.1 mmol). Accordingly, a white solid product was obtained (99.4 mg, yield of two steps: 29.1%). m.p. 154.3-156.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.64 (d, J=1.3 Hz, 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=1.0 Hz, 3H). EI-MS m/z: 340[M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-(p-ethylphenoxy)propyne (176.0 mg, 1.1 mmol). Accordingly, a white solid product was obtained (110.3 mg, yield of two steps: 31.1%). m.p. 172.4-174.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.65 (d, J=1.2 Hz, 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, 1.1 Hz, 2H), 1.19 (t, J=6.6 Hz, 3H). EI-MS m/z: 354[M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-(p-tert-butylphenoxy)propyne (206.8 mg, 1.1 mmol). Accordingly, a white solid product was obtained (110.3 mg, yield of two steps: 31.1%). m.p. 180.1-182.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.64 (d, J=1.2 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-(2,3-dimethylphenyl)oxypropyne (176.0 mg, 1.1 mmol). Accordingly, a white solid product was obtained (60.3 mg, yield of two steps: 16.9%). m.p. 182.2-184.3° C. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.65 (d, J=1.2 Hz, 1H), 7.06 (t, J=7.5 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-p-methoxyphenoxypropyne (180.0 mg, 1.1 mmol). Accordingly, a white solid product was obtained (80.1 mg, yield of two steps: 22.4%). m.p. 223.3-225.6° C. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.65 (d, J=1.2 Hz, 1H), 6.79 (s, 4H), 4.68 (s, 2H), 3.80 (s, 3H), 3.60 (s, 2H). EI-MS m/z: 356[M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-m-tert-butoxyphenoxypropyne (224.4 mg, 1.1 mmol). Accordingly, a white solid product was obtained (85.5 mg, yield of two steps: 21.5%). m.p. 237.2-239.4° C. 1H NMR (300 MHz, DMSO-d6) δ 8.68 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.62 (d, J=1.2 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 6.69-6.67 (m, J=5.7, 1.9 Hz, 2H), 6.48 (t, J=2.0 Hz, 1H), 4.68 (s, 2H), 3.60 (s, 2H), 1.41 (s, 9H). EI-MS m/z: 398[M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-m-cyclopropoxyphenoxypropyne (206.8 mg, 1.1 mmol). Accordingly, a white solid product was obtained (95.0 mg, yield of two steps: 24.9%). m.p. 212.3-214.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.78 (d, J=1.2 Hz, 1H), 7.25 (t, J=7.5 Hz, 1H), 6.69-6.67 (m, 2H), 6.48 (t, J=2.1 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-p-trifluoromethylphenoxypropyne (220.0 mg, 1.1 mmol). Accordingly, a white solid product was obtained (79.0 mg, yield of two steps: 20.3%). m.p. 197.2-199.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.66 (d, J=1.2 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-(5-fluoromethylfuran-2-yloxy)propyne (180.0 mg, 1.1 mmol). Accordingly, a white solid product was obtained (95.0 mg, yield of two steps: 26.5%). m.p. 187.2-189.3° C. 1H NMR (300 MHz, DMSO-d6) δ 8.71 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.63 (d, J=1.2 Hz, 1H), 7.35-7.31 (m, 1H), 6.90-6.79 (m, 1H), 5.43 (t, J=1.1 Hz, 1H), 5.27 (t, J=1.1 Hz, 1H), 4.68 (s, 2H), 3.60 (s, 2H). EI-MS m/z: 348 [M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-p-chlorophenoxypropyne (182.6 mg, 1.1 mmol). Accordingly, a white solid product was obtained (95.0 mg, yield of two steps: 26.5%). m.p. 132.7-134.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.65 (d, J=1.3 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-o-chlorophenoxypropyne (182.6 mg, 1.1 mmol). Accordingly, a white solid product was obtained (84.0 mg, yield of two steps: 23.6%). m.p. 127.1-129.4° C. 1H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.64 (d, J=1.3 Hz, 1H), 7.31 (dd, J=7.5, 2.0 Hz, 1H), 7.16-7.10 (m, 1H), 6.98-6.92 (m, 1H), 6.83 (dd, J=7.5, 2.1 Hz, 1H), 4.68 (s, 2H), 3.60 (s, 2H). EI-MS m/z: 360 [M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-m-chlorophenoxypropyne (182.6 mg, 1.1 mmol). Accordingly, a white solid product was obtained (74.0 mg, yield of two steps: 20.5%). m.p. 110.2-112.6° C. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.64 (d, J=1.2 Hz, 1H), 7.24 (t, J=7.5 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-p-fluorophenoxypropyne (165.0 mg, 1.1 mmol). Accordingly, a white solid product was obtained (88.0 mg, yield of two steps: 25.5%). m.p. 171.2-173.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.64 (d, J=1.3 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-m-bromophenoxypropyne (165.0 mg, 1.1 mmol). Accordingly, a white solid product was obtained (88.0 mg, yield of two steps: 25.5%). m.p. 132.1-134.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.64 (d, J=1.3 Hz, 1H), 7.37-7.33 (m, 1H), 7.15 (t, J=7.5 Hz, 1H), 7.01-6.84 (m, 2H), 4.68 (s, 2H), 3.60 (s, 2H). EI-MS m/z: 404 [M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-m-cyanophenoxypropyne (127.7 mg, 1.1 mmol). Accordingly, a white solid product was obtained (68.0 mg, yield of two steps: 19.4%). m.p. 181.2-183.4° C. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=1.3 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-p-acetamidophenoxypropyne (207.9 mg, 1.1 mmol). Accordingly, a yellow solid product was obtained (77.0 mg, yield of two steps: 20.1%). m.p. 117.1-119.3° C. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.65 (d, J=1.2 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-(p-tert-butylcarbamoylphenoxy)propyne (254.1 mg, 1.1 mmol). Accordingly, a brown solid product was obtained (77.0 mg, yield of two steps: 20.1%). m.p. 141.2-143.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (d, J=1.3 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-p-carbamoylphenoxypropyne (190.3 mg, 1.1 mmol). Accordingly, a brown solid product was obtained (76.0 mg, yield of two steps: 20.6%). m.p. 122.1-124.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=1.2 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-((N-methyl-N-tert-butylcarbamoyl)pyridin-3-yloxy)propyne (269.5 mg, 1.1 mmol). Accordingly, a white solid product was obtained (106.0 mg, yield of two steps: 24.1%). m.p. 137.1-139.3° C. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J=1.2 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-((4-(pyrrolidin-1-carbonyl)phenoxy))propyne (251.9 mg, 1.1 mmol). Accordingly, a white solid product was obtained (56.0 mg, yield of two steps: 13.2%). m.p. 154.1-156.8° C. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.64 (d, J=1.2 Hz, 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-MS m/z: 423 [M]+.
-
- The preparation method is the same as that of Example 1, and 3-hydroxy-5-bromopyridine-2-carboxylic acid was replaced by 3-hydroxy-5-bromo-6-chloropyridine-2-carboxylic acid, and propyne was replaced by 3-((4-(aziridinyl-1-carbonyl))phenoxy)propyne (251.9 mg, 1.1 mmol). Accordingly, a white solid product was obtained (76.0 mg, yield of three steps: 17.7%). m.p. 147.2-149.2° C. 1H NMR (300 MHz, DMSO-d6) δ 8.20 (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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-((4-(4-methyl-1,4-diazepan-1-carbonyl)phenoxy))propyne (299.2 mg, 1.1 mmol). Accordingly, a white solid product was obtained (86.0 mg, yield of two steps: 18.4%). m.p. 168.9-172.1° C. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.66 (d, J=1.3 Hz, 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=5.9 Hz, 2H), 2.66 (t, J=6.4 Hz, 2H), 2.27 (s, 3H), 1.73-1.65 (m, 2H). EI-MS m/z: 466 [M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-p-phenylphenoxypropyne (228.8 mg, 1.1 mmol). Accordingly, a white solid product was obtained (95.0 mg, yield of two steps: 23.6%). m.p. 201.5-203.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.73 (d, J=1.3 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-(naphthalen-2-oxy)propyne (200.2 mg, 1.1 mmol). Accordingly, a white solid product was obtained (45.0 mg, yield of two steps: 11.9%). m.p. 211.5-213.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.76 (d, J=1.3 Hz, 1H), 7.72-7.62 (m, 2H), 7.56 (dt, J=7.3, 1.6 Hz, 1H), 7.41-7.36 (m, 2H), 7.14 (dd, J=7.9, 1.5 Hz, 1H), 6.97 (t, J=1.7 Hz, 1H), 4.91 (s, 2H), 3.89 (s, 2H). EI-MS m/z: 376 [M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-(quinolin-5-oxy)propyne (201.3 mg, 1.1 mmol). Accordingly, a brown solid product was obtained (65.0 mg, yield of two steps: 17.2%). m.p. 223.1-225.6° C. 1H NMR (300 MHz, DMSO-d6) δ 8.83-8.71 (m, 2H), 8.44 (dd, J=7.4, 1.5 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-(benzofuran-7-oxy)propyne (201.3 mg, 1.1 mmol). Accordingly, a brown solid product was obtained (75.0 mg, yield of two steps: 20.4%). m.p. 196.1-198.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.66 (d, J=1.3 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.23-7.06 (m, 2H), 6.99 (dd, J=7.3, 1.8 Hz, 1H), 6.72 (dd, J=7.5, 1.5 Hz, 1H), 4.68 (s, 2H), 3.60 (s, 2H). EI-MS m/z: 366 [M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-(2,3-dichlorophenyl)oxypropyne (218.9 mg, 1.1 mmol). Accordingly, a white solid product was obtained (62.0 mg, yield of two steps: 15.7%). m.p. 152.2-154.6° C. 1H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.64 (d, J=1.3 Hz, 1H), 7.28 (dd, J=7.5, 2.1 Hz, 1H), 7.17 (t, J=7.5 Hz, 1H), 6.71 (dd, J=7.4, 2.0 Hz, 1H), 4.68 (s, 2H), 3.60 (s, 2H). EI-MS m/z: 394 [M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-(3,5-dichlorophenyl)oxypropyne (218.9 mg, 1.1 mmol). Accordingly, a white solid product was obtained (74.0 mg, yield of two steps: 18.7%). m.p. 157.5-159.4° C. 1H NMR (300 MHz, DMSO-d6) δ 8.68 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.26 (dd, J=7.5, 2.0 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 4.68 (s, 2H), 3.60 (s, 2H). EI-MS m/z: 394 [M]+.
-
- In accordance with the method of Example 1, 3-hydroxy-5-bromopicolinic acid was replaced by 3-hydroxy-5-bromo-6-methylpicolinic acid (372 mg, 2 mmol), and propyne was replaced by 3-p-cyclopropylphenoxypropyne (189.2 mg, 1.1 mmol). Accordingly, a light yellow solid product was obtained (82 mg, yield: 21.5%). m.p. 177.5-179.4° C. 1H NMR (300 MHz, DMSO-d6) δ 8.91 (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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-anilinopropyne (144.1 mg, 1.1 mmol). Accordingly, a white solid product was obtained (64.0 mg, yield of two steps: 20.0%). m.p. 131.1-133.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.75 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.63 (d, J=1.2 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-p-chloroanilinopropyne (181.1 mg, 1.1 mmol). Accordingly, a white solid product was obtained (78.0 mg, yield of two steps: 21.7%). m.p. 137.2-139.3° C. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.71 (d, J=1.2 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-p-ethylanilinopropyne (174.9 mg, 1.1 mmol). Accordingly, a white solid product was obtained (68.0 mg, yield of two steps: 19.2%). m.p. 145.1-147.3° C. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.64 (d, J=1.2 Hz, 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=6.6 Hz, 3H). EI-MS m/z: 353 [M]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-((N-methyl-N-p-imidazol-2-ylphenyl)amino)propyne (131.2 mg, 1.1 mmol). Accordingly, a white solid product was obtained (68.0 mg, yield of two steps: 16.7%). m.p. 199.1-201.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J=1.3 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-((N-phenyl-N-3,4-difluorophenyl)amino)propyne (267.3 mg, 1.1 mmol). Accordingly, a white solid product was obtained (72.0 mg, yield of two steps: 16.4%). m.p. 205.2-207.3° C. 1H NMR (300 MHz, DMSO-d) δ 8.80 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.63 (d, J=1.3 Hz, 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]+.
-
- The preparation method is the same as that of Example 1, and propyne was replaced by 3-((N-tert-butyl-N-3-ethoxy-4-methylphenyl)amino)propyne (269.5 mg, 1.1 mmol). Accordingly, a white solid product was obtained (82.0 mg, yield of two steps: 18.6%). m.p. 210.2-212.6° C. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (d, J=1.3 Hz, 1H), 8.20 (s, 1H), 7.37 (d, J=1.2 Hz, 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=1.0 Hz, 3H), 1.43 (t, J=5.9 Hz, 3H), 1.22 (s, 10H). EI-MS m/z: 439 [M]+.
Claims (15)
1. A method for treating anemia or ischemic disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:
wherein X represents NH, NCH3 or CH2;
Y represents hydrogen, hydroxy, methoxy or ethoxy;
L represents —CH2—, —CH2O— or
R6 represents hydrogen, C1-C4 alkyl or phenyl;
n represents 1;
R1 represents C1-C4 alkyl, phenyl, quinolinyl, benzofuranyl, naphthyl, substituted phenyl, 5- to 6-membered heteroaryl containing oxygen or nitrogen, or substituted 5- to 6-membered heteroaryl containing oxygen or nitrogen, wherein the substituent is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, halogen, cyano,
phenyl or 5- to 6-membered heteroaryl containing oxygen or nitrogen, wherein R7 represents C1-C4 alkyl; R8 and R9 each independently represent hydrogen or C1-C4 alkyl, or R8 and R9 are attached to form a 3- to 7-membered heterocyclyl containing nitrogen;
R2 represents hydrogen, halogen or methyl;
R3 and R4 each independently represent hydrogen, methyl or ethyl; and
R5 represents hydroxy, C1-C4 alkoxy, cyclopropoxy, or —NR10R11, wherein R10 and R11 each independently represent hydrogen, methyl or ethyl.
2. The method according to claim 1 , wherein X represents NH.
4. The method according to claim 1 , wherein R1 represents substituted phenyl, wherein the substituent is methyl, ethyl, isopropyl, tert-butyl, methoxy, tert-butoxy, phenyl, cyano, halogen, fluoromethyl, trifluoromethyl, imidazolyl, acetylamino, or
wherein R8 and R9 each independently represent hydrogen, methyl, butyl or tert-butyl, or R8 and R9 are attached to form aziridinyl, tetrahydropyrrolyl or N-methylhomopiperazinyl.
5. The method according to claim 1 , wherein R1 represents phenyl, naphthyl, quinolinyl or benzofuranyl.
6. The method according to claim 1 , wherein R3 or R4 represents hydrogen.
7. The method according to claim 1 , wherein R5 represents —NH2, —NHCH3, hydroxy, methoxy, isopropoxy, or cyclopropoxy.
8. A method for treating anemia or ischemic disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:
13. The method according to claim 1 , wherein the ischemic disease is ischemic stroke or myocardial ischemia-related disease.
14. The method according to claim 8 , wherein the ischemic disease is ischemic stroke or myocardial ischemia-related disease.
15. The method according to claim 9 , wherein the ischemic disease is ischemic stroke or myocardial ischemia-related disease.
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PCT/CN2015/095728 WO2017059623A1 (en) | 2015-10-09 | 2015-11-27 | Alkynyl pyridine prolyl hydroxylase inhibitor, and preparation method and medical use thereof |
US201815765387A | 2018-04-02 | 2018-04-02 | |
US17/018,221 US20200407319A1 (en) | 2015-10-09 | 2020-09-11 | Alkynyl pyridine prolyl hydroxylase inhibitor, and preparation method and medical use thereof |
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CN105130888A (en) * | 2015-10-09 | 2015-12-09 | 中国药科大学 | Pyridylacetylene prolyl hydroxylase inhibitor and preparation method and medical application thereof |
CN107417605A (en) * | 2017-08-02 | 2017-12-01 | 江苏艾立康药业股份有限公司 | Act on the pyridine derivative compound of prolyl hydroxylase |
RU2020111829A (en) | 2017-10-25 | 2021-11-25 | Цзянсу Хэнжуй Медсин Ко., Лтд. | CRYSTALLINE FORM OF ALKYNYLPYRIDINE PROLYL HYDROXYLASE INHIBITOR AND METHOD FOR ITS PREPARATION |
CN110240562B (en) * | 2018-03-08 | 2022-04-12 | 江苏恒瑞医药股份有限公司 | Medicinal salt and crystal form of prolyl hydroxylase inhibitor and preparation method thereof |
KR20210013095A (en) * | 2018-05-24 | 2021-02-03 | 쑤저우 선카디아 바이오파마수티컬즈 컴퍼니 리미티드 | Method for producing an alkynyl pyridine prolyl hydroxylase inhibitor |
CN109593084B (en) * | 2019-01-23 | 2021-09-28 | 中国药科大学 | Prolyl hydroxylase small-molecule photosensitive prodrug and preparation method and application thereof |
WO2020177681A1 (en) * | 2019-03-04 | 2020-09-10 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition of prolyl hydroxylase inhibitor and preparation method therefor |
CN112741834A (en) * | 2021-02-07 | 2021-05-04 | 复旦大学附属中山医院 | Application of HIF-1 alpha degradation inhibitor in preparing medicine for treating coronary heart disease with elevated ketone body level |
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PL3357911T3 (en) * | 2006-06-26 | 2022-09-05 | Akebia Therapeutics Inc. | Prolyl hydroxylase inhibitors and methods of use |
ES2393326T3 (en) * | 2006-12-18 | 2012-12-20 | Amgen, Inc | Azaquinolone-based compounds that exhibit prolyl hydroxylase inhibitory activity, compositions and uses thereof |
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