CN107739378A - Indole derivative and its application in medicine - Google Patents

Indole derivative and its application in medicine Download PDF

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Publication number
CN107739378A
CN107739378A CN201711123713.7A CN201711123713A CN107739378A CN 107739378 A CN107739378 A CN 107739378A CN 201711123713 A CN201711123713 A CN 201711123713A CN 107739378 A CN107739378 A CN 107739378A
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compound
alkyl groups
isomer
alkyl
aryl
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刘栋
陈冬冬
邓彪
涂相云
方子楠
吴浩浩
顾丹燕
刘静
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Hangzhou Ando Pharmaceutical Co Ltd
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Hangzhou Ando Pharmaceutical Co Ltd
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Priority to PCT/CN2018/115013 priority patent/WO2019096089A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Application the present invention relates to indole derivative and its in medicine.Specifically, the invention discloses the indole derivative of formula I new substituted or its compound isotopically labelled or its optical isomer, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine.The invention further relates to application of these compounds in terms of medical science.

Description

Indole derivative and its application in medicine
Technical field
The invention belongs to field of medicaments, is related to indole derivative, it is prepared and its application in medicine.Especially, The present invention relates to the treatment of the disease related to proline hydroxylase (such as anemia).
Background technology
Anaemia is that mean constant of red blood cell is reduced in body blood or corpuscular hemoglobin concentration reduces caused disease.Cause Major function for hemoglobin is to carry oxygen to be used to each internal organs, so low-level hemoglobin just directly results in The oxygen supply deficiency of each organ of body.Because the normal physiological activity of body is dependent on making full use of oxygen, therefore different journeys The anaemia of degree will cause various clinical symptoms.Common anaemia secondary disease has disease of cardiovascular system, and (heart failure, atrial fibrillation, the heart twist Pain etc.), disease in the urological system (kidney failure, albuminuria), the nervous system disease (dizziness, headache, tinnitus, dim eyesight, lassitude, Burnout is drowsiness, haves the fidgets, difficult concentrating.Anaemia severe patient can faint), disease of digestive system (poor appetite, Constipation), genital system diseases (sexual hypoesthesia, irregular menstruation) etc. it is several.Anaemia can not only have a strong impact on that the body of patient is good for Health and quality of life, and if anaemia cannot correct in time, it might even be possible to threaten the life security of patient.
The cause of disease of anaemia is a lot, is often as caused by hematopoietin (EPO) generation reduction.Chronic kidney disease (CKD, Chronic Kidney Disease) causes hematopoietin synthesis to reduce, therefore most of chronic kidney disease patient With anaemia.In addition, cancer patient, after radiation and chemotherapy is received, marrow hemopoietic stem cells are suppressed, can also cause poor Blood.Some antiviral drugs (such as treatment hepatitis and HIV medicine) and inflammation may also lead to anaemia.
By suppress proline hydroxylase so as to stablize hypoxia inducible factor (Hypoxia-inducible factor, HIF the generation (Cell, 2001,107,43-54) of hematopoietin can) be increased.Hypoxia inducible factor is a kind of transcription Regulatory factor, vital regulation oxygen equilibrium (Molecular can be played a part of in the reaction of body anoxic Cellular Biology 1992,12,5447-5454).HIF-1 is heterodimer, when it is connected to Anoxic Phase When answering the promoter region of factor (hypoxia-responsive element, HRE), the expression of many genes can be raised (Nature Reviews Cancer 2003,3,721-732).By the albumen of the coded by said gene of HIF-1 regulation Matter can cause many biological effects, including RBC acceptor garland rate, angiogenesis, vasodilation, glycolysis, immune tune Section, neuroprotection, heart ischemia protection, Cerebral ischemia protection etc..In the case of oxygen content is normal, hypoxia-inducible factor-1 alpha is sub- Unit is by proline hydroxylase in proline residue hydroxylating.Von is connected to by hydroxylated hypoxia-inducible factor-1 alpha Hippel Lindau albumen, then by ubiquitination by proteosomal degradation.In the case of anoxic, the suppression of proline hydroxylase Activity inhibited processed, therefore hypoxia-inducible factor-1 alpha subunit is stablized, the content increase of hypoxia-inducible factor-1 alpha subunit, Erythropoietin rise (Science 2001,292,464-468) is included by the gene of its regulation and control.
Early stage has document to be disclosed collagen prolyl hydroxylase inhibitors, such as J.Med.Chem.1992, and 35,800- 804；J.Med.Chem.1992,35,2652-2658；J.Med.Chem.1993,36,3853-3858；Patent document EP661269 also discloses that collagen prolyl hydroxylase inhibitors.In the proline hydroxylase related to hypoxia inducible factor Field, also there are the inhibitor that patent document discloses this respect, such as WO2004108681, WO2007070359, WO2007150011,WO2008076425,WO2011007856,WO201206472,WO2013043621,WO2014102818 Deng.Major part in these patents prolyl hydroxylase inhibitors related to hypoxia inducible factor are all a-KGs Analogies.
But so far, prolyl hydroxylase inhibitors medicine still not related to hypoxia inducible factor goes through Into market.Therefore, be still necessary to find new prolyl hydroxylase inhibitors, so with hypoxia inducible factor relevant disease Patient future can have multiple choices.
The content of the invention
1.The compound of the present invention
It is an object of the invention to provide a kind of new prolyl hydroxylase inhibitors.Another object of the present invention is A kind of new compound for being used for treatment or prevention and hypoxia inducible factor relevant disease (such as anaemia) is provided.
Therefore, one aspect of the present invention provides the compound or its isotope marks chemical combination shown in a kind of formula I Thing or its optical isomer, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor Medicine, its formula of I are as follows：
Wherein：
R1And R2Independently selected from cyano group, alkyl, heterocyclic radical, alkenyl, alkynyl, aryl, heteroaryl, acyl group, amino, R9O-、R9S-、R9(O=) S-, R9(O=)2S-, R therein9It is alkyl, heterocyclic radical, alkenyl, alkynyl, aryl or heteroaryl；Its In, above-mentioned alkyl, heterocyclic radical, alkenyl, alkynyl, aryl, heteroaryl, acyl group, amino are optionally by one or more substituents Substituted, substituent therein is independently selected from halogen, cyano group, hydroxyl, amino, carboxyl, acyl group, alkyl, heterocyclic radical, alkene Base, alkynyl, aryl, heteroaryl ,=O ,=S ,-SH, R10O-、R10S-、R10(O=) S-, R10(O=)2S-, R therein10It is alkane Base, heterocyclic radical, alkenyl, alkynyl, aryl or heteroaryl；Or R1And R2It is combined cyclization；
R3、R4And R5Independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano group, amino, acyl group, alkyl, heterocyclic radical, alkene Base, alkynyl, aryl, heteroaryl, R11O-、R11S-、R11(O=) S-, R11(O=)2S-, wherein R11Be alkyl, heterocyclic radical, alkenyl, Alkynyl, aryl or heteroaryl；Wherein, above-mentioned alkyl, heterocyclic radical, alkenyl, alkynyl, aryl, heteroaryl, acyl group, amino are optional Ground is substituted by one or more substituents, substituent therein independently selected from halogen, cyano group, hydroxyl, amino, carboxyl, Acyl group, alkyl, heterocyclic radical, alkenyl, alkynyl, aryl, heteroaryl ,=O ,=S ,-SH, R12O-、R12S-、R12(O=) S-, R12(O =)2S-, R therein12It is alkyl, heterocyclic radical, alkenyl, alkynyl, aryl or heteroaryl；
R6And R6’Independently selected from hydrogen and optionally substituted alkyl；
R7Selected from hydrogen, alkyl and acyl group；Wherein alkyl and acyl group are optionally substituted by following group：Halogen, cyano group, hydroxyl Base, amino, carboxyl, acyl group, alkyl, heterocyclic radical, alkenyl, alkynyl, aryl, heteroaryl ,=O ,=S ,-SH, R13O-、R13S-、R13 (O=) S-, R13(O=)2S-, R therein13It is alkyl, heterocyclic radical, alkenyl, alkynyl, aryl or heteroaryl；
R8Selected from hydrogen, alkyl and-OC (O) R14, R therein14It is alkyl, heterocyclic radical, alkenyl, alkynyl, aryl or heteroaryl Base；Wherein alkyl, heterocyclic radical, alkenyl, alkynyl, aryl or heteroaryl are optionally substituted by following group：Halogen, cyano group, hydroxyl Base, amino, carboxyl, acyl group, alkyl, heterocyclic radical, alkenyl, alkynyl, aryl, heteroaryl ,=O ,=S ,-SH, R15O-、R15S-、R15 (O=) S-, R15(O=)2S-；R therein15It is alkyl, heterocyclic radical, alkenyl, alkynyl, aryl or heteroaryl；
X is oxygen atom or sulphur atom or NH.
Another aspect of the present invention provide a kind of compound shown in formula I or its compound isotopically labelled or Its optical isomer, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine, its Formula of I is as follows：
Wherein：
R1And R2Independently selected from cyano group, C1-C12 alkyl groups, C2-C12 alkenyls, C2-C12 alkynyl groups, C6-C14 virtues Base, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, the Heterocyclylalkyl containing 3 to 8 annular atoms, the heterocycloalkenyl containing 3 to 8 annular atoms, Heteroaryl containing 5 to 14 annular atoms, C1-C12 alkyl groups-C (=O)-, C2-C12 alkenyls-C (=O)-, amino, R9O-、 R9S-、R9(O=) S-, R9(O=)2S-, R therein9It is C1-C12 alkyl groups, C2-C12 alkenyls, C2-C12 alkynyl groups, C6- C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, the Heterocyclylalkyl containing 3 to 8 annular atoms, the heterocycle containing 3 to 8 annular atoms Alkenyl；Wherein, above-mentioned C1-C12 alkyl groups, C2-C12 alkenyls, C2-C12 alkynyl groups, C6-C14 aryl, C3-C8 cycloalkanes Base, C3-C8 cycloalkenyl groups, the Heterocyclylalkyl containing 3 to 8 annular atoms, the heterocycloalkenyl containing 3 to 8 annular atoms, containing 5 to 14 rings The heteroaryl of atom, C1-C12 alkyl groups-C (=O)-, C2-C12 alkenyls-C (=O)-, amino is optionally by 1 to 3 substitution Base is substituted, and substituent therein is independently selected from hydroxyl, halogen, cyano group, amino, carboxyl, C1-C6 alkyl groups, C3-C8 rings Alkyl, C2-C6 alkenyls-, C2-C6 alkynyl groups-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, C6-C14 aryl, containing 5 to 14 rings Heteroaryl, C1-C6 alkyl groups-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyls-O-, C2-C6 alkynyl groups-O-, the C3- of atom C8 cycloalkenyl groups-O-, C6-C14 aryl-O-, the heteroaryl-O- containing 5 to 14 annular atoms, C1-C6 alkyl groups-S-, C3-C8 cycloalkanes Base-S-, C2-C6 alkenyls-S-, C2-C6 alkynyl groups-S-, C3-C8 cycloalkenyl groups-S-, C6-C14 aryl-S-, containing 5 to 14 rings Heteroaryl-the S- of atom, the Heterocyclylalkyl containing 3 to 8 annular atoms, the heterocycloalkenyl containing 3 to 8 annular atoms ,=O ,=S ,- SH、-CF3、-CO2C1-C6Alkyl group, C1-C6 alkyl groups-S-, C1-C6 alkyl groups (O=) S- and C1-C6 alkyl groups (O=)2S-； Or
R1And R2It is combined to form the optionally substituted cycloalkanes hydrocarbon ring containing 3-8 annular atom, cyclenes hydrocarbon ring, heterocycle Alkane ring, heterocyclic alkene ring；
R3、R4And R5Independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano group, C1-C12 alkyl groups, C2-C12 alkenyls, C2-C12 alkynyl groups, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, the Heterocyclylalkyl containing 3 to 8 annular atoms, containing 3 Heterocycloalkenyl to 8 annular atoms, the heteroaryl containing 5 to 14 annular atoms, C1-C12 alkyl groups-C (=O)-, C2-C12 alkenes Base-C (=O)-, amino, R11O-、R11S-、R11(O=) S-, R11(O=)2S-, R therein11It is C1-C12 alkyl groups, C2-C12 Alkenyl, C2-C12 alkynyl groups, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, the heterocycle alkane containing 3 to 8 annular atoms Base, the heterocycloalkenyl containing 3 to 8 annular atoms；Wherein, above-mentioned C1-C12 alkyl groups, C2-C12 alkenyls, C2-C12 alkynes Base, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, the Heterocyclylalkyl containing 3 to 8 annular atoms, containing 3 to 8 annular atoms Heterocycloalkenyl, the heteroaryl containing 5 to 14 annular atoms, C1-C12 alkyl groups-C (=O)-, C2-C12 alkenyls-C (=O)-, Amino is optionally substituted by 1 to 3 substituent, and substituent therein is independently selected from hydroxyl, halogen, cyano group, amino, carboxylic Base, C1-C6 alkyl groups, C3-C8 cycloalkyl, C2-C6 alkenyls-, C2-C6 alkynyl groups-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, C6-C14 aryl, the heteroaryl containing 5 to 14 annular atoms, C1-C6 alkyl groups-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyls- O-, C2-C6 alkynyl group-O-, C3-C8 cycloalkenyl groups-O-, C6-C14 aryl-O-, heteroaryl-O-, C1- containing 5 to 14 annular atoms C6 alkyl groups-S-, C3-C8 cycloalkyl-S-, C2-C6 alkenyls-S-, C2-C6 alkynyl groups-S-, C3-C8 cycloalkenyl groups-S-, C6- C14 aryl-S-, the heteroaryl-S- containing 5 to 14 annular atoms, the Heterocyclylalkyl containing 3 to 8 annular atoms, containing 3 to 8 annular atoms Heterocycloalkenyl ,=O ,=S ,-SH ,-CF3、-CO2C1-C6Alkyl group, C1-C6 alkyl groups-S-, C1-C6 alkyl groups (O=) S- With C1-C6 alkyl groups (O=)2S-；
R6And R6’Independently selected from hydrogen, C1-C6 alkyl groups and C3-C8 cycloalkyl；Above-mentioned C1-C6 alkyl groups and C3-C8 rings Alkyl is optionally substituted by 1 to 3 substituent, and substituent therein is independently selected from hydroxyl, halogen, cyano group, amino, carboxylic Base, C1-C6 alkyl groups, C3-C8 cycloalkyl, C2-C6 alkenyls-, C2-C6 alkynyl groups-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, C6-C14 aryl, the heteroaryl containing 5 to 14 annular atoms, C1-C6 alkyl groups-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyls- O-, C2-C6 alkynyl group-O-, C3-C8 cycloalkenyl groups-O-, C6-C14 aryl-O- and the heteroaryl-O- containing 5 to 14 annular atoms；
R7Selected from hydrogen, C1-C6 alkyl groups, C3-C8 cycloalkyl, C1-C6 alkyl groups-C (=O)-and C2-C6 alkenyls-C (=O)-；Wherein C1-C6 alkyl groups, C3-C8 cycloalkyl, C1-C6 alkyl groups-C (=O)-, C2-C6 alkenyls-C (=O)-appoint Selection of land is substituted by 1 to 3 substituent, and substituent therein is independently selected from hydroxyl, halogen, cyano group, amino, carboxyl, C1- C6 alkyl groups, C3-C8 cycloalkyl, C2-C6 alkenyls-, C2-C6 alkynyl groups-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, C6-C14 Aryl, the heteroaryl containing 5 to 14 annular atoms, C1-C6 alkyl groups-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyls-O-, C2- C6 alkynyl groups-O-, C3-C8 cycloalkenyl groups-O-, C6-C14 aryl-O- and the heteroaryl-O- containing 5 to 14 annular atoms；
R8Selected from hydrogen, C1-C12 alkyl groups, C3-C8 cycloalkyl and-OC (O)-C1-C12 alkyl groups；Wherein C1-C12 chains Alkyl, C3-C8 cycloalkyl and-OC (O)-C1-C12 alkyl groups are optionally substituted by 1 to 3 substituent, substituent therein Independently selected from hydroxyl, halogen, cyano group, amino, carboxyl, C1-C6 alkyl groups, C3-C8 cycloalkyl, C2-C6 alkenyls-, C2- C6 alkynyl groups-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, C6-C14 aryl, the heteroaryl containing 5 to 14 annular atoms, C1-C6 chains Alkyl-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyls-O-, C2-C6 alkynyl groups-O-, C3-C8 cycloalkenyl groups-O-, C6-C14 virtues Base-O- and heteroaryl-the O- containing 5 to 14 annular atoms；
X is oxygen atom or sulphur atom or NH.
In some preferred embodiments of the present invention, in formula I, R1And R2Independently selected from cyano group, amino, not Substitute C1-C6 alkyl groups；Or R1And R2Be combined to be formed the optionally substituted cycloalkanes hydrocarbon ring containing 3-8 annular atom or Heterocycloalkane ring.
In some preferred embodiments of the present invention, in formula I, R1And R2Independently selected from methyl, ethyl；Or Person R1And R2Be combined to be formed cyclopropane ring, cyclobutane ring, pentamethylene ring, cyclohexane ring, cycloheptane ring, tetrahydrofuran ring or Amylene oxide ring or through these methyl substituted rings.
In some preferred embodiments of the present invention, in formula I, R3、R4And R5Independently selected from hydrogen, halogen, hydroxyl Base, carboxyl, cyano group, amino, C1-C6 alkyl groups, C6-C14 aryl, C3-C8 cycloalkyl, C1-C6 alkyl groups-O-, containing 5 to 14 The heteroaryl of annular atom；Wherein, above-mentioned C1-C6 alkyl groups, C6-C14 aryl, C3-C8 cycloalkyl, C1-C6 alkyl groups-O-, Amino is optionally substituted by 1 to 3 substituent, and substituent therein is independently selected from hydroxyl, halogen, cyano group, amino, carboxylic Base, C6-C14 aryl and C1-C6 alkyl groups.
In some preferred embodiments of the present invention, in formula I, R3、R4And R5Independently selected from hydrogen, halogen, hydroxyl Base, carboxyl, cyano group, amino, methyl, ethyl, propyl group, butyl, phenyl, benzyl, tolyl, anisyl, chlorphenyl, fluorobenzene Base, bromophenyl, dimethoxy phenyl, dichlorophenyl, difluorophenyl, dibromo phenyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and Pyridine radicals.
In some preferred embodiments of the present invention, in formula I, R6And R6’Independently selected from hydrogen, unsubstituted C1- The C1-C6 alkyl groups of C6 alkyl groups, unsubstituted C3-C8 cycloalkyl and 1-3 halogen substitution.
In some preferred embodiments of the present invention, in formula I, R6And R6’Independently selected from hydrogen, methyl, ethyl, Propyl group, cyclopropyl and cyclobutyl.
In some preferred embodiments of the present invention, in formula I, R7Selected from hydrogen, unsubstituted C1-C6 alkanes Base, unsubstituted C1-C6 alkyl groups-C (=O)-and unsubstituted C2-C6 alkenyls-C (=O)-.
In some preferred embodiments of the present invention, in formula I, R7Selected from hydrogen, methyl, ethyl, formoxyl and second Acyl group.
In some preferred embodiments of the present invention, in formula I, R8Selected from hydrogen, C1-C6 alkyl groups and-OC (O)-C1-C12 alkyl groups；Wherein C1-C6 alkyl groups and-OC (O)-C1-C12 alkyl groups are optionally by 1 to 3 substituent institute Substitution, substituent therein is independently selected from hydroxyl, halogen, cyano group, amino, carboxyl, C1-C6 alkyl groups and C1-C6 alkanes Base-O-.
In some preferred embodiments of the present invention, in formula I, R8Selected from hydrogen, methyl, ethyl, propyl group, fourth Base, amyl group, formyloxy, acetoxyl group, propionyloxy, butyryl acyloxy and valeryl epoxide.
In some preferred embodiments of the present invention, in formula I, R1And R2Independently selected from methyl, ethyl, or Person R1And R2It is combined to form cyclopropane ring, cyclobutane ring, pentamethylene ring, cyclohexane ring or through these methyl substituted rings； R3、R4And R5Independently selected from hydrogen, halogen, methyl, ethyl, propyl group, butyl, cyclohexyl, phenyl and above-mentioned group by halogen Element or the group of methyl or methoxy substitution；R6And R6’Independently selected from hydrogen, methyl, ethyl, propyl group, butyl；R7Selected from hydrogen, first Base, ethyl；R8Selected from hydrogen, methyl, ethyl, propyl group, butyl；X is oxygen atom.
In the different preferred embodiment of the above, the preferred option of each substituent can be mutually combined, its various combination Form is within.
In the most preferred embodiment of the present invention, compounds of formula I is shown in embodiment hereof 1 to embodiment 17 Each particular compound.
" compound shown in formula I " or " compounds of formula I " or " compound of the invention " described herein are also covered by Any optical isomer of compound of Formula I, geometric isomer, the mixture of dynamic isomer or isomers.
Term " optical isomer " is it is meant that when compound has one or more chiral centres, each chiral centre There may be R configurations or S configurations, the various isomers thus formed are optical isomer.Optical isomer includes all non- Enantiomter, enantiomter, mesomer, racemic modification or its form of mixtures.For example, pass through chiral chromatographic column or logical Crossing chiral synthesis can be with separating optical isomers.
Term " geometric isomer " it is meant that when double bond in compound be present, the compound there may be cis-isomer, Transisomer, E-isomer and Z-type isomers.Geometric isomer includes cis-isomer, transisomer, E type isomeries Body, Z-type isomers or its form of mixtures.
Term " dynamic isomer " refer to because in molecule a certain atom in two rapid movements in position and caused by isomers.This Art personnel are appreciated that：Between dynamic isomer can mutual phase in version, may reach a kind of under a certain state Poised state and coexist." compound shown in formula I " described herein is also covered by any dynamic isomer of compound of Formula I. Specifically, inventor has found that compound of formula I there may be following dynamic isomer：
Therefore, unless otherwise specified, " compound shown in formula I " or " compounds of formula I " or " this hair is mentioned herein The compound shown in formula above I-a, I-b, I-c or I-d is also covered by during bright compound ".Equally, herein any one Tautomerism in embodiment in the form of the particular compound that concrete structure formula represents also includes its I-a, I-b, I-c or I-d Body.
Unless otherwise specified, it is mentioned herein " compound shown in formula I " or " compounds of formula I " or " of the invention Isotope marks chemical combination obtained from any of compound atom is replaced by its isotope atom is also covered by during compound " Thing.
The present invention includes all pharmaceutically acceptable compound isotopically labelleds of compound of Formula I, wherein, one Or multiple atoms by with from the atom same atoms ordinal number generally found in nature but different atomic masses or The atom of person's mass number is replaced.
The example for the isotope being suitable for inclusion in the compound of the present invention includes the isotope of hydrogen, such as2H (D) and3H (T), the isotope of carbon, such as11C、13C and14C, the isotope of chlorine, such as36Cl, the isotope of fluorine, such as18F, the same position of iodine Element, such as123I and125I, the isotope of nitrogen, such as13N and15N, the isotope of oxygen, such as15O、17O and18O, and the same position of sulphur Element, such as35S。
Formula I some compound isotopically labelleds (such as comprising radioisotopic those) can be used for medicine and/ Or substrate tissue distribution research.The convenience of easiness and detection means in view of introducing, radio isotope deuterium is (i.e.2H) With carbon-14 (i.e.14C it is) particularly useful for the purpose.
Using such as deuterium (i.e.2H higher isotope) carry out substitution can provide benefit in terms of some treatments and because This is probably preferable in some cases, and the benefit in terms of the treatment is (for example, increasing by bigger metabolism stability The dose requirements of half-life period or reduction inside length) bring.
Using positron emitting isotopes (such as11C、18F、15O and13N) carry out substitution and can be used for positron emission acceptor Image (Positron Emission Topography (PET)) is studied, for detection substrate acceptor seizure condition.
Formula I compound isotopically labelled can typically pass through routine techniques well known by persons skilled in the art or logical Cross replace previously used non-marked reagent with similar in the example appended by this paper using suitable isotope labeling reagent and Method described in preparation, to be prepared.
Some compounds of the present invention can exist with nonsolvated forms and solvation form (including hydrated form). In general, no matter compounds of formula I, exist by solvation form or exist in the form of unsolvated, it is included in this In the range of invention.
Some compounds of the present invention can exist in the form of different crystal forms or indefinite form, no matter exist in what manner, lead to The compound of Formulas I is included within the scope of the invention.
In order to avoid ambiguity, definition is provided to term used herein below.Unless otherwise indicated, it is used herein The implication of term is as follows.
Term " hydroxyl " refers to-OH.
Term " halogen " or " halogen " refers to-F ,-Cl ,-Br, or-I.
Term " amino " refers to-NH2。
Term " cyano group " refers to-CN.
Term " carboxyl " refers to-C (=O) OH.
Term " substituted " refers to one or more of group (preferably 1 to 5, more preferably 1 to 3) hydrogen atom independence Ground is replaced by the substituent of respective number.
Term " independently " refers to when the number of substituent is more than one, these substituents can with it is identical can not also Together.
Term " optional " " optionally " represents that the event described by it may or may not occur.A for example, group " being optionally substituted " represents：The group can be unsubstituted or substituted.
Terms used herein " hetero atom " represents oxygen (O), nitrogen (N) or S (O)m(wherein m can be 0,1 or 2, i.e., sulphur is former Sub- S or sulfoxide group SO or sulfonyl S (O)2)。
The saturated hydrocarbon that term " alkyl " refers to only be made up of two kinds of elements of C and H loses one in any carbon atom The group formed after individual hydrogen atom." alkyl " as described herein includes the alkyl groups such as straight chained alkyl and branched alkyl；Also include single The cycloalkyl such as cycloalkyl, spiro cycloalkyl group, cycloalkyl and bridge ring alkyl.Alkyl can be unsubstituted or be taken Generation.
" alkyl " as described herein includes optionally substituted alkyl group, and it preferably has 1-20 carbon atom, more preferably With 1-12 carbon atom, most preferably with 1-6 carbon atom；For example, methyl, ethyl, n-propyl, isopropyl, normal-butyl, Sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, n-hexyl, chloromethyl, fluoro ethyl, trifluoromethyl or 1,1,1- trifluoroethyls etc. Deng.
" alkyl " as described herein also includes optionally substituted cycloalkyl (such as C3-C20 cycloalkyl or C3-C12 cycloalkanes Base or C3-C8 cycloalkyl), for example, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, decahydronaphthalene naphthyl, drop Pinane base, adamantyl, fluorine cyclopropyl, 2- iodine cyclobutyl, 2,3- dimethylcyclopentyls, 2,2- dimethoxycyclohexyls and 3- benzene Cyclopentyl etc..
" C1-C6 alkyl groups " is also known as " lower alkanols alkyl ", refers to a subset of alkyl, and it refers to 1-6 carbon atom Straight chained alkyl and branched alkyl, including, for example, methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, uncle Butyl, n-pentyl, n-hexyl etc..
" alkyl " as described herein is optionally substituted by one or more substituents, substituent therein independently selected from In halogen, cyano group, nitro (- NO2), hydroxyl, amino, carboxyl, acyl group, alkyl, heterocyclic radical, alkenyl, alkynyl, aryl, heteroaryl, =O ,=S ,-SH, R16O-、R16S-、R16(O=) S-, R16(O=)2S-, R therein16Be alkyl, heterocyclic radical, alkenyl, alkynyl, Aryl or heteroaryl.
Preferably, " alkyl " as described herein is optionally substituted by 1 to 3 substituent, and substituent therein is independently Selected from hydroxyl, halogen, nitro, cyano group, amino, carboxyl, C1-C6 alkyl groups, C3-C8 cycloalkyl, C2-C6 alkenyls-, C2- C6 alkynyl groups-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, C6-C14 aryl, the heteroaryl containing 5 to 14 annular atoms, C1-C6 chains Alkyl-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyls-O-, C2-C6 alkynyl groups-O-, C3-C8 cycloalkenyl groups-O-, C6-C14 virtues Base-O-, the heteroaryl-O- containing 5 to 14 annular atoms, C1-C6 alkyl groups-S-, C3-C8 cycloalkyl-S-, C2-C6 alkenyls- S-, C2-C6 alkynyl group-S-, C3-C8 cycloalkenyl groups-S-, C6-C14 aryl-S-, the heteroaryl-S- containing 5 to 14 annular atoms, containing 3 Heterocyclylalkyl to 8 annular atoms, the heterocycloalkenyl containing 3 to 8 annular atoms ,=O ,=S ,-SH ,-CF3、-CO2C1-C6Alkane Base, C1-C6 alkyl groups-S-, C1-C6 alkyl groups (O=) S- and C1-C6 alkyl groups (O=)2S-。
Term " alkenyl " refers to any being only made up of two kinds of elements of C and H and contains one or more carbon-carbon double bonds but be free of The hydrocarbon of triple carbon-carbon bonds or aromatic gp loses the group formed after a hydrogen atom in any carbon atom.It is as described herein " alkenyl " includes the alkenyls such as straight-chain alkenyl, branched-chain alkenyl；Also monocyclic alkenyl, loop coil alkenyl, condensed ring alkenyl and bridged ring alkene are included The loop chain alkene such as base.Alkenyl can be unsubstituted or substituted.
" alkenyl " as described herein includes optionally substituted alkenyl, preferably with 2-20 carbon atom, more preferably has There is 2-12 carbon atom, most preferably with 2-6 carbon atom；For example, vinyl, 1- acrylic, 2- acrylic, 1- butylene It is base, 2- cyclobutenyls, isobutenyl, 1- pentenyls, 2- pentenyls, isopentene group, 1- hexenyls, 2- hexenyls, 3- hexenyls, different Hexenyl, 1- heptenyls, 2- heptenyls, 3- heptenyls, 1- octenyls, 2- octenyls, 3- octenyls, 4- octenyls, 1- nonenes Base, 1- decene base, 1- hendecanes alkenyl, 1- dodecane alkenyls etc..
Term " alkenyl " as described herein also includes optionally substituted cycloalkenyl group (such as C3-C20 cycloalkenyl groups or C3-C12 Cycloalkenyl group or C3-C8 cycloalkenyl groups), for example, cyclobutane base, cyclopentenyl, cyclohexenyl group, cycloheptenyl, cyclobutadiene base, ring penta Dialkylene, cycloheptatriene base etc..
" alkenyl " as described herein is optionally substituted by one or more (such as 1-3) substituents, wherein substituent Selection and preferred scope it is identical with the substituent of " alkyl ".
It is that term " alkynyl " refers to only to be made up of two kinds of elements of C and H and containing one or more triple carbon-carbon bonds but without virtue The hydrocarbon of fragrant key loses the group formed after a hydrogen atom in any carbon atom." alkynyl " as described herein includes straight The alkynyl groups such as alkynyl group, branch alkynyl；Also the cycloalkynyl radicals such as monocyclic alkynyl, loop coil alkynyl, condensed ring alkynyl and bridged ring alkynyl are included.Alkynes Base can optionally include one or more carbon-carbon double bonds.Alkynyl can be unsubstituted or substituted.
" alkynyl " as described herein includes optionally substituted alkynyl group, preferably with 2-20 carbon atom, more preferably has There is 2-12 carbon atom, most preferably with 2-6 carbon atom；For example, acetenyl, propinyl, 1- butynyls, 2- butynyls, Butynyl, 1- pentynyls, valerylene base, isoamyl alkynyl, 3- methyl -3- butynyls, 1- hexin bases, 2- hexin bases, 3- hexins Base, 3- heptynyls, l- octynyls, 1- n-heptylacetylenes base, 1- decynyls, 1- hendecanes alkynyl, 1- dodecane alkynyls etc..
Term " alkynyl " as described herein also includes optionally substituted cycloalkynyl radical (such as C8-C18 cycloalkynyl radicals), for example, Cyclooctyne base etc..
" alkynyl " as described herein is optionally substituted by one or more (such as 1-3) substituents, wherein substituent Selection and preferred scope it is identical with the substituent of " alkyl ".
Term " heterocyclic radical " refers to saturation or the monocyclic or polycyclic compound substituent containing carbon-carbon double bond or triple carbon-carbon bonds；Its Include 3 to 20 annular atoms (preferably 3 to 12 annular atoms, more preferably 3 to 8 annular atoms), wherein one or more annular atoms Selected from hetero atom, remaining annular atom is carbon；Any one ring therein does not all have armaticity." heterocyclic radical " as described herein also wraps Include spiro heterocyclic radical, condensed hetero ring base and bridge heterocyclic radical.Heterocyclic radical can be unsubstituted or substituted.Heterocyclic radical Can be Heterocyclylalkyl, heterocycloalkenyl or heterocycle alkynyl.The example of suitable monocyclic heterocycles includes, but not limited to piperidyl, pyrrole Cough up alkyl, piperazinyl, azelidinyl, aziridinyl, morpholinyl, thietanyl, oxocyclopentyl (tetrahydrofuran base), Oxacyclohexyl (THP trtrahydropyranyl) etc..
It should be understood that " heterocyclic radical " as described herein is optionally substituted by one or more (such as 1-3) substituents, its The selection of middle substituent and preferred scope are identical with the substituent of " alkyl ".
Term " aryl " refer to the pi-electron system with conjugation 6 to 14 yuan of full carbon are monocyclic or the group of fused polycycle.Virtue Basic ring can be with hetero-aromatic ring, heterocycle, cycloalkanes, spirocyclane, condensed ring alkane, bridged ring alkane, cyclenes, loop coil alkene, condensed ring alkene, bridged ring alkene, ring Alkynes, loop coil alkynes, condensed ring alkynes or the fusion of bridged ring alkynes.Aryl can be unsubstituted or substituted.Example includes, But it is not limited to, phenyl, naphthyl, 2- aminomethyl phenyls, 3- aminomethyl phenyls, 4- aminomethyl phenyls, anisyl (such as 2- methoxybenzenes Base, 3- methoxyphenyls, 4- methoxyphenyls), chlorphenyl (such as 2- chlorphenyls, 3- chlorphenyls, 4- chlorphenyls), fluorophenyl (such as 2- fluorophenyls, 3- fluorophenyls, 4- fluorophenyls), bromophenyl (such as 2- bromophenyls, 3- bromophenyls, 4- bromophenyls), the chloro- 3- methyl of 2- The chloro- 4- aminomethyl phenyls of phenyl, 2-, the chloro- 5- aminomethyl phenyls of 2-, 3- chloro-2-methyls phenyl, the chloro- 4- aminomethyl phenyls of 3-, the chloro- 2- of 4- The chloro- 3- aminomethyl phenyls of aminomethyl phenyl, 4-, 5- chloro-2-methyls phenyl, 2,3- dichlorophenyls, 2,5- dichlorophenyls, 3,4- dichloro-benzenes Base, 2,3- 3,5-dimethylphenyls, 3,4- 3,5-dimethylphenyls etc..
" aryl " as described herein is optionally substituted by 1-4 or 1-3 substituent, wherein the selection of substituent and excellent Select scope identical with the substituent of " alkyl ".
Term " heteroaryl " refers to include 5 to 18 annular atoms (preferably 5 to 14 annular atoms) and wherein 1 to 4 ring originals Son is the heteroatomic aroma system selected from oxygen, nitrogen and sulphur.Heteroaryl in itself can be with aromatic ring, heterocycle, cycloalkanes, spirocyclane, thick Cycloalkanes, bridged ring alkane, cyclenes, loop coil alkene, condensed ring alkene, bridged ring alkene, cycloalkyne, loop coil alkynes, condensed ring alkynes or the fusion of bridged ring alkynes.Can be not Substituted or substituted.The example of heteroaryl includes, but not limited to thienyl, furyl, pyrrole radicals, pyridine Base, pyrimidine radicals, imidazole radicals, pyrazinyl, oxazolyls, thiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzo miaow Oxazolyl, indyl, quinolyl, isoquinolyl and quinazolyl etc..
" heteroaryl " as described herein is optionally substituted by 1-4 or 1-3 substituent, wherein the selection of substituent with Preferred scope is identical with the substituent of " alkyl ".
Terms used herein " acyl group " refer to RC (=O)-, wherein R is C1-C18 (preferably C1-C12, more preferably C1-C6) Alkyl." acyl group " example includes, but not limited to formoxyl, acetyl group, benzoyl, nicotinoyl base, propiono, isobutyryl, grass Acyl group etc..
Acyl group RC (=O)-optionally substituted by one or more (such as 1-3) substituents, the wherein choosing of substituent Select identical with the substituent of " alkyl " with preferred scope.
Terms used herein " cyclization " refer to be formed cycloalkanes hydrocarbon ring, cyclenes hydrocarbon ring, cycloalkyne hydrocarbon ring, aromatic ring, heterocycloalkane ring, The cyclic structures such as heterocyclic alkene ring, heterocycle alkyne hydrocarbon ring, hetero-aromatic ring, the cyclic structure can be monocyclic, bicyclic or multiring structures, Including its condensed ring, bridged ring, spirane structure.Especially, substituent R herein1And R2The ring of formation is preferably 3 to 12 yuan of rings, especially It is preferred that 3 to 12 yuan of cycloalkane rings, cyclenes hydrocarbon ring, heterocycloalkane ring, heterocyclic alkene ring, most preferably 3 to 8 yuan of cycloalkane rings, cyclenes Hydrocarbon ring, heterocycloalkane ring, heterocyclic alkene ring, for example, cyclopropane ring, cyclobutane ring, pentamethylene ring, cyclohexane ring, cycloheptane ring, Tetrahydrofuran ring, amylene oxide ring etc..The ring structure is optionally substituted by one or more (such as 1-3) substituents, Wherein the selection of substituent and preferred scope are identical with the substituent of " alkyl ".
Herein, the number range related to substituent number, carbon atom number, annular atom number represents institute in the range of this There is enumerating one by one for integer, and scope is only as a kind of representation of simplification.Such as：
" 1-4 substituent " represents 1,2,3 or 4 substituent；
" 1-3 substituent " represents 1,2 or 3 substituents；
" 3 to 12 yuan of rings " represent 3,4,5,6,7,8,9,10,11 or 12 yuan of rings；
" 3 to 8 yuan of rings " represent 3,4,5,6,7 or 8 yuan of rings；
" 1-12 carbon atom " or " C1-C12 " represent 1 (C1), 2 (C2), 3 (C3), 4 (C4), 5 (C5), 6 (C6), 7 (C7), 8 (C8), 9 (C9), 10 (C10), 11 (C11) or 12 carbon atoms (C12)；
" 1-6 carbon atom " or " C1-C6 " represent 1 (C1), 2 (C2), 3 (C3), 4 (C4), 5 (C5) or 6 carbon atoms (C6)；
" 2-6 carbon atom " or " C2-C6 " represents 2 (C2), 3 (C3), 4 (C4), 5 (C5) or 6 carbon originals Sub (C6)；
" C3-C8 " represents 3 (C3), 4 (C4), 5 (C5), 6 (C6), 7 (C7) or 8 carbon atoms (C8)；
" 3 to 8 annular atoms " represents 3,4,5,6,7 or 8 annular atoms.
Therefore, the number range related to substituent number, carbon atom number, annular atom number is also covered by its any one Subrange, and each subrange is also considered as being disclosed herein.
2.The application of the compound of the present invention
Applicants experimentally found that it is a kind of HIF proline hydroxylases according to the compound of the present invention Special effect inhibitor.The compound of the present invention provides a simulation body anoxic concerted reaction, by suppressing proline hydroxylase, Hematopoietin is raised, increases hemoglobin levels.Have found, can be used for treating according to the compound of the present invention and/or pre- The anti-disease related to hypoxia inducible factor HIF, such as anemia, angiocardiopathy, diabetes, sacred disease etc., particularly It is cardiac insufficiency, coronary heart diseases and angina pectoris, myocardial infarction, apoplexy, artery sclerosis, spontaneous hypertension, pulmonary hypertension, pernicious Hypertension and peripheral arterial occlusive disease.
Specifically, the disease for being suitable for treating and/or preventing according to the compound of Formula I of the present invention includes：
Blood forms disease, such as essential anemia, kidney anaemia and anaemia (the particularly chemotherapy induction with tumor disease Anaemia), infectious disease (particularly HIV infectious diseases) or other inflammatory disease, such as rheumatoid arthritis；
Due to the anaemia lost blood, hypoferric anemia, vitamin-deficiency anaemia (such as due to vitamin B12 deficiency or Due to folic acid deficiency), hypopsials and alpastic anemia either hemolytic anemia or (iron loses using disease due to iron Usability anaemia) anaemia or due to other endocrine system diseases (such as hypothyroidism (hypothyroidosis) anaemia)；
The situation of the surgical site infections ischaemic relevant with operation and its consecutive symptom, especially with regard to using heart-lung machine Cardiac interventional (such as bypass surgery, transplantation of heart valve), arteria carotis intervention, sustainer intervention and with skull Container The intervention that tool is opened or penetrated；
Acute and extension property cerebral ischemic condition consecutive symptom (such as apoplexy, birth asphyxia)；
The infringement of cancer and the health status occurred in cancer therapeutic process, particularly with cytostatics, antibiotic and spoke The infringement of the health status occurred is penetrated after treatment；
Rheumatism type and other disease forms for being considered as autoimmune disease, particularly treat and/or prevent at this The infringement of the health status occurred in the drug treatment of kind disease；
Illness in eye (such as glaucoma), central nervous system disease (such as dull-witted, the chronic pain sensation), chronic kidney disease, kidney function Incomplete and acute renal failure；
Sex dysfunction (such as sexual hypoesthesia)；
Diabetes and its consecutive symptom, such as diabetic vascular disease and microangiopathy, diabetic nephropathy and neuropathy；
Fibrotic conditions, such as the heart, lung and the fibrosis of liver；
Nerve degenerative diseases, for example, Alzheimer's, Parkinson's disease, BSE, gram refined Er Shi diseases, Huntington's disease, cerebral atrophy etc.；
Ischemic disease, such as ischemic cerebrovascular disease (ischemic cerebrovascular disease), ischemic Property nephrosis (ischemicrenaldisease, IRD), ischemic cardiomyopathy (ischemic cardiomyopathy, ICM) etc..
In addition, general treatement and/or prevention when being also adapted to occur surgical operation according to the compound of the present invention, purpose It is to promote wound healing and shorten recovery time.
It is also adapted to increase the external application of hematocrit according to the compound of the present invention, it is therefore an objective to obtain for performing the operation Preceding blood itself contributes the blood of (autodonation).
Therefore, another aspect of the present invention is related to as treating and/or preventing the disease related to hypoxia inducible factor The compounds of formula I (or preferable compound of Formula I) or its compound isotopically labelled or its optical siomerism of the medicine of disease Body, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine.
Another aspect of the present invention is related to compounds of formula I (or preferable compound of Formula I) or its isotope marks Compound or its optical isomer, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its Purposes of the precursor medicine in treating and/or preventing the disease related to hypoxia inducible factor.
Another aspect of the present invention is related to compounds of formula I (or preferable compound of Formula I) or its isotope marks Compound or its optical isomer, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its Purposes of the precursor medicine in prolyl hydroxylase inhibitors are prepared.
Another aspect of the present invention is related to compounds of formula I (or preferable compound of Formula I) or its isotope marks Compound or its optical isomer, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its Precursor medicine is preparing the purposes in being used to treat and/or prevent the medicine of the disease related to hypoxia inducible factor.
Another aspect of the present invention is related to a kind of side treated and/or prevent the disease related to hypoxia inducible factor HIF Method, this method include to needs patient therapeuticallv's effective dose compounds of formula I (or preferable compound of Formula I) or Its compound isotopically labelled or its optical isomer, geometric isomer, dynamic isomer or isomer mixture or its can Medicinal salt or its precursor medicine.
Another aspect of the present invention is related to a kind of side treated and/or prevent the disease related to hypoxia inducible factor HIF Method, this method include the pharmaceutical composition of patient therapeuticallv's effective dose to needs, and described pharmaceutical composition contains formula I's Compound (or preferable compound of Formula I) or its compound isotopically labelled or its optical isomer, geometric isomer, mutually Tautomeric or isomer mixture or its pharmaceutically useful salt or its precursor medicine, and it is one or more pharmaceutically acceptable Carrier, diluent or excipient.
Another aspect of the present invention is related to compounds of formula I (or preferable compound of Formula I) or its isotope marks Compound or its optical isomer, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its Precursor medicine is used for wound healing in surgical operation and/or shortens the purposes of recovery time.
Another aspect of the present invention is related to compounds of formula I (or preferable compound of Formula I) or its isotope marks Compound or its optical isomer, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its Purposes of the precursor medicine in preparing for surgical operation accelerating wound healing and/or shortening the medicine of recovery time.
Another aspect of the present invention is related to compounds of formula I (or preferable compound of Formula I) or its isotope marks Compound or its optical isomer, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its Precursor medicine is used for the purposes for increasing hematocrit, and the purposes can be used for therapeutic purposes, for diagnostic purposes or for non- Treat non-diagnostic purpose (such as increasing hematocrit only for experimental study).
Another aspect of the present invention is related to the method for the blood for obtaining itself donation before surgery, and its method is included to blood sample Compounds of formula I (or preferable compound of Formula I) or its compound isotopically labelled or its optical siomerism are added in product Body, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine.
Herein, term " patient " means all mammals, and including the mankind.The example of patient include the mankind, ox, Dog, cat, goat, sheep, mouse, pig and rabbit.
Herein, term " disease related to hypoxia inducible factor " includes, but not limited to anaemia (for example, idiopathic is poor Blood, kidney anaemia, with tumor disease the anaemia anaemia of chemotherapy induction (particularly), by losing blood, caused anaemia, iron-deficient are poor Blood, vitamin-deficiency anaemia, hypopsials and alpastic anemia, hemolytic anemia, sideroachrestic anemia, thyroid gland Anaemia caused by hypofunction etc.), angiocardiopathy (for example, cardiac insufficiency, coronary heart diseases and angina pectoris, myocardial infarction, apoplexy, Artery sclerosis, spontaneous hypertension, pulmonary hypertension, accelerated hypertension and peripheral arterial occlusive disease), sacred disease, HIV Infectious disease, rheumatoid arthritis, the ischaemic relevant with operation, birth asphyxia, cancer and cancer related symptoms (such as The infringement of the health status occurred after with cytostatics, antibiotic and radiation therapy), illness in eye (such as glaucoma), maincenter The nervous system disease (such as dull-witted, chronic pain sensation), chronic kidney disease, renal insufficiency and acute renal failure, sex dysfunction is (such as Sexual hypoesthesia), diabetes and complication (such as diabetic vascular disease and microangiopathy, diabetic nephropathy), nervus retrogression Disease (such as Alzheimer's, Parkinson's disease etc.), ischemic disease (such as ischemic cerebrovascular disease, ischemic kidney Disease, ischemic cardiomyopathy etc.) and fibrotic conditions (such as the heart, lung and fibrosis of liver).
Preferably, " disease related to hypoxia inducible factor " refers to anaemia, includes but is not limited to, essential anemia, kidney Anaemia, with the anaemia anaemia of chemotherapy induction (particularly) of tumor disease, by caused anaemia, hypoferric anemia, the dimension of losing blood Raw plain deficiency disease anaemia, hypopsials and alpastic anemia, hemolytic anemia, sideroachrestic anemia, thyroid function Anaemia caused by decline etc.；Nerve degenerative diseases (such as Alzheimer's, Parkinson's disease etc.)；Ischemic disease (such as ischemic cerebrovascular disease, ischemic nephropathy, ischemic cardiomyopathy etc.) and fibrotic disease (such as the heart, lung and the fibre of liver Dimensionization).
" the pharmaceutically useful salt " of compound of Formula I specifically described herein refers to suitable for mammal vivo applications (when applying With security and validity) the compound inorganic acid and organic acid addition salt or organic base and inorganic base addition salts.These Salt in situ during the final separation and purifying of compound can be prepared, or by respectively by the pure compound of free form and conjunction Suitable organic or inorganic acid or alkali reaction, and the salt formed is separated to prepare.Typical salt includes hydrobromide, hydrogen chloride Thing, sulfate, disulfate, nitrate, acetate, oxalates, valerate, oleate, palmitate, stearate, bay Hydrochlorate, borate, benzoate, lactate, phosphate, toluene fulfonate, citrate, maleate, fumarate, amber Hydrochlorate, tartrate, gluceptate, Lactobionate, lauryl sulfonate etc..These salt can include being based on alkali metal and alkali The cation of earth metal (such as sodium, lithium, potassium, calcium, magnesium etc.), and nontoxic ammonium, quaternary ammonium and amine cation (include, but not limited to Ammonium, tetramethyl-ammonium, tetraethyl ammonium, methyl amine, dimethyl amine, Trimethylamine, triethylamine, ethylamine etc.) salt.
" precursor medicine " of compound of Formula I specifically described herein refers to (to be had suitable for mammal vivo applications when applying Security and validity) the compound derivative, it discharges compounds of formula I in vivo after application or its is pharmaceutically acceptable Salt.The example of prodrug includes amino acid addition salt, ester, acid amides etc..
3.The pharmaceutical composition and pharmaceutical dosage form of compound containing the present invention
For treatment use, compounds of formula I is generally bestowed in the form of pharmaceutical composition to patient, said composition bag Containing at least one above-claimed cpd as active component, at the same optionally include pharmaceutically acceptable adjuvant and/excipient and Pharmaceutically acceptable solid or liquid-carrier.
Another aspect of the present invention is related to a kind of pharmaceutical composition, and it contains compounds of formula I (or preferable formula I Compound) or its compound isotopically labelled or its optical isomer, geometric isomer, dynamic isomer or isomers mixing Thing or its pharmaceutically useful salt or its precursor medicine, and one or more pharmaceutically acceptable carriers, adjuvant or excipient.
It is (or preferable logical the invention further relates to a kind of method for preparing aforementioned pharmaceutical compositions, including by the compound of Formulas I Compound of formula I) or its compound isotopically labelled or its optical isomer, geometric isomer, dynamic isomer or isomers mix Compound or its pharmaceutically useful salt or its precursor medicine, are mixed with pharmaceutically acceptable carrier, adjuvant or excipient.
The pharmaceutical composition of the present invention can be configured to be applied to oral, parenteral (including subcutaneous, muscle, skin as needed Layer and vein) bestow, the formulation that bronchus is bestowed or nose is bestowed.Therefore, if using solid carriers, said preparation can be into Piece, it is placed in powder or particle form in hard gelatin capsules, or with lozenge or lozenge form.Solid carriers can include conventional Excipient, such as adhesive, filler, tabletting lubricants, disintegrant, wetting agent etc..If necessary by conventional skill The art film coating tablet.If using liquid carrier, said preparation can be syrup, emulsion, soft gel capsule, for injection It is sterile carrier, water-based or non-aqueous liquid suspensions form, or can be answered before use with water or other suitable carriers Former dry product.Liquid preparation can include conventional additives, such as suspending agent, emulsifying agent, wetting agent, non-aqueous carrier (including Edible oil), preservative and flavouring agent and/or colouring agent.Bestowed in order to parenteral, usual carrier is at least most of including nothing Bacterium water, but saline solution, glucose solution etc. can also be used.Injectable suspensions can also be used, in this case, can To use Conventional suspending agents.Conventional preservatives, buffer reagent etc. can also be added in parenteral dosage form.Pharmaceutical composition passes through It is prepared by the suitable routine techniques of required preparation comprising appropriate active component (i.e. compound of Formula I of the invention).
Composition suitable for parenteral injection can include physiologically being subjected to sterile aqueous or non-aqueous solution, disperse Liquid, suspension or emulsion and for sterile injectable solution or the aseptic powdery of dispersion liquid.Suitable water-based and non-aqueous carrier, Diluent, solvent example include water, ethanol, polyalcohol (propane diols, polyethylene glycol, glycerine etc.), its suitable mixture, Vegetable oil (for example, olive oil) and injectable organic ester (for example, ethyl oleate).
These compositions can also include various excipient, for example, preservative, wetting agent, emulsifying agent and dispersant.Can be with Ensured by various antiseptics and antifungal agent (for example, p-hydroxybenzoate, methaform, phenol, sorbic acid etc.) to micro- The suppression of the effect of biology.Isotonic agent can also be included, for example, sugar, sodium chloride etc..Can be by using delay absorption reagent (for example, aluminum monostearate and gel) extends the absorption of injectable pharmaceutical formulation.
Include capsule, tablet, pill, powder and particle for oral solid dosage forms.In this solid dosage forms, by work Property compound mixes with least one inertia excipients (or carrier) (for example, sodium citrate or Dicalcium Phosphate), wherein can be with Including：(a) filler or intermixture (for example, starch, lactose, sucrose, glucose, mannitol and silicic acid)；(b) binding agent (for example, Carboxy methyl cellulose, alginic acid ester, gel, PVP, sucrose and gum arabic)；(c) NMF (example Such as, glycerine)；(d) disintegrant is (for example, aga agar, calcium carbonate, potato or tapioca, alginic acid, some synthesis Esters of silicon acis, sodium carbonate)；(e) solution retarding agents (for example, paraffin)；(f) sorbefacient (for example, quaternary ammonium compound)；(g) moisten Humectant (for example, hexadecanol and monostearate glycerine ester)；(h) adsorbent (for example, kaolin and bentonite) and (i) lubrication Agent (for example, talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, NaLS) or the mixing of its mixture.
The solid composite of similar type can also be being used such as lactose and high molecular weight polyethylene glycol as tax Filler is used as in the soft filling of type agent and hard gel filled capsule.
Solid dosage forms (for example, tablet, dragee, capsule, pill and particle) can use coating and shell (for example, intestines Road coating and known in the art other) prepare.They can include opacifier, and they can also be with delayed mode in intestines The composition of release of active compounds or various reactive compounds in certain part in road.The example of available embedding composition is Polymeric material and wax.Active component if appropriate, can also can have in one or more with microencapsulated form State excipients.
Liquid dosage forms for oral administration includes pharmaceutically acceptable emulsion, solution, dispersion liquid, syrup and elixir.Except work Property compound beyond, liquid dosage form can include conventionally used inert diluent (for example, water or other solvents) in this area, Solubilizer and emulsifying agent (for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, phenmethylol, benzyl benzoate, propane diols, 1,3 butanediol, dimethyl formyl ammonium), oil (specifically, cottonseed oil, arachis oil, corn oil, olive oil, castor oil, sesame Oil), glycerine, tetrahydrofuran alcohol, polyethylene glycol and the mixture of the fatty acid ester of sorbitan or these materials etc..
Except these inert diluents, composition can also include, for example, wetting agent, emulsification and suspending agent, sweetening agent, Flavor enhancement and aromatizing agent.
Except reactive compound, suspension can include suspending agent, such as ethoxylation isooctadecane alcohol, polyethylene glycol oxide Sorbierite, sorbitan ester, microcrystalline cellulose, inclined aluminium hydroxide, bentonite, aga agar and tragacanth or these materials it is mixed Compound etc..
The forms for topical administration of the compound of the present invention includes ointment, powder, spraying and inhalant.The active component exists Under aseptic condition with physiologically acceptable carriers and any required preservative, buffer or propellants.It is ophthalmically acceptable to match somebody with somebody Side, spongaion, powder and solution are intended to be included within the scope of the present invention.
Can be appropriate as needed by those skilled in the art in the amount of pharmaceutical composition and dosage form formula of I compound Ground is determined, such as compounds of formula I can be present in pharmaceutical composition or formulation with therapeutically effective amount.
4.The dosage of the compound of the present invention
Herein, term " therapeutically effective amount " is when giving the compound of the present invention to patient, effectively can to delay or disappear Except patient symptom or the dosage of improvement patient health status.The concrete condition that specifically application dose can be by doctor according to patient To determine.The exact dose to be used depends not only on route of administration, illness, wants the sanatory order of severity, Yi Jiyu The related various physical factors of treated individual, and can be determined according to the judgement of health care practitioner.Optional use External or in vivo studies assists in optimal dose scope.
For example, the present invention compound of Formula I can with about 0.01-4000mg daily (or 0.05-2000mg or 0.1-1000mg or 0.1-500mg) dosage give patient.For the adult that normal body weight is about 70 kilograms, dosage Can be that for example about 0.001- about 100mg/ kg body weights or 0.01- about 100mg/ kg body weights or 0.05- be about daily 50mg/ kg body weights.However, specific dosage used can change.It is known to those skilled in the art for particular patient how Determine optimal dosage.
Daily dose described above periodically can be bestowed continuously, for example, every 2 hours, it is every 6 hours, for every eight hours, it is every 12 small When, about every 24 hours apply once, or every 2 days, daily, weekly, every two weeks, it is every three weeks, be administered once a month.Corresponding to whole The dosage and frequency of the individual course for the treatment of determine the judgement according to health care practitioner.In one embodiment, it is of the invention Compound or its pharmaceutically-acceptable salts be administered simultaneously with another therapeutic reagent.
In one embodiment, the compound of the invention or its that effective dose is included in same composition can be applied in The composition of pharmaceutically-acceptable salts and another therapeutic reagent of effective dose.The effective dose of other treatment reagent is this area skill Known to art personnel.Moreover, determine cognitive range of the scope in those of skill in the art of the best available amount of other treatment reagent Within.
5.The preparation method of the compounds of this invention
The compounds of formula I of the present invention can be used in a variety of methods known to the technical staff of organic synthesis field and close Into.Some exemplary synthetic methods are following present, these methods are well known to synthesis chemical field.Retouched according to following The combination or change of the method and synthetic organic chemist's commonly used approach and these methods stated synthesizes formula I's Compound.The synthetic route of compound in the present invention is not limited to following summarized method.Individual compound may need to adjust Operating condition is saved to meet the requirement of various functional groups.Various blocking groups well known by persons skilled in the art are probably necessary 's.If desired, purifying can in the silicagel column eluted with appropriate organic solvent system by or recrystallized Into.In addition, the method that this paper each specific embodiment also illustrate that synthesis the compounds of this invention.
The compound of the present invention is mainly adopted the following technical scheme that to synthesize.
R3The acetoacetic ester raw material (I-0) of group substitution occurs alkylated reaction and obtains intermediate in the basic conditions I-1.Intermediate compound I -1 occurs two substitutions (disubstituted in the embodiment having can be with ring) and obtains centre in the basic conditions again Body I-2.Intermediate compound I -2 reacts generation pyrroles intermediate compound I -3 with ammonium acetate under acid medium；Preferable acid medium is second Acid；Reaction temperature is that room temperature to acid medium flows back；Preferable reaction temperature is 80 DEG C and arrives acetic acid reflux temperature.Pyrroles's intermediate I-3 through three-step reaction highly basic (such as lithium hydroxide, sodium hydroxide, potassium hydroxide etc.) hydrolysis obtain carboxylic acid, gained carboxylic acid again with HOBT and DCC react HOBT Acibenzolars, last Acibenzolar (react through malonate and NaH and are made) with malonate sodium salt again Obtain three carbonyl intermediates I-4.Three carbonyl intermediates I-4 obtain cyclization product I-5 through alkali process；Preferable alkali is sodium methoxide. I-5 finally heats to obtain embodiment compound I-X in the basic conditions with amino acid；Preferable alkali is sodium methoxide, preferable temperature Degree is methanolic reflux temperature.
(more than, base represents alkali, and malonate represents malonate)
The Representative synthetic procedures of the I-X compounds of the representative example as compound of Formula I illustrated above, this area Technical staff understands：By suitably selecting different reactants, using same or similar synthetic method, can obtain and I-X Other different compound of Formula I of the substituent of compound.
In addition, the specific reaction condition of each step can be by those skilled in the art according to normal in each synthetic schemes above The principle to chemically react and requirement are advised suitably to determine.And the reaction condition provided in following embodiments of the invention can To be used as reference.
Specific embodiment
Illustrate the present invention in conjunction with the embodiments further below；But these embodiments are not limit the scope of the invention.
The structure of compound is determined by liquid chromatograph mass spectrography (LCMS) or nuclear magnetic resonance (NMR).Nmr chemical Displacement (δ) is with 10-6(ppm) unit represents.The measure of nuclear-magnetism Bruker-500 type NMRs, measure solvent are deuterium For dimethyl sulfoxide (DMSO) (DMSO-d6), deuterochloroform (CDCl3) etc., inside it is designated as tetramethylsilane (TMS).LCMS Shimadzu LCMS-2020 is determined.
Tlc silica gel plate uses Yantai, Shandong Province Huanghai Sea HSGF254 or Shandong Province Qingdao GF254 silica gel plates.Column chromatography It is carrier typically using the mesh silica gel of Yantai, Shandong Province Huanghai Sea silica gel 200 to 300.
All initiation materials that the present invention uses be purchased from chemical supplier or can by literature method synthesize and .
It is as follows that the middle abbreviation used is described herein：
DMSO-d6：The dimethyl sulfoxide (DMSO) that six hydrogen atoms are all substituted by deuterium
CDCl3:Deuterochloroform
CAS：Chemical abstracts accession number
NMR:Nuclear magnetic resonance
LCMS：Liquid chromatography-mass spectrography
ESI：Electron spray ionisation
ppm:Hundred a ten thousandths
δ：Chemical shift of NMR
TMS：Tetramethylsilane
s:Nuclear-magnetism is unimodal
d:Nuclear-magnetism doublet
t:Nuclear-magnetism triplet
br:Nuclear-magnetism broad peak
CDI：Carbonyl dimidazoles
DCC：N, N '-dicyclohexylcarbodiimide
HOBT：1H- benzos [d] [1,2,3] triazole -1- alcohol
NBS：N- bromo ring succimides
Embodiment 1
(7'- hydroxyls -5'- oxo -1'- phenyl -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) glycine (1)
The first step
5- (1,3- dioxolane -2- bases) -3- oxo -4- phenylpentanoic acids ethyl ester (1b)
By 3- oxos -4-phenylbutyrate ethyl ester (1.03g, according to document【European Journal of Medicinal Chemistry,2014,vol 84,312-334】It is prepared by methods described) it is dissolved in anhydrous tetrahydro furan (20 milliliters), ice-water bath Cooling, add the mineral oil and sodium hydride hybrid solid (200 millis of 60% purity under nitrogen flowing the slow aliquot of an aliquot one Gram), stir 0.5 hour；Then hexamethyl phosphoramide (2.7 grams) and 1.6M lithium hexane solution (3.13 are sequentially added Milliliter)；Then 2- bromomethyl -1,3- dioxolanes (840 milligrams) are added.React on and be stirred overnight at room temperature.Reaction solution is small The heart is poured into saturated aqueous ammonium chloride, is then extracted with ethyl acetate；Ethyl acetate layer is separated, it is then water-soluble with dilute sodium chloride Liquid washes twice；Ethyl acetate phase is dried with anhydrous sodium sulfate solid；It is filtered to remove drier, filtrate on Rotary Evaporators in revolving It is dry；Residue purifies to obtain product through column chromatography1b(870 milligrams).LCMS ESI(+):293(M+1)+。
Second step
1- (3- (1,3- dioxolane -2- bases) -2- PHENYLPROPIONYLs) pentamethylene -1- Ethyl formates(1c)
By product 5- (1,3- dioxolane -2- the bases) -3- oxo -4- phenylpentanoic acids ethyl ester of previous step (1b) (580 millis Gram), the butyl iodide of Isosorbide-5-Nitrae-two (620 milligrams), Anhydrous potassium carbonate (830 milligrams) and tetrabutylammonium iodide (74 milligrams) are mixed in Dimethylformamide (10 milliliters), is stirred overnight at room temperature.Reaction solution is diluted with water, is carefully added into the acidifying of 2M diluted hydrochloric acid aqueous solutions Arrive pH4 or so；Then it is extracted with ethyl acetate；Ethyl acetate layer is separated, is then washed twice with the dilute sodium chloride aqueous solution；With nothing Aqueous sodium persulfate solid dries ethyl acetate phase；It is filtered to remove drier, filtrate on Rotary Evaporators in being spin-dried for；Residue is through post layer Analysis purifying obtains product1c(415 milligrams).LCMS ESI(+):347(M+1)+。
3rd step
1- (3- phenyl -1H- pyrroles -2- bases) pentamethylene -1- Ethyl formates (1d)
By product 1- (3- (1,3- dioxolane -2- bases) -2- PHENYLPROPIONYLs) pentamethylene -1- Ethyl formates of previous step (1c) (1 equivalent) and ammonium acetate (6 equivalent) be mixed in acetic acid (3 volume), return stirring is overnight.Cooling, reaction solution is being rotated It is spin-dried for, is then diluted with water, then be extracted with ethyl acetate as far as possible on evaporimeter；Ethyl acetate layer is separated, then uses dilute sodium chloride The aqueous solution washes twice；Ethyl acetate phase is dried with anhydrous sodium sulfate solid；Drier is filtered to remove, filtrate is in Rotary Evaporators On be spin-dried for；Residue purifies to obtain product through column chromatography1d。LCMS ESI(+):284(M+1)+。
4th step
2- (1- (3- phenyl -1H- pyrroles -2- bases) pentamethylene -1- carbonyls) dimethyl malenate (1e)
By product 1- (3- phenyl -1H- pyrroles -2- bases) pentamethylene -1- Ethyl formates of previous step (1d) (1 equivalent) suspension In the second alcohol and water (totally 10 volume) of volume ratio 1/1, lithium hydroxide monohydrate solid (4 equivalent) is added；It is small in 50 DEG C of reactions 5 When.Cooling, is diluted with water, is carefully added into 2M diluted hydrochloric acid aqueous solutions and is acidified to pH4 or so after having reacted；Then extracted with ethyl acetate Take；Ethyl acetate layer is separated, is then washed twice with the dilute sodium chloride aqueous solution；Ethyl acetate is dried with anhydrous sodium sulfate solid Phase；It is filtered to remove drier, filtrate is in being spin-dried for obtaining residue on Rotary Evaporators.
Gained residue, 1H- benzos [d] [1,2,3] triazole -1- alcohol (1.2 equivalent) and DCC (1.2 equivalent) are mixed above Together in tetrahydrofuran (4 volume), and it is stirred at room temperature 1 hour.Solid is filtered to remove, it is solid with the washing of a small amount of anhydrous tetrahydro furan Body, merging filtrate and cleaning solution.
Dimethyl malenate (1.2 equivalent) is dissolved in anhydrous tetrahydro furan (4 volume), ice-water bath in another reaction bulb Cool down, the mineral oil and sodium hydride hybrid solid (1.2 equivalent) of 60% purity are carefully added under nitrogen stream；Stirring 1 hour.Then Above-mentioned filtrate and cleaning solution are added in second reaction bulb；Stirring reaction 1 hour.It is diluted with water, is carefully added into 2M watery hydrochloric acid water Solution is acidified to pH4 or so；Then it is extracted with ethyl acetate；Ethyl acetate layer is separated, is then washed with the dilute sodium chloride aqueous solution Twice；Ethyl acetate phase is dried with anhydrous sodium sulfate solid；It is filtered to remove drier, filtrate on Rotary Evaporators in being spin-dried for.It is residual Thing is stayed to purify to obtain product through column chromatography1e。LCMS ESI(+):370(M+1)+。
5th step
7'- hydroxyls -5'- oxo -1'- phenyl -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- methyl formates (1f)
By product 2- (1- (3- phenyl -1H- pyrroles -2- bases) pentamethylene -1- carbonyls) dimethyl malenate of previous step (1e) (1 equivalent) and 0.5M methanol solution of sodium methylate (1 equivalent) mixing；It is stirred at room temperature 5 minutes.Reaction solution is diluted with water, It is carefully added into 2M diluted hydrochloric acid aqueous solutions and is acidified to pH4 or so；Then it is extracted with ethyl acetate；Separate ethyl acetate layer, Ran Houyong The dilute sodium chloride aqueous solution washes twice；Ethyl acetate phase is dried with anhydrous sodium sulfate solid；Drier is filtered to remove, filtrate is in rotation Turn to be spin-dried on evaporimeter；Residue purifies to obtain product through column chromatography1f。LCMS ESI(+):338(M+1)+。
6th step
(7'- hydroxyls -5'- oxo -1'- phenyl -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) glycine (1)
By the product 7'- hydroxyl -5'- oxo -1'- phenyl -5'H- loop coils [pentamethylene -1,8'- indolizines] of previous step - 6'- methyl formates (1f) (1 equivalent), glycine (6 equivalent) and 0.5M methanol solution of sodium methylate (5 equivalent) mixing；It is spin-dried for；So Afterwards plus normal propyl alcohol (5 volume), flow back 2 hours.Cooling, reaction solution is diluted with water, and is carefully added into the acidifying of 2M diluted hydrochloric acid aqueous solutions Arrive pH4 or so；Separate out solid；Solid is collected by filtration, is washed with water solid；Then it is dried to obtain product1。LCMS ESI(+): 381(M+1)+。
Embodiment 2
(1'- (4- difluorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls Base) glycine (2)
The first step
5- (1,3- dioxolane -2- bases) -4- (4- difluorophenyls) -3- oxopentanoic acid methyl esters (2b)
Compound2bAccording to the first step of embodiment 11bSynthetic method prepare, wherein raw material2a：4- (4- difluorophenyls)- Ethyl 3-oxobutanoate is according to document【European Journal of Medicinal Chemistry,2014,vol 84, 312-334】It is prepared by methods described.LCMS ESI(+):311(M+1)+。
Second step
1- (3- (1,3- dioxolane -2- bases) -2- (4- difluorophenyls) propiono) pentamethylene -1- Ethyl formates (2c)
Compound2cAccording to the second step of embodiment 11cSynthetic method from compound2bPrepare.LCMS ESI(+):365(M +1)+。
3rd step
1- (3- (4- difluorophenyls) -1H- pyrroles 0-2- yls) pentamethylene -1- Ethyl formates (2d)
Compound2dAccording to the step of embodiment 1 the 3rd1dSynthetic method from compound2cPrepare.LCMS ESI(+):302(M +1)+。
4th step
2- (1- (3- (4- difluorophenyls) -1H- pyrroles -2- bases) pentamethylene -1- carbonyls) dimethyl malenate (2e)
Compound2eAccording to the step of embodiment 1 the 4th1eSynthetic method from compound2dPrepare.LCMS ESI(+):388(M +1)+。
5th step
1'- (4- difluorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- formic acid Methyl esters (2f)
Compound2fAccording to the step of embodiment 1 the 5th1fSynthetic method from compound2ePrepare.LCMS ESI(+):356(M +1)+。
6th step
(7'- hydroxyls -5'- oxo -1'- phenyl -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) glycine (2)
Compound2Synthetic method according to the step 1 of embodiment 1 the 6th is from compound2fPrepare.LCMS ESI(+):399(M+ 1)+。
Embodiment 3
(1'- (4- difluorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls Base) glycine ethyl ester (3)
Compound2(1 equivalent) is suspended in ethanol (5 volume), and thionyl chloride (4 equivalent) is carefully added dropwise；It is then refluxed for straight It is complete to reaction.Naturally cool to and room temperature and then cooled down with ice-water bath, solid is collected by filtration and washs solid with cold ethanol produces Compound3。LCMS ESI(+):427(M+1)+。
Embodiment 4
(1'- (4- difluorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls Base)-ALANINE (4)
Compound4According to the step of embodiment 1 the 6th1Synthetic method from compound2fPrepared with ALANINE.LCMS ESI (+):413(M+1)+。
Embodiment 5
(1'- (4- difluorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls Base)-D-alanine (5)
Compound5According to the step of embodiment 1 the 6th1Synthetic method from compound2fPrepared with D-alanine.LCMS ESI (+):413(M+1)+。
Embodiment 6
(1'- (4- chlorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls Base) glycine (6)
The first step
5- (1,3- dioxolane -2- bases) -4- (4- chlorophenyls) -3- oxopentanoic acid methyl esters (6b)
Compound6bAccording to the first step of embodiment 11bSynthetic method prepare, wherein raw material6a：4- (4- chlorophenyls)- Ethyl 3-oxobutanoate is according to document【European Journal of Medicinal Chemistry,2014,vol 84, 312-334】It is prepared by methods described.LCMS ESI(+):327(M+1)+。
Second step
1- (3- (1,3- dioxolane -2- bases) -2- (4- chlorophenyls) propiono) pentamethylene -1- Ethyl formates (6c)
Compound6cAccording to the second step of embodiment 11cSynthetic method from compound6bPrepare.LCMS ESI(+):381(M +1)+。
3rd step
1- (3- (4- chlorophenyls) -1H- pyrroles -2- bases) pentamethylene -1- Ethyl formates (6d)
Compound6dAccording to the step of embodiment 1 the 3rd1dSynthetic method from compound6cPrepare.LCMS ESI(+):318(M +1)+。
4th step
2- (1- (3- (4- chlorophenyls) -1H- pyrroles -2- bases) pentamethylene -1- carbonyls) dimethyl malenate (6e)
Compound6eAccording to the step of embodiment 1 the 4th1eSynthetic method from compound6dPrepare.LCMS ESI(+):404(M +1)+。
5th step
1'- (4- chlorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- formic acid Methyl esters (6f)
Compound6fAccording to the step of embodiment 1 the 5th1fSynthetic method from compound6ePrepare.LCMS ESI(+):372(M +1)+。
6th step
(1'- (4- chlorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls Base) glycine (6)
Compound6According to the step of embodiment 1 the 6th1Synthetic method from compound6fPrepare.LCMS ESI(+):415(M+ 1)+。
Embodiment 7
(7'- hydroxyls -1'- (4- methoxyphenyls) -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls Base) glycine (7)
The first step
5- (1,3- dioxolane -2- bases) -4- (4- methoxyphenyls) -3- oxopentanoic acid methyl esters (7b)
Compound7bAccording to the first step of embodiment 11bSynthetic method prepare, wherein raw material7a：4- (4- methoxybenzenes Base)-ethyl 3-oxobutanoate is according to document【European Journal of Medicinal Chemistry,2014,vol 84,312-334】It is prepared by methods described.LCMS ESI(+):323(M+1)+。
Second step
1- (3- (1,3- dioxolane -2- bases) -2- (4- methoxyphenyls) propiono) pentamethylene -1- Ethyl formates (7c)
Compound7cAccording to the second step of embodiment 11cSynthetic method from compound7bPrepare.LCMS ESI(+):377(M +1)+。
3rd step
1- (3- (4- methoxyphenyls) -1H- pyrroles -2- bases) pentamethylene -1- Ethyl formates (7d)
Compound7dAccording to the step of embodiment 1 the 3rd1dSynthetic method from compound7cPrepare.LCMS ESI(+):314(M +1)+。
4th step
2- (1- (3- (4- methoxyphenyls) -1H- pyrroles -2- bases) pentamethylene -1- carbonyls) dimethyl malenate (7e)
Compound7eAccording to the step of embodiment 1 the 4th1eSynthetic method from compound7dPrepare.LCMS ESI(+):400(M +1)+。
5th step
7'- hydroxyls -1'- (4- methoxyphenyls) -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- first Sour methyl esters (7f)
Compound7fAccording to the step of embodiment 1 the 5th1fSynthetic method from compound7ePrepare.LCMS ESI(+):368(M +1)+。
6th step
(7'- hydroxyls -1'- (4- methoxyphenyls) -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls Base) glycine (7)
Compound7According to the step of embodiment 1 the 6th1Synthetic method from compound7fPrepare.LCMS ESI(+):411(M+ 1)+。
Embodiment 8
(1'- (3,4- difluoro-benzenes base) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- Carbonyl) glycine (8)
The first step
4- (3,4- difluoro-benzenes base) -5- (1,3- dioxolane -2- bases) -3- oxopentanoic acid methyl esters (8b)
Compound8bAccording to the first step of embodiment 11bSynthetic method prepare, wherein raw material8a：4- (3,4- difluoro-benzenes Base)-ethyl 3-oxobutanoate is according to document【European Journal of Medicinal Chemistry,2014,vol 84,312-334】It is prepared by methods described.LCMS ESI(+):329(M+1)+。
Second step
1- (2- (3,4- difluoro-benzenes base) -3- (1,3- dioxolane -2- bases) propiono) pentamethylene -1- Ethyl formates (8c)
Compound8cAccording to the second step of embodiment 11cSynthetic method from compound8bPrepare.LCMS ESI(+):383(M +1)+。
3rd step
1- (3- (3,4- difluoro-benzenes base) -1H- pyrroles -2- bases) pentamethylene -1- Ethyl formates (8d)
Compound8dAccording to the step of embodiment 1 the 3rd1dSynthetic method from compound8cPrepare.LCMS ESI(+):320(M +1)+。
4th step
2- (1- (3- (3,4- difluoro-benzenes base) -1H- pyrroles -2- bases) pentamethylene -1- carbonyls) dimethyl malenate (8e)
Compound8eAccording to the step of embodiment 1 the 4th1eSynthetic method from compound8dPrepare.LCMS ESI(+):406(M +1)+。
5th step
1'- (3,4- difluoro-benzenes base) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- Methyl formate (8f)
Compound8fAccording to the step of embodiment 1 the 5th1fSynthetic method from compound8ePrepare.LCMS ESI(+):374(M +1)+。
6th step
(7'- hydroxyls -1'- (3,4- difluoro-benzenes base) -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- Carbonyl) glycine (8)
Compound8According to the step of embodiment 1 the 6th1Synthetic method from compound8fPrepare.LCMS ESI(+):417(M+ 1)+。
Embodiment 9
(7'- hydroxyls -5'- oxo -1'- phenyl -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls) glycine (9)
The first step
1- (3- (1,3- dioxolane -2- bases) -2- PHENYLPROPIONYLs) hexamethylene -1- Ethyl formates (9c)
Compound9cAccording to the second step of embodiment 11cSynthetic method from compound2bPrepared with the iodo-pentanes of 1,5- bis-. LCMS ESI(+):361(M+1)+。
Second step
1- (3- phenyl -1H- pyrroles -2- bases) hexamethylene -1- Ethyl formates (9d)
Compound9dAccording to the step of embodiment 1 the 3rd1dSynthetic method from compound9cPrepare.LCMS ESI(+):298(M +1)+。
3rd step
2- (1- (3- phenyl -1H- pyrroles -2- bases) hexamethylene -1- carbonyls) dimethyl malenate (9e)
Compound9eAccording to the step of embodiment 1 the 4th1eSynthetic method from compound9dPrepare.LCMS ESI(+):384(M +1)+。
4th step
7'- hydroxyls -5'- oxo -1'- phenyl -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- methyl formates (9f)
Compound9fAccording to the step of embodiment 1 the 5th1fSynthetic method from compound9ePrepare.LCMS ESI(+):352(M +1)+。
5th step
(7'- hydroxyls -5'- oxo -1'- phenyl -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls) glycine
Compound9According to the step of embodiment 1 the 6th1Synthetic method from compound9fPrepare.LCMS ESI(+):395(M+ 1)+。
Embodiment 10
(1'- (4- difluorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls Base) glycine (10)
The first step
1- (3- (1,3- dioxolane -2- bases) -2- (4- difluorophenyls) propiono) hexamethylene -1- Ethyl formates (10c)
Compound10cAccording to the second step of embodiment 11cSynthetic method from compound2bPrepared with the iodo-pentanes of 1,5- bis-. LCMS ESI(+):378(M+1)+。
Second step
1- (3- (4- difluorophenyls) -1H- pyrroles -2- bases) hexamethylene -1- Ethyl formates (10d)
Compound10dAccording to the step of embodiment 1 the 3rd1dSynthetic method from compound10cPrepare.LCMS ESI(+):316 (M+1)+。
3rd step
2- (1- (3- (4- difluorophenyls) -1H- pyrroles -2- bases) hexamethylene -1- carbonyls) dimethyl malenate (10e)
Compound10eAccording to the step of embodiment 1 the 4th1eSynthetic method from compound10dPrepare.LCMS ESI(+):402 (M+1)+。
4th step
1'- (4- difluorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- formic acid Methyl esters (10f)
Compound10fAccording to the step of embodiment 1 the 5th1fSynthetic method from compound10ePrepare.LCMS ESI(+):370 (M+1)+。
5th step
(1'- (4- difluorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls Base) glycine (10)
Compound10According to the step of embodiment 1 the 6th1Synthetic method from compound10fPrepare.LCMS ESI(+):413(M +1)+。
Embodiment 11
(1'- (4- chlorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls Base) glycine (11)
The first step
1- (3- (1,3- dioxolane -2- bases) -2- (4- chlorophenyls) propiono) hexamethylene -1- Ethyl formates (11c)
Compound11cAccording to the second step of embodiment 11cSynthetic method from compound6bPrepared with the iodo-pentanes of 1,5- bis-. LCMS ESI(+):395(M+1)+。
Second step
1- (3- (4- chlorophenyls) -1H- pyrroles -2- bases) hexamethylene -1- Ethyl formates (11d)
Compound11dAccording to the step of embodiment 1 the 3rd1dSynthetic method from compound11cPrepare.LCMS ESI(+):332 (M+1)+。
3rd step
2- (1- (3- (4- chlorophenyls) -1H- pyrroles -2- bases) hexamethylene -1- carbonyls) dimethyl malenate (11e)
Compound11eAccording to the step of embodiment 1 the 4th1eSynthetic method from compound11dPrepare.LCMS ESI(+):418 (M+1)+。
4th step
1'- (4- chlorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- formic acid Methyl esters (11f)
Compound11fAccording to the step of embodiment 1 the 5th1fSynthetic method from compound11ePrepare.LCMS ESI(+):386 (M+1)+。
5th step
(1'- (4- chlorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls Base) glycine (11)
Compound11According to the step of embodiment 1 the 6th1Synthetic method from compound11fPrepare.LCMS ESI(+):429(M +1)+。
Embodiment 12
(7'- hydroxyls -1'- (4- methoxyphenyls) -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls Base) glycine (12)
The first step
1- (3- (1,3- dioxolane -2- bases) -2- (4- methoxyphenyls) propiono) hexamethylene -1- Ethyl formates (12c)
Compound12cAccording to the second step of embodiment 11cSynthetic method from compound7bPrepared with the iodo-pentanes of 1,5- bis-. LCMS ESI(+):391(M+1)+。
Second step
1- (3- (4- methoxyphenyls) -1H- pyrroles -2- bases) hexamethylene -1- Ethyl formates (12d)
Compound12dAccording to the step of embodiment 1 the 3rd1dSynthetic method from compound12cPrepare.LCMS ESI(+):328 (M+1)+。
3rd step
2- (1- (3- (4- methoxyphenyls) -1H- pyrroles -2- bases) hexamethylene -1- carbonyls) dimethyl malenate (12e)
Compound12eAccording to the step of embodiment 1 the 4th1eSynthetic method from compound12dPrepare.LCMS ESI(+):414 (M+1)+。
4th step
7'- hydroxyls -1'- (4- methoxyphenyls) -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- first Sour methyl esters (12f)
Compound12fAccording to the step of embodiment 1 the 5th1fSynthetic method from compound12ePrepare.LCMS ESI(+):382 (M+1)+。
5th step
(7'- hydroxyls -1'- (4- methoxyphenyls) -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls Base) glycine (12)
Compound12According to the step of embodiment 1 the 6th1Synthetic method from compound12fPrepare.LCMS ESI(+):425(M +1)+。
Embodiment 13
(1'- (4- chlorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [cyclobutane -1,8'- indolizines] -6'- carbonyls Base) glycine (13)
The first step
1- (2- (4- chlorophenyls) -3- (1,3- dioxolane -2- bases) propiono) cyclobutane -1- Ethyl formates (13c)
Compound13cAccording to the second step of embodiment 11cSynthetic method from compound6bPrepared with the bromo propane of 1,3- bis-. LCMS ESI(+):367(M+1)+。
Second step
1- (3- (4- chlorophenyls) -1H- pyrroles -2- bases) cyclobutane -1- Ethyl formates (13d)
Compound13dAccording to the step of embodiment 1 the 3rd1dSynthetic method from compound13cPrepare.LCMS ESI(+):304 (M+1)+。
3rd step
2- (1- (3- (4- chlorophenyls) -1H- pyrroles -2- bases) cyclobutane -1- carbonyls) dimethyl malenate (13e)
Compound13eAccording to the step of embodiment 1 the 4th1eSynthetic method from compound13dPrepare.LCMS ESI(+):390 (M+1)+。
4th step
1'- (4- chlorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [cyclobutane -1,8'- indolizines] -6'- formic acid Methyl esters (13f)
Compound13fAccording to the step of embodiment 1 the 5th1fSynthetic method from compound13ePrepare.LCMS ESI(+):358 (M+1)+。
5th step
(1'- (4- chlorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [cyclobutane -1,8'- indolizines] -6'- carbonyls Base) glycine (13)
Compound13According to the step of embodiment 1 the 6th1Synthetic method from compound13fPrepare.LCMS ESI(+):401(M +1)+。
Embodiment 14
(1'- cyclohexyl -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) sweet ammonia Acid (14)
The first step
4- cyclohexyl -5- (1,3- dioxolane -2- bases) -3- oxopentanoic acid methyl esters (14b)
Compound14bAccording to the first step of embodiment 11bSynthetic method prepare, wherein raw material14a：4- cyclohexyl -3- oxygen For ethyl butyrate according to document【European Journal of Medicinal Chemistry,2014,vol 84,312- 334】It is prepared by methods described.LCMS ESI(+):299(M+1)+。
Second step
1- (2- cyclohexyl -3- (1,3- dioxolane -2- bases) propiono) pentamethylene -1- Ethyl formates (14c)
Compound14cAccording to the second step of embodiment 11cSynthetic method from compound14bPrepare.LCMS ESI(+):353 (M+1)+。
3rd step
1- (3- cyclohexyl -1H- pyrroles -2- bases) pentamethylene -1- Ethyl formates (14d)
Compound14dAccording to the step of embodiment 1 the 3rd1dSynthetic method from compound14cPrepare.LCMS ESI(+):290 (M+1)+。
4th step
2- (1- (3- cyclohexyl -1H- pyrroles -2- bases) pentamethylene -1- carbonyls) dimethyl malenate (14e)
Compound14eAccording to the step of embodiment 1 the 4th1eSynthetic method from compound14dPrepare.LCMS ESI(+):376 (M+1)+。
5th step
1'- cyclohexyl -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- methyl formates (14f)
Compound14fAccording to the step of embodiment 1 the 5th1fSynthetic method from compound14ePrepare.LCMS ESI(+):344 (M+1)+。
6th step
(1'- cyclohexyl -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) sweet ammonia Acid (14)
Compound14According to the step of embodiment 1 the 6th1Synthetic method from compound14fPrepare.LCMS ESI(+):387(M +1)+。
Embodiment 15
(1'-7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) glycine (15)
The first step
5- (1,3- dioxolane -2- bases) -3- oxopentanoic acid methyl esters (15a)
10 grams of ethyl acetoacetates are dissolved in anhydrous tetrahydro furan, are cooled to 0 degree Celsius, are then carefully added portionwise Sodium hydride (60% mineral oil mixture, 3.07 grams)；Half an hour is stirred at room temperature after adding；Then hexamethyl phosphoramide is added (13.7 grams), subzero 78 degree are cooled to, are carefully added into the hexane solution (48 milliliters, concentration 1.6M) of n-BuLi, then add 2- bromomethyl -1,3- dioxolanes (CAS:4360-63-8,12.9 grams).Reaction solution is stirred at room temperature overnight.
After reaction terminates, add saturated aqueous ammonium chloride and be quenched；Add ethyl acetate to extract, separating ethyl acetate layer, Then washed twice with the dilute sodium chloride aqueous solution；Organic phase anhydrous sodium sulfate drying, filter, concentration, residue is through silicagel column Chromatographic purifying obtains product15a(6.2 grams, brown oil).1H NMR(500MHz,DMSO-d6)δ(ppm):4.93-4.91 (t,1H),4.21-3.83(m,6H),3.46(s,2H),2.69-2.66(t,2H),2.02-1.99(m,2H),1.29-1.27 (t,3H)。
Second step
1- (3- (1,3- dioxolane -2- bases) propiono) pentamethylene -1- Ethyl formates (15b)
By compound15a(6.2 grams), the iodobutanes of 1,4- bis- (8.89 grams), potassium carbonate (11.9 grams) and tetra-n-butyl iodate Ammonium (1.06 grams) is mixed in DMF (62 milliliters), is then stirred at room temperature overnight.
Then, ethyl acetate (60 milliliters) is added, filters out solid；Filtrate is collected, filtrate extracts in ethyl acetate and water Take, collect organic phase, then organic phase is through the washing of the dilute sodium chloride aqueous solution twice, anhydrous sodium sulfate drying；Filtering, concentration are residual Thing is stayed to purify to obtain brown oil through silica gel column chromatography,15b(5.7 grams).1H NMR(500MHz,DMSO-d6)δ(ppm): 5.08-5.06(t,1H),4.14-3.84(m,6H),3.50(d,2H),2.11(s,2H),1.18-1.16(t,3H)。
3rd step
1- (1H- pyrroles -2- bases) pentamethylene -1- Ethyl formates (15c)
Compound15b(5.1 grams) backflow 16 hours in acetic acid (51 milliliters) with ammonium acetate (8.73 grams).Then, cool down, Rotation pumps most acetic acid, adds ethyl acetate and water extraction；Ethyl acetate layer is collected, then is washed with the dilute sodium chloride aqueous solution To wash twice, with anhydrous sodium sulfate drying, filter, concentration, residue purifies to obtain white solid product through silica gel column chromatography,15c (2.4 grams).1H NMR(500MHz,CDCl3)δ(ppm):8.54(s,1H),6.76-6.06(m,3H),4.18-4.14(d,2H), 2.46-1.72(m,8H),1.25-1.24(t,3H)。
4th step
1- (1H- pyrroles -2- bases) pentamethylene -1- formic acid (15d)
Compound 15c (1.2 grams) is mixed in the ethanol water of 20 milliliters of isometric ratios with lithium hydroxide monohydrate (1.5 grams) In, stirred 5 hours in 50 degrees Celsius.
Then, reaction solution cools down, and adds ethyl acetate and water, adds 2M hydrochloric acid and be acidified to aqueous phase pH 2-3 or so.Point From ethyl acetate layer, ethyl acetate layer washes twice through the dilute sodium chloride aqueous solution, then through anhydrous sodium sulfate drying, filters, concentration Obtain product15d(1.05 grams).LCMS ESI(+):180(M+1)+。
5th step
5'- hydroxyl -7'- oxo -7'H- loop coils [pentamethylene -1,8'- indolizines] -6'- Ethyl formates (15f)
By compound15d(1.05 grams), HOBT hydrates (874 milligrams), DCC (1.34 grams) are mixed in tetrahydrofuran (20 Milliliter) in, it is stirred at room temperature 1 hour；Compound is filtered, collects filtrate.Malonic acid two is added in another reaction bulb Ethyl ester (1.04 grams) and tetrahydrofuran；0 degree Celsius is cooled to, carefully adds (260 milligrams of sodium hydride portionwise；60%, mineral oil Mixture), stir 1 hour；Then above-mentioned filtrate adds and continues to be stirred at room temperature 1 hour.Now system is15eWith15f's Mixture；Then a small amount of alcohol sodium alcohol solution is added, continues stirring until not having intermediate 15e.
Then, react through ethyl acetate and water extraction, add watery hydrochloric acid acidifying；Ethyl acetate layer is collected, then through dilute chlorination Sodium water solution washes twice, anhydrous sodium sulfate drying, filtering, concentration, column chromatography purify to obtain product15f。1H NMR (500MHz,CDCl3)δ(ppm):15.3(s,1H),7.45(br,1H),6.29(br,1H),6.07(br,1H),4.25(m, 2H),2.5-1.5(m,8H),1.26(t,3H)。
6th step
(1'-7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) glycine (15)
Compound15According to the 6th step in embodiment 11Synthetic method from compound15fPrepare.1H NMR(500MHz, DMSO-d6)δ(ppm):18.6(s,1H),13.0(s,1H),9.91(br,1H),7.39(br,1H),6.37(br,1H),6.25 (s,1H),4.13(d,2H),4.15-4.11(2H,d,HNCH2CO),2.32(m,2H),2.1-1.7(m,6H)。LCMS ESI (+):305(M+1)+。
Embodiment 16
(1'-7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls)-ALANINE (16)
Compound 16 is according to the 6th step in embodiment 11Synthetic method from compound15fPrepared with ALANINE.1H NMR(500MHz,DMSO-d6) δ 13.30 (s, 1H), 10.04 (s, 1H), 7.38 (dd, J=3.3,1.6Hz, 1H), 6.37 (t, J =3.3Hz, 1H), 6.25 (dd, J=3.3,1.6Hz, 1H), 4.52 (p, J=7.1Hz, 1H), 2.31 (m, 2H), 1.99-1.85 (m, 6H), 1.46 (d, J=7.2Hz, 3H).
Embodiment 17
(1'-7'- hydroxyl -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls) glycine (17)
The first step
1- (3- (1,3- dioxolane -2- bases) propiono) hexamethylene -1- Ethyl formates (17b)
Compound17bAccording to second step in embodiment 1515bSynthesis (replace 1,4- diiodo- fourths with pentamethylene bromide Alkane, potassium carbonate is replaced with cesium carbonate) method be prepared.1H NMR(500MHz,CDCl3)δ(ppm):4.87-4.85(t, 1H),4.19-3.80(m,2H),,2.59-2.56(d,2H),2.08-1.29(m,10H),1.26-1.23(t,3H)。
Second step
1- (1H- pyrroles -2- bases) hexamethylene -1- Ethyl formates (17c)
Compound17cAccording to the 3rd step in embodiment 1515cThe method of synthesis be prepared.LCMS ESI(+):222 (M+1)+。
3rd step
1- (1H- pyrroles -2- bases) hexamethylene -1- formic acid (17d)
Compound17dAccording to the 4th step in embodiment 1515dThe method of synthesis be prepared.LCMS ESI(-):192 (M+1)+。
4th step
5'- hydroxyl -7'- oxo -7'H- loop coils [hexamethylene -1,8'- indolizines] -6'- formic acid add ester (17f)
Compound17fAccording to the 5th step in embodiment 1515fSynthesis method (wherein alcohol sodium alcohol solution methanol The replacement of sodium methanol solution) it is prepared.1H NMR(500MHz,CDCl3)δ(ppm):8.31(s,1H),6.71(m,1H),6.12 (m,1H),6.04(m,1H),3.68(s,3H),1.8-1.2(m,10H),12H)。
5th step
(1'-7'- hydroxyl -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls) glycine (17)
Compound17According to the 6th step in embodiment 1515Synthetic method from compound17fIt is prepared.1H NMR (500MHz,DMSO-d6)δ(ppm):18.9(s,1H),13.1(s,1H),9.95(br,1H),7.45(dd,1H),6.52(dd, 1H), 6.38 (t, 1H), 1H, s, OH), 4.12 (d, J=5.5Hz, 2H), 2.1-1.95 (m, 2H), 1.8-1.6 (m, 6H), 1.5- 1.4(m,2H)。LCMS ESI(+):319(M+1)+。
Pharmacological activity is evaluated
1. effect of the compound to the activity of proline hydroxylase -2
The measure of proline hydroxylase activity slightly changed according to literature method (Anal Biochem, 2004,330:74- 80).96 orifice plates are handled 30 minutes with retarding agent casein and 1mM biotin in advance, the HIF-1 α for then connecting biotin 556-574 (biotinyl-DLDLEMLAPYIPMDDDFQL) are fixed on 96 orifice plates.Then 96 orifice plates are contained with appropriate HIF-PHD2 buffer solution (20mM Tris (pH 7.5), 5mM KCl, 1.5mM MgCl2,20mM 2-oxoglutarate (2-oxoglutaric acid), 10mM FeSO4, 2mM ascorbic acid, 4% be free of EDTA protease inhibitors) at room temperature be incubated 1 to 60 minutes.Reactant mixture also includes the prolyl hydroxylase inhibitors to be tested of various concentrations.Rinsed with lavation buffer solution 96 orifice plates terminating reaction three times.(50mM tri- (hydroxymethyl)-aminomethane, pH7.5,120mM in 100 μ l combination buffers NaCl), by the Eu-VBC albumen in hydroxylated HIF-1 α 556-574 and combination buffer in room temperature reaction 60 minutes.Suction out Reaction solution, the Eu-VBC albumen washed off for 3 times and be not bound with is rinsed with elution buffer.Then add 10 μ l rabbit-antis Eu-VBC's Polyclonal antibody.After 30 minutes, the immune ball of anti-rabbit that 10 μ l are coupled to HRPO is added in combination buffer Albumen.In order to determine the amount of the Eu-VBC albumen of combination, cultivated 15 minutes with TMB.Terminate to show by adding 100 μ l 1M sulfuric acid Colour response.By the content that the Eu-VBC albumen that spectrodensitometry combines is determined in 450nm.It and hydroxyl in peptide substrates The amount of the proline of change is directly proportional.
IC in following table50For representational data.These numerical value only represent the data that applicant measures when filing an application. Due to the variation of reagent, measuring condition and mode of operation in method presented above, the IC of test50Data may show some changes Change；Therefore, these values should regard relativity rather than critical value as.
Above IC50The compound of the as shown by data present invention can effectively suppress proline hydroxylase.
2. effect of the embodiment compound to mouse hemoglobin
To the oral 30mg/kg of male C57Bl/6 mouse (Shanghai Slac Experimental Animal Co., Ltd.) of 8-10 weeks Test compound (his (CAS of positive control sieve sauce:Dosage 808118-40-3) is 60mg/kg), administration 3 times a week continues Administration 2 weeks；With after last time administration 6 hours before being administered respectively in first time, about 30 μ l blood is taken from lower jaw vein, is utilized Hemocue hemoglobin determinators determine the content of hemoglobin.Hemoglobin lift-off value is blood red after last time is administered Protein value is subtracted to the Hemoglobin Value before first time medicine.
In addition, using Luo Shasi he as positive control with same method hemoglobin testing lift-off value.Luo Shasi he purchase From Selleckchem, the compound is the effective inhibitor of proline hydroxylase known in the art, can increase hemoglobin Generation.
Listed by following table is the hemoglobin lift-off value of representational compound.
Embodiment Hemoglobin lift-off value (g/dL)
1 3.5
6 3.0
7 2.2
9 1.1
10 1.9
11 2.0
15 1.8
16 1.7
17 1.0
Luo Shasi he 1.7
As can be known from the above table, under same measuring condition, compound of the invention shows that with Luo Shasi he is suitable, even More preferable hemoglobin lift-off value, this shows that the compound of the present invention can stablize hypoxia inducible by suppressing proline hydroxylase The factor, through but not limited to increase hematopoietin generation and rise hemoglobin, so as to for treat and/or Prevent the medicine of the diseases related to hypoxia inducible factor such as anaemia.
Although having illustrated and having described embodiments of the present invention, it is not meant to that these embodiments are illustrated and retouched That has stated the present invention is possible to form.More properly, word used in this specification is only that descriptive word is not Restricted, it should be noted that, various change can be carried out and without departing from the spirit and scope of the present invention.

Claims (20)

1. the compound shown in formula I
Or its compound isotopically labelled or its optical isomer, geometric isomer, dynamic isomer or isomer mixture, Or its pharmaceutically useful salt or its precursor medicine,
Wherein：
R1And R2Independently selected from cyano group, alkyl, heterocyclic radical, alkenyl, alkynyl, aryl, heteroaryl, acyl group, amino, R9O-、 R9S-、R9(O=) S-, R9(O=)2S-, R therein9It is alkyl, heterocyclic radical, alkenyl, alkynyl, aryl or heteroaryl；Wherein, on Alkyl, heterocyclic radical, alkenyl, alkynyl, aryl, heteroaryl, acyl group, the amino stated optionally are taken by one or more substituents In generation, substituent therein is independently selected from halogen, cyano group, hydroxyl, amino, carboxyl, acyl group, alkyl, heterocyclic radical, alkenyl, alkynes Base, aryl, heteroaryl ,=O ,=S ,-SH, R10O-、R10S-、R10(O=) S-, R10(O=)2S-, R therein10It is alkyl, miscellaneous Ring group, alkenyl, alkynyl, aryl or heteroaryl；Or R1And R2It is combined cyclization；
R3、R4And R5Independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano group, amino, acyl group, alkyl, heterocyclic radical, alkenyl, alkynes Base, aryl, heteroaryl, R11O-、R11S-、R11(O=) S-, R11(O=)2S-, wherein R11Be alkyl, heterocyclic radical, alkenyl, alkynyl, Aryl or heteroaryl；Wherein, above-mentioned alkyl, heterocyclic radical, alkenyl, alkynyl, aryl, heteroaryl, acyl group, amino optionally by One or more substituents are substituted, substituent therein independently selected from halogen, cyano group, hydroxyl, amino, carboxyl, acyl group, Alkyl, heterocyclic radical, alkenyl, alkynyl, aryl, heteroaryl ,=O ,=S ,-SH, R12O-、R12S-、R12(O=) S-, R12(O=)2S-, R therein12It is alkyl, heterocyclic radical, alkenyl, alkynyl, aryl or heteroaryl；
R6And R6’Independently selected from hydrogen and optionally substituted alkyl；
R7Selected from hydrogen, alkyl and acyl group；Wherein alkyl and acyl group are optionally substituted by following group：Halogen, cyano group, hydroxyl, ammonia Base, carboxyl, acyl group, alkyl, heterocyclic radical, alkenyl, alkynyl, aryl, heteroaryl ,=O ,=S ,-SH, R13O-、R13S-、R13(O=) S-、R13(O=)2S-, R therein13It is alkyl, heterocyclic radical, alkenyl, alkynyl, aryl or heteroaryl；
R8Selected from hydrogen, alkyl and-OC (O) R14, R therein14It is alkyl, heterocyclic radical, alkenyl, alkynyl, aryl or heteroaryl； Wherein alkyl, heterocyclic radical, alkenyl, alkynyl, aryl or heteroaryl are optionally substituted by following group：Halogen, cyano group, hydroxyl, Amino, carboxyl, acyl group, alkyl, heterocyclic radical, alkenyl, alkynyl, aryl, heteroaryl ,=O ,=S ,-SH, R15O-、R15S-、R15(O =) S-, R15(O=)2S-；R therein15It is alkyl, heterocyclic radical, alkenyl, alkynyl, aryl or heteroaryl；
X is oxygen atom or sulphur atom or NH.
2. compound as claimed in claim 1 or its compound isotopically labelled or its optical isomer, geometric isomer, Dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine, wherein
R1And R2Independently selected from cyano group, C1-C12 alkyl groups, C2-C12 alkenyls, C2-C12 alkynyl groups, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, the Heterocyclylalkyl containing 3 to 8 annular atoms, the heterocycloalkenyl containing 3 to 8 annular atoms, containing 5 Heteroaryl, C1-C12 alkyl groups-C (=O) to 14 annular atoms-, C2-C12 alkenyls-C (=O)-, amino, R9O-、R9S-、 R9(O=) S-, R9(O=)2S-, R therein9It is C1-C12 alkyl groups, C2-C12 alkenyls, C2-C12 alkynyl groups, C6-C14 virtues Base, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, the Heterocyclylalkyl containing 3 to 8 annular atoms, the heterocycloalkenyl containing 3 to 8 annular atoms； Wherein, above-mentioned C1-C12 alkyl groups, C2-C12 alkenyls, C2-C12 alkynyl groups, C6-C14 aryl, C3-C8 cycloalkyl, C3- C8 cycloalkenyl groups, the Heterocyclylalkyl containing 3 to 8 annular atoms, the heterocycloalkenyl containing 3 to 8 annular atoms, containing 5 to 14 annular atoms Heteroaryl, C1-C12 alkyl groups-C (=O)-, C2-C12 alkenyls-C (=O)-, amino optionally takes by 1 to 3 substituent Generation, substituent therein independently selected from hydroxyl, halogen, cyano group, amino, carboxyl, C1-C6 alkyl groups, C3-C8 cycloalkyl, C2-C6 alkenyls-, C2-C6 alkynyl groups-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, C6-C14 aryl, containing 5 to 14 annular atoms Heteroaryl, C1-C6 alkyl groups-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyls-O-, C2-C6 alkynyl groups-O-, C3-C8 rings Alkenyl-O-, C6-C14 aryl-O-, the heteroaryl-O- containing 5 to 14 annular atoms, C1-C6 alkyl groups-S-, C3-C8 cycloalkyl- S-, C2-C6 alkenyl-S-, C2-C6 alkynyl groups-S-, C3-C8 cycloalkenyl groups-S-, C6-C14 aryl-S-, containing 5 to 14 annular atoms Heteroaryl-S-, the Heterocyclylalkyl containing 3 to 8 annular atoms, the heterocycloalkenyl containing 3 to 8 annular atoms ,=O ,=S ,-SH ,- CF3、-CO2C1-C6Alkyl group, C1-C6 alkyl groups-S-, C1-C6 alkyl groups (O=) S- and C1-C6 alkyl groups (O=)2S-；Or
R1And R2It is combined to form the optionally substituted cycloalkanes hydrocarbon ring containing 3-8 annular atom, cyclenes hydrocarbon ring, heterocycloalkane Ring, heterocyclic alkene ring；
R3、R4And R5Independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano group, C1-C12 alkyl groups, C2-C12 alkenyls, C2- C12 alkynyl groups, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, the Heterocyclylalkyl containing 3 to 8 annular atoms, containing 3 to 8 The heterocycloalkenyl of individual annular atom, the heteroaryl containing 5 to 14 annular atoms, C1-C12 alkyl groups-C (=O)-, C2-C12 alkenyls- C (=O)-, amino, R11O-、R11S-、R11(O=) S-, R11(O=)2S-, R therein11It is C1-C12 alkyl groups, C2-C12 chains Alkenyl, C2-C12 alkynyl groups, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, the heterocycle alkane containing 3 to 8 annular atoms Base, the heterocycloalkenyl containing 3 to 8 annular atoms；Wherein, above-mentioned C1-C12 alkyl groups, C2-C12 alkenyls, C2-C12 alkynes Base, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, the Heterocyclylalkyl containing 3 to 8 annular atoms, containing 3 to 8 annular atoms Heterocycloalkenyl, the heteroaryl containing 5 to 14 annular atoms, C1-C12 alkyl groups-C (=O)-, C2-C12 alkenyls-C (=O)-, Amino is optionally substituted by 1 to 3 substituent, and substituent therein is independently selected from hydroxyl, halogen, cyano group, amino, carboxylic Base, C1-C6 alkyl groups, C3-C8 cycloalkyl, C2-C6 alkenyls-, C2-C6 alkynyl groups-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, C6-C14 aryl, the heteroaryl containing 5 to 14 annular atoms, C1-C6 alkyl groups-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyls- O-, C2-C6 alkynyl group-O-, C3-C8 cycloalkenyl groups-O-, C6-C14 aryl-O-, heteroaryl-O-, C1- containing 5 to 14 annular atoms C6 alkyl groups-S-, C3-C8 cycloalkyl-S-, C2-C6 alkenyls-S-, C2-C6 alkynyl groups-S-, C3-C8 cycloalkenyl groups-S-, C6- C14 aryl-S-, the heteroaryl-S- containing 5 to 14 annular atoms, the Heterocyclylalkyl containing 3 to 8 annular atoms, containing 3 to 8 annular atoms Heterocycloalkenyl ,=O ,=S ,-SH ,-CF3、-CO2C1-C6Alkyl group, C1-C6 alkyl groups-S-, C1-C6 alkyl groups (O=) S- With C1-C6 alkyl groups (O=)2S-；
R6And R6’Independently selected from hydrogen, C1-C6 alkyl groups and C3-C8 cycloalkyl；Above-mentioned C1-C6 alkyl groups and C3-C8 cycloalkyl Optionally substituted by 1 to 3 substituent, substituent therein independently selected from hydroxyl, halogen, cyano group, amino, carboxyl, C1-C6 alkyl groups, C3-C8 cycloalkyl, C2-C6 alkenyls-, C2-C6 alkynyl groups-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, C6- C14 aryl, the heteroaryl containing 5 to 14 annular atoms, C1-C6 alkyl groups-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyls-O-, C2-C6 alkynyl groups-O-, C3-C8 cycloalkenyl groups-O-, C6-C14 aryl-O- and the heteroaryl-O- containing 5 to 14 annular atoms；
R7Selected from hydrogen, C1-C6 alkyl groups, C3-C8 cycloalkyl, C1-C6 alkyl groups-C (=O)-and C2-C6 alkenyls-C (= O)-；Wherein C1-C6 alkyl groups, C3-C8 cycloalkyl, C1-C6 alkyl groups-C (=O)-, C2-C6 alkenyls-C (=O)-optionally Substituted by 1 to 3 substituent, substituent therein is independently selected from hydroxyl, halogen, cyano group, amino, carboxyl, C1-C6 chains Alkyl, C3-C8 cycloalkyl, C2-C6 alkenyls-, C2-C6 alkynyl groups-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, C6-C14 virtue Base, the heteroaryl containing 5 to 14 annular atoms, C1-C6 alkyl groups-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyls-O-, C2-C6 Alkynyl group-O-, C3-C8 cycloalkenyl groups-O-, C6-C14 aryl-O- and the heteroaryl-O- containing 5 to 14 annular atoms；
R8Selected from hydrogen, C1-C12 alkyl groups, C3-C8 cycloalkyl and-OC (O)-C1-C12 alkyl groups；Wherein C1-C12 alkyl groups, C3-C8 cycloalkyl and-OC (O)-C1-C12 alkyl groups are optionally substituted by 1 to 3 substituent, and substituent therein is independently Selected from hydroxyl, halogen, cyano group, amino, carboxyl, C1-C6 alkyl groups, C3-C8 cycloalkyl, C2-C6 alkenyls-, C2-C6 alkynes Base-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl groups, C6-C14 aryl, the heteroaryl containing 5 to 14 annular atoms, C1-C6 alkyl groups- O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyls-O-, C2-C6 alkynyl groups-O-, C3-C8 cycloalkenyl groups-O-, C6-C14 aryl-O-, With the heteroaryl-O- containing 5 to 14 annular atoms；
X is oxygen atom or sulphur atom or NH.
3. compound as claimed in claim 2 or its compound isotopically labelled or its optical isomer, geometric isomer, Dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine, wherein
R1And R2Independently selected from cyano group, amino, unsubstituted C1-C6 alkyl groups；Or R1And R2It is combined to be formed containing 3-8 The optionally substituted cycloalkanes hydrocarbon ring or heterocycloalkane ring of individual annular atom.
4. compound as claimed in claim 3 or its compound isotopically labelled or its optical isomer, geometric isomer, Dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine, wherein
R1And R2Independently selected from methyl, ethyl；Or R1And R2It is combined to form cyclopropane ring, cyclobutane ring, pentamethylene Ring, cyclohexane ring, cycloheptane ring, tetrahydrofuran ring or amylene oxide ring or through these methyl substituted rings.
5. compound or its compound isotopically labelled or its optical isomer, geometry as described in claim any one of 1-4 Isomers, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine, wherein
R3、R4And R5Independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano group, amino, C1-C6 alkyl groups, C6-C14 aryl, C3-C8 cycloalkyl, C1-C6 alkyl groups-O-, the heteroaryl containing 5 to 14 annular atoms；Wherein, above-mentioned C1-C6 alkyl groups, C6- C14 aryl, C3-C8 cycloalkyl, C1-C6 alkyl groups-O-, the heteroaryl containing 5 to 14 annular atoms, amino are optionally by 1 to 3 Substituent is substituted, and substituent therein is independently selected from hydroxyl, halogen, cyano group, amino, carboxyl, C6-C14 aryl and C1- C6 alkyl groups.
6. compound as claimed in claim 5 or its compound isotopically labelled or its optical isomer, geometric isomer, Dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine, wherein
R3、R4And R5Independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano group, amino, methyl, ethyl, propyl group, butyl, phenyl, Benzyl, tolyl, anisyl, chlorphenyl, fluorophenyl, bromophenyl, dimethoxy phenyl, dichlorophenyl, difluorophenyl, dibromobenzene Base, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and pyridine radicals.
7. compound or its compound isotopically labelled or its optical isomer, geometry as described in claim any one of 1-6 Isomers, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine, wherein
R6And R6’Independently selected from hydrogen, unsubstituted C1-C6 alkyl groups, unsubstituted C3-C8 cycloalkyl and 1-3 halogen substitution C1-C6 alkyl groups.
8. compound as claimed in claim 7 or its compound isotopically labelled or its optical isomer, geometric isomer, Dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine, wherein
R6And R6’Independently selected from hydrogen, methyl, ethyl, propyl group, cyclopropyl and cyclobutyl.
9. compound or its compound isotopically labelled or its optical isomer, geometry as described in claim any one of 1-8 Isomers, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine, wherein
R7Selected from hydrogen, unsubstituted C1-C6 alkyl groups, unsubstituted C1-C6 alkyl groups-C (=O)-and unsubstituted C2-C6 Alkenyl-C (=O)-.
10. compound as claimed in claim 9 or its compound isotopically labelled or its optical isomer, geometric isomer, Dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine, wherein
R7Selected from hydrogen, methyl, ethyl, formoxyl and acetyl group.
It is 11. compound or its compound isotopically labelled or its optical isomer as described in claim any one of 1-10, several What isomers, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine, wherein
R8Selected from hydrogen, C1-C6 alkyl groups and-OC (O)-C1-C12 alkyl groups；Wherein C1-C6 alkyl groups and-OC (O)-C1- C12 alkyl groups are optionally substituted by 1 to 3 substituent, and substituent therein is independently selected from hydroxyl, halogen, cyano group, ammonia Base, carboxyl, C1-C6 alkyl groups and C1-C6 alkyl groups-O-.
12. compound as claimed in claim 11 or its compound isotopically labelled or its optical isomer, geometrical isomerism Body, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine, wherein
R8Selected from hydrogen, methyl, ethyl, propyl group, butyl, amyl group, formyloxy, acetoxyl group, propionyloxy, butyryl acyloxy and Valeryl epoxide.
13. compound as claimed in claim 1 or its compound isotopically labelled or its optical isomer, geometric isomer, Dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine, wherein：R1And R2Independently selected from Yu Jia Base, ethyl, or R1And R2It is combined to form cyclopropane ring, cyclobutane ring, pentamethylene ring, cyclohexane ring or through methyl substitute These rings；R3、R4And R5Independently selected from hydrogen, halogen, methyl, ethyl, propyl group, butyl, cyclohexyl, phenyl and above-mentioned The group that group is substituted by halogen or methyl or methoxy；R6And R6’Independently selected from hydrogen, methyl, ethyl, propyl group, butyl；R7 Selected from hydrogen, methyl, ethyl；R8Selected from hydrogen, methyl, ethyl, propyl group, butyl；X is oxygen atom.
14. selected from the compound such as the following group or its compound isotopically labelled or its optical isomer, geometric isomer, change Isomers or isomer mixture or its pharmaceutically useful salt or its precursor medicine,
(7'- hydroxyls -5'- oxo -1'- phenyl -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) glycine；
(1'- (4- difluorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) is sweet Propylhomoserin；
(1'- (4- difluorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) is sweet Propylhomoserin ethyl ester；
(1'- (4- difluorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls)-L- Alanine；
(1'- (4- difluorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls)-D- Alanine；
(1'- (4- chlorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) is sweet Propylhomoserin；
(7'- hydroxyls -1'- (4- methoxyphenyls) -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) Glycine；
(1'- (3,4- difluoro-benzenes base) -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls Base) glycine；
(7'- hydroxyls -5'- oxo -1'- phenyl -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls) glycine；
(1'- (4- difluorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls) is sweet Propylhomoserin；
(1'- (4- chlorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls) is sweet Propylhomoserin；
(7'- hydroxyls -1'- (4- methoxyphenyls) -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls) Glycine；
(1'- (4- chlorophenyls) -7'- hydroxyl -5'- oxo -5'H- loop coils [cyclobutane -1,8'- indolizines] -6'- carbonyls) is sweet Propylhomoserin；
(1'- cyclohexyl -7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) glycine；
(1'-7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls) glycine；
(1'-7'- hydroxyl -5'- oxo -5'H- loop coils [pentamethylene -1,8'- indolizines] -6'- carbonyls)-ALANINE；
(1'-7'- hydroxyl -5'- oxo -5'H- loop coils [hexamethylene -1,8'- indolizines] -6'- carbonyls) glycine.
15. a kind of pharmaceutical composition, it contains the compound or its isotope mark as described in any one in claim 1-14 Remember compound or its optical isomer, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or Its precursor medicine, and one or more pharmaceutically acceptable carriers, adjuvant or excipient.
16. compound or its compound isotopically labelled or its optical siomerism as described in any one in claim 1-14 Body, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine are preparing proline Purposes in hydroxylase inhibitors.
17. compound or its compound isotopically labelled or its optical siomerism as described in any one in claim 1-14 Body, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine are being prepared for controlling Treat and/or the medicine of the prevention disease related to hypoxia inducible factor in purposes.
18. purposes as claimed in claim 17, wherein the disease related to hypoxia inducible factor is selected from：Anaemia (for example, Essential anemia, kidney anaemia, with tumor disease the anaemia anaemia of chemotherapy induction (particularly), by caused anaemia of losing blood, Hypoferric anemia, vitamin-deficiency anaemia, hypopsials and alpastic anemia, hemolytic anemia, iron mistake usability are poor Anaemia etc. caused by blood, hypothyroidism), angiocardiopathy is (for example, cardiac insufficiency, coronary heart diseases and angina pectoris, cardiac muscle Infarct, apoplexy, artery sclerosis, spontaneous hypertension, pulmonary hypertension, accelerated hypertension and peripheral arterial occlusive disease), god Through disease, HIV infectious diseases, rheumatoid arthritis, the ischaemic relevant with operation, birth asphyxia, cancer and cancer phase Pass symptom (such as infringement of the health status occurred after with cytostatics, antibiotic and radiation therapy), illness in eye (such as it is blue or green Light eye), central nervous system disease (such as dull-witted, the chronic pain sensation), chronic kidney disease, renal insufficiency and acute renal failure, property Dysfunction (such as sexual hypoesthesia), diabetes and complication (such as diabetic vascular disease and microangiopathy, diabetic nephropathy), Nerve degenerative diseases (such as Alzheimer's, Parkinson's disease etc.), ischemic disease (such as ischemic cerebral vascular Disease, ischemic nephropathy, ischemic cardiomyopathy etc.) and fibrotic conditions (such as the heart, lung and fibrosis of liver).
19. compound or its compound isotopically labelled or its optical siomerism as described in any one in claim 1-14 Body, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine are being prepared for outer Purposes in section's operation accelerating wound healing and/or the medicine of shortening recovery time.
20. compound or its compound isotopically labelled or its optical siomerism as described in any one in claim 1-14 Body, geometric isomer, dynamic isomer or isomer mixture or its pharmaceutically useful salt or its precursor medicine are thin for increasing blood The purposes of born of the same parents' specific volume.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108484598A (en) * 2017-05-09 2018-09-04 杭州安道药业有限公司 Indole derivative and its application in medicine
WO2019096089A1 (en) * 2017-11-14 2019-05-23 杭州安道药业有限公司 Indolizine derivative and application thereof in medicine
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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007136990A2 (en) * 2006-05-16 2007-11-29 Smithkline Beecham Corporation Prolyl hydroxylase inhibitors
CN102471337A (en) * 2009-07-17 2012-05-23 日本烟草产业株式会社 Triazolopyridine compound, and action thereof as prolyl hydroxylase inhibitor or erythropoietin production-inducing agent
WO2013043621A1 (en) * 2011-09-23 2013-03-28 Merck Sharp & Dohme Corp. Substituted pyrimidines
WO2016049099A1 (en) * 2014-09-28 2016-03-31 Merck Sharp & Dohme Corp. Inhibitors of hif prolyl hydroxylase
CN106146395A (en) * 2015-03-27 2016-11-23 沈阳三生制药有限责任公司 3-hydroxypyridine compound, its preparation method and pharmaceutical applications thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2446416T3 (en) * 2005-12-09 2014-03-07 Amgen, Inc. Quinolone-based compounds that have prolyl hydroxylase inhibitory activity, compositions and uses thereof
EP2097416B1 (en) * 2006-12-18 2012-09-12 Amgen, Inc Azaquinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
CN107739378A (en) * 2017-11-14 2018-02-27 杭州安道药业有限公司 Indole derivative and its application in medicine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007136990A2 (en) * 2006-05-16 2007-11-29 Smithkline Beecham Corporation Prolyl hydroxylase inhibitors
CN102471337A (en) * 2009-07-17 2012-05-23 日本烟草产业株式会社 Triazolopyridine compound, and action thereof as prolyl hydroxylase inhibitor or erythropoietin production-inducing agent
WO2013043621A1 (en) * 2011-09-23 2013-03-28 Merck Sharp & Dohme Corp. Substituted pyrimidines
WO2016049099A1 (en) * 2014-09-28 2016-03-31 Merck Sharp & Dohme Corp. Inhibitors of hif prolyl hydroxylase
CN106146395A (en) * 2015-03-27 2016-11-23 沈阳三生制药有限责任公司 3-hydroxypyridine compound, its preparation method and pharmaceutical applications thereof

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108484598A (en) * 2017-05-09 2018-09-04 杭州安道药业有限公司 Indole derivative and its application in medicine
WO2018205928A1 (en) * 2017-05-09 2018-11-15 杭州安道药业有限公司 Indolizine derivatives and application thereof in medicine
AU2018264313B2 (en) * 2017-05-09 2020-06-04 Kind Pharmaceutical Indolizine derivatives and application thereof in medicine
US11021478B2 (en) 2017-05-09 2021-06-01 Kind Pharmaceutical Indolizine derivatives and their application in medicine
US11655249B2 (en) 2017-05-09 2023-05-23 Kind Pharmaceutical Indolizine derivatives and their application in medicine
US11945817B2 (en) 2017-05-09 2024-04-02 Kind Pharmaceutical Indolizine derivatives and their application in medicine
US11970495B2 (en) 2017-05-09 2024-04-30 Kind Pharmaceutical Indolizine derivatives and their application in medicine
WO2019096089A1 (en) * 2017-11-14 2019-05-23 杭州安道药业有限公司 Indolizine derivative and application thereof in medicine
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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