WO2024061172A1 - 一种脯氨酰羟化酶抑制剂及其用途 - Google Patents

一种脯氨酰羟化酶抑制剂及其用途 Download PDF

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WO2024061172A1
WO2024061172A1 PCT/CN2023/119468 CN2023119468W WO2024061172A1 WO 2024061172 A1 WO2024061172 A1 WO 2024061172A1 CN 2023119468 W CN2023119468 W CN 2023119468W WO 2024061172 A1 WO2024061172 A1 WO 2024061172A1
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nitrogen
oxygen
group
heterocyclic group
substituted
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French (fr)
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唐海涛
汤凡
葛海涛
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苏中药业集团股份有限公司
江苏苏中药业研究院有限公司
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Publication of WO2024061172A1 publication Critical patent/WO2024061172A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medical technology, and specifically relates to a pyridotriazole compound with prolyl hydroxylase inhibitory effect and its pharmaceutical composition, and further relates to its preparation method and its pharmaceutical use.
  • hypoxia inducible factor is a transcription factor activated by somatic cells under hypoxia. It responds to cellular hypoxia by mediating a series of gene regulation in biological cells.
  • HIF is a heterodimer containing an oxygen-regulated ⁇ -subunit (HIF ⁇ ) and a constitutively expressed ⁇ -subunit (HIF ⁇ /ARNT).
  • HIF ⁇ subunit In oxygenated (normoxic) cells, the HIF ⁇ subunit is rapidly ubiquitinated by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. degradation. Under hypoxic conditions, HIF ⁇ is not degraded, and the active HIF ⁇ / ⁇ complex accumulates in the nucleus and activates the expression of various genes, including glycolytic enzymes, glucose transporters, erythropoietin (EPO), and vasculature. Endothelial growth factor (VEGF).
  • pVHL von Hippel-Lindau tumor suppressor
  • Erythropoietin is a naturally occurring hormone produced with HIF ⁇ that stimulates the production of red blood cells (red blood cells) that carry oxygen throughout the body. EPO is normally secreted by the kidneys, and endogenous EPO increases under conditions of reduced oxygen (hypoxia). All types of anemia are characterized by a reduction in the blood's ability to carry oxygen and are associated with similar signs and symptoms, including pale skin and mucous membranes, weakness, dizziness, fatigue, and lethargy, resulting in a reduced quality of life. Anemia is usually associated with a lack of blood in red blood cells or hemoglobin.
  • anemia Common causes of anemia include iron, vitamin B12, and folate deficiencies, which can also be complicated by chronic diseases, such as inflammatory diseases, including those with secondary inflammatory suppression of the bone marrow.
  • Anemia is also associated with renal dysfunction, and most patients with renal failure who undergo frequent dialysis have chronic anemia.
  • Prolyl hydroxylase domain is a key factor in regulating HIF.
  • PHD can hydroxylate the two key proline residues Pro402 and Pro564 of HIF ⁇ , increasing its affinity with pVHL and accelerating the degradation process.
  • hypoxia and other pathological conditions the HIF reaction catalyzed by PHD is blocked and the degradation rate of protease is slowed down, causing HIF ⁇ to accumulate in cells, which in turn triggers a series of adaptive responses of cells to hypoxia.
  • PHD inhibitors prolonging the effect of HIF, and thereby increasing the expression of EPO and other genes, it can effectively treat and prevent HIF-related and/or EPO-related diseases, such as anemia, ischemia and hypoxia.
  • U.S. patent application US16757333 discloses a crystal form of an alkynylpyridine-based paraamyl hydroxylase inhibitor and a preparation method thereof.
  • the structural formula of the alkynylpyridine-based paraamyl hydroxylase inhibitor is as follows:
  • the object of the present invention is to provide a pyridotriazole compound as a HIF-PHD inhibitor and a pharmaceutical composition thereof, which can be used to treat various HIF-related or EPO-related diseases, such as anemia.
  • the present invention provides a compound represented by formula (I) or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, and pharmaceutically acceptable salts or prodrug;
  • R is a unit selected from the following atoms or groups:
  • L is -CH 2 - or -CH 2 O-;
  • n is an integer between 0 and 2;
  • R 1 , R 2 , and R 3 are each independently selected from substituted or unsubstituted alkyl, cycloalkyl, aryl, and heterocyclic groups.
  • the aryl group includes an aromatic heterocycle.
  • L is -CH 2 - or -CH 2 O-;
  • n 0 or 1
  • R 1 is a substituted or unsubstituted C 1-4 alkyl group, phenyl group, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group, oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group, so
  • the substituents are C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, cyano, phenyl, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group, At least one of the 5-6-membered heterocyclic groups containing oxygen and/or nitrogen;
  • R 2 is a substituted or unsubstituted C 1-4 alkyl group, phenyl group, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group, oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group, so
  • the substituents are C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, cyano, phenyl, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group, At least one of the 5-6-membered heterocyclic groups containing oxygen and/or nitrogen;
  • R 3 is a substituted or unsubstituted C 1-10 alkyl group, phenyl group, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group, oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group, so
  • the substituents are C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, cyano, phenyl or oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group, At least one of 5-6 membered heterocyclic groups containing oxygen and/or nitrogen.
  • R 4 is selected from at least one of hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, and heterocyclyl.
  • L is -CH 2 - or -CH 2 O-;
  • n 0 or 1
  • R 1 is substituted or unsubstituted phenyl, and the substituent is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, cyano, phenyl or oxygen-containing and/ Or at least one of a nitrogen-containing 5-6-membered aromatic heterocyclic group and an oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group;
  • R 2 is substituted or unsubstituted phenyl, and the substituent is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, cyano, phenyl, oxygen-containing and/ Or at least one of a nitrogen-containing 5-6-membered aromatic heterocyclic group and an oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group;
  • R 3 is a substituted or unsubstituted C 1-10 alkyl group, phenyl group, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group, oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group, so
  • the substituents are C 1-4 alkyl, C 1-4 alkoxy, halogen, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group, oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group at least one of the bases.
  • R 4 is hydrogen, at least one of substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, and heterocyclyl.
  • R 4 is hydrogen, substituted or unsubstituted C 1-10 alkyl, C 1-10 alkoxy, phenyl, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group, oxygen-containing and/or Or nitrogen 5-6 membered heterocyclyl, the substituent is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, cyano, phenyl or oxygen-containing and/ Or at least one of a nitrogen-containing 5-6-membered aromatic heterocyclic group and an oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group.
  • R 4 is hydrogen, substituted or unsubstituted C 1-10 alkyl, C 1-10 alkoxy, phenyl, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group, oxygen-containing and/or Or nitrogen 5-6 membered heterocyclic group, the substituent is C 1-4 alkyl, C 1-4 alkoxy, halogen, oxygen and/or nitrogen-containing 5-6 membered aromatic heterocyclic group, containing At least one of the 5-6 membered heterocyclic groups of oxygen and/or nitrogen.
  • n 0 or 1
  • R 1 is a substituted or unsubstituted phenyl group, and the substituent is a C 1-4 alkyl group, a C 1-4 alkoxy group, a halogen, an oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or a 5-6-membered aromatic heterocyclic group containing 5-6 membered heterocyclic group of oxygen and/or nitrogen; preferably, the C 1-4 alkyl group, C 1-4 alkoxy group, 5-6 membered aromatic heterocyclic group containing oxygen and/or nitrogen or The 5-6-membered heterocyclic group containing oxygen and/or nitrogen is substituted in the para position relative to the parent core structure, and the halogen is substituted in the ortho position, meta position or para position relative to the parent core structure;
  • R 2 is a substituted or unsubstituted phenyl group, and the substituent is a C 1-4 alkyl group, a C 1-4 alkoxy group, a halogen or an oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or a Oxygen and/or nitrogen 5-6 membered heterocyclic group;
  • R 3 is a substituted or unsubstituted C 1-5 alkyl group, phenyl group, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group, so
  • the substituents are C 1-4 alkyl, C 1-4 alkoxy, halogen, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic ring or oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group.
  • the base is para-substituted relative to the parent core structure, and the halogen is ortho-, meta- or para-substituted relative to the parent core structure.
  • R 4 is hydrogen, substituted or unsubstituted C 1-5 alkyl, C 1-5 alkoxy, phenyl, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or oxygen- and/or nitrogen-containing 5-6 membered heterocyclic group, the substituent is C 1-4 alkyl, C 1-4 alkoxy, halogen, oxygen- and/or nitrogen-containing 5-6-member aromatic heterocyclic ring or oxygen-containing and/or Or nitrogen 5-6 membered heterocyclic group;
  • the C 1-4 alkyl group, C 1-4 alkoxy group, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group, or oxygen-containing and /or the 5-6 membered heterocyclic group of the nitrogen is para-substituted relative to the parent core structure, and the halogen is ortho-, meta- or para-substituted relative to the parent core structure.
  • n 0 or 1
  • R1 is a substituted or unsubstituted phenyl group, and the substituent is a C1-3 alkyl group, a C1-3 alkoxy group, a halogen, a 5-6-membered aromatic heterocyclic group containing oxygen and/or nitrogen, or a 5-6-membered heterocyclic group containing oxygen and/or nitrogen; preferably, the C1-3 alkyl group, the C1-3 alkoxy group, the 5-6-membered aromatic heterocyclic group containing oxygen and/or nitrogen, or the 5-6-membered heterocyclic group containing oxygen and/or nitrogen is para-substituted relative to the parent core structure, and the halogen is ortho-, meta- or para-substituted relative to the parent core structure;
  • R 2 is substituted or unsubstituted phenyl, and the substituent is C 1-3 alkyl, C 1-3 alkoxy, halogen, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or 5-6-membered heterocyclic group containing oxygen and/or nitrogen; preferably, the C 1-3 alkyl group, C 1-3 alkoxy group, oxygen- and/or nitrogen-containing group
  • the 5-6-membered aromatic heterocyclic group or the 5-6-membered heterocyclic group containing oxygen and/or nitrogen is para-substituted relative to the parent core structure, and the halogen is ortho-, meta- or para-substituted relative to the parent core structure. ;
  • R 3 is a substituted or unsubstituted C 1-5 alkyl group, phenyl group, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group, so The substituents are C 1-3 alkyl, C 1-3 alkoxy, halogen, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group.
  • the ring group is para-substituted relative to the parent core structure, and the halogen is ortho-, meta- or para-substituted relative to the parent core structure.
  • R 4 is hydrogen, substituted or unsubstituted C 1-5 alkyl, C 1-5 alkoxy, phenyl, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or oxygen- and/or nitrogen-containing 5-6 membered heterocyclic group, the substituent is C 1-3 alkyl, C 1-3 alkoxy, halogen, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or oxygen- and / or nitrogen 5-6 membered heterocyclic group; preferably, the C 1-3 alkyl group, C 1-3 alkoxy group, oxygen-containing and/or nitrogen-containing 5-6 membered aromatic heterocyclic group or oxygen-containing And/or the 5-6 membered heterocyclic group of nitrogen is para-substituted relative to the parent core structure, and the halogen is ortho-, meta- or para-substituted relative to the parent core structure.
  • n 0 or 1
  • R 1 is substituted or unsubstituted phenyl, and the substituent is C 1-2 alkyl, C 1-2 alkoxy, F, Cl, Br, I, 5-6 yuan containing oxygen and/or nitrogen Aromatic heterocyclic group or oxygen- and/or nitrogen-containing 5-6 membered heterocyclic group; preferably, the C 1-2 alkyl group, C 1-2 alkoxy group, oxygen- and/or nitrogen-containing 5-6.
  • the aromatic heterocyclic group or the oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group is para-position substituted relative to the parent core structure, and F, Cl, Br, and I are ortho-, meta-, or para-position relative to the parent core structure. bit substitution;
  • R 2 is substituted or unsubstituted phenyl, and the substituent is C 1-2 alkyl, C 1-2 alkoxy, F, Cl, Br, I, 5-6 yuan containing oxygen and/or nitrogen Aromatic heterocyclic group or oxygen- and/or nitrogen-containing 5-6 membered heterocyclic group; preferably, the C 1-2 alkyl group, C 1-2 alkoxy group, oxygen- and/or nitrogen-containing 5-6.
  • the aromatic heterocyclic group or the oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group is para-position substituted relative to the parent core structure, and F, Cl, Br, and I are ortho-, meta-, or para-position relative to the parent core structure. bit substitution;
  • R 3 is a substituted or unsubstituted C 1-4 alkyl group, phenyl group, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group, so
  • the substituents are C 1-2 alkyl, C 1-2 alkoxy, F, Cl, Br, I, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic groups or oxygen- and/or nitrogen-containing 5-6 membered heterocyclic group; preferably, the C 1-2 alkyl group, C 1-2 alkoxy group, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or oxygen- and/or nitrogen-containing
  • the 5-6 membered heterocyclic group is para-substituted relative to the parent core structure, and the halogen is ortho-, meta- or para-substituted relative to the parent core structure.
  • R 4 is hydrogen, substituted or unsubstituted C 1-4 alkyl, C 1-4 alkoxy, phenyl, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or oxygen- and/or nitrogen-containing 5-6 membered heterocyclic group, the substituent is C 1-2 alkyl, C 1-2 alkoxy, F, Cl, Br, I, oxygen-containing and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group; preferably, the C 1-2 alkyl group, C 1-2 alkoxy group,
  • the 5-6-membered aromatic heterocyclic group containing oxygen and/or nitrogen or the 5-6-membered heterocyclic group containing oxygen and/or nitrogen is para-substituted relative to the parent core structure, and the halogen is ortho- or meta-substituted relative to the parent core structure. Bit or paraposition substitution.
  • n 0 or 1
  • R 1 is substituted or unsubstituted phenyl, and the substituent is methyl, methoxy, F, Cl, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or oxygen- and/or nitrogen-containing 5-6-membered heterocyclic group; preferably, the methyl, methoxy, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic ring is para-substituted relative to the parent core structure, and F and Cl are substituted relative to the parent core structure.
  • the nuclear structure is ortho-, meta- or para-substituted;
  • R 2 is a substituted or unsubstituted phenyl group, and the substituent is methyl, methoxy, F, Cl or a 5-6 membered aromatic heterocycle containing oxygen and/or nitrogen; preferably, the methyl group, The methoxy group and the oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocycle are para-substituted relative to the parent core structure, and F and Cl are ortho-, meta- or para-substituted relative to the parent core structure;
  • R 3 is a substituted or unsubstituted C 1-3 alkyl group, phenyl group, oxygen- and/or nitrogen-containing 5-6 membered aromatic heterocyclic ring, and the substituents of the substituted phenyl group are methyl, methoxy, F , Cl or a 5-6 membered aromatic heterocycle containing oxygen and/or nitrogen; preferably, the methyl group, methoxy group and the 5-6 membered aromatic heterocycle containing oxygen and/or nitrogen are relative to the parent core structure.
  • Para-position substitution the halogen is ortho-, meta- or para-substituted relative to the parent core structure.
  • R 4 is hydrogen, substituted or unsubstituted C 1-3 alkyl, C 1-3 alkoxy, phenyl, oxygen- and/or nitrogen-containing 5-6 membered aromatic heterocycle, and the substitution of the substituted phenyl
  • the base is methyl, methoxy, F, Cl or an oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic ring; preferably, the methyl, methoxy and oxygen- and/or nitrogen-containing 5-6
  • the aromatic heterocycle is para-substituted relative to the parent core structure, and the halogen is ortho-, meta- or para-substituted relative to the parent core structure.
  • n 0 or 1
  • R 1 is a substituted or unsubstituted phenyl group, and the substituent is a methyl group or an oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic ring; preferably, the methyl group, an oxygen- and/or nitrogen-containing 5-membered aromatic heterocycle -The 6-membered aromatic heterocycle is para-substituted relative to the parent core structure;
  • R 2 is a substituted or unsubstituted phenyl group, and the substituent is a methyl group or an oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic ring; preferably, the methyl group, an oxygen- and/or nitrogen-containing 5-membered aromatic heterocyclic ring -The 6-membered aromatic heterocycle is para-substituted relative to the parent core structure;
  • R 3 is a substituted or unsubstituted C 1-3 alkyl group, phenyl group, oxygen- and/or nitrogen-containing 5-6 membered aromatic heterocyclic ring, and the substituent is methyl, methoxy, F, Cl or 5-6 membered aromatic heterocycles containing oxygen and/or nitrogen;
  • the methyl group, methoxy group and 5-6 membered aromatic heterocycles containing oxygen and/or nitrogen are para-substituted relative to the parent core structure, The halogen is substituted in the ortho, meta or para position relative to the parent core structure.
  • R 4 is hydrogen, substituted or unsubstituted C 1-3 alkyl, C 1-3 alkoxy, phenyl, oxygen- and/or nitrogen-containing 5-6 membered aromatic heterocycle, and the substituent is methyl , methoxy, F, Cl or a 5-6 membered aromatic heterocyclic ring containing oxygen and/or nitrogen; preferably, the methyl, methyl
  • the oxygen group and the 5-6 membered aromatic heterocycle containing oxygen and/or nitrogen are para-substituted relative to the parent core structure, and the halogen is ortho-, meta- or para-substituted relative to the parent core structure.
  • n 0 or 1
  • R 1 is phenyl
  • R 2 is phenyl
  • R 3 is a substituted or unsubstituted C 1-3 alkyl group, phenyl group, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic ring, and the substituent is methyl, methoxy, halogen or oxygen- and/or nitrogen-containing. / or nitrogen-containing 5-6-membered aromatic heterocyclic group; preferably, the methyl group, methoxy group, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group or oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group
  • the heterocyclic group is para-substituted relative to the parent core structure, and the halogen is ortho-, meta- or para-substituted relative to the parent core structure.
  • R 4 is hydrogen
  • parent core structure refers to the remaining main structure except the R group in the compound structure represented by formula (I).
  • the compound is selected from the following structures:
  • the compound is selected from the following structures:
  • the compound is selected from the following structures:
  • the compound is selected from the following structures:
  • the compound is selected from the following structures:
  • the present invention provides a compound represented by formula (II) or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable accepted salts or prodrugs;
  • n is an integer between 0 and 3;
  • R1 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, and heterocyclic groups which are mono- or poly-substituted on the aromatic ring.
  • the aromatic compound of formula (II) or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug include aromatic heterocycles.
  • n of the compound of formula (II) or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs is an integer between 0 and 2;
  • R1 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, heterocyclic group.
  • n of the compound of formula (II) or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs is 0 or 1 ;
  • R1 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, heterocyclyl.
  • n of the compound of formula (II) or its stereoisomer, geometric isomer, tautomer, nitrogen oxide hydrate, solvate, pharmaceutically acceptable salt or prodrug The value is 0 or 1;
  • R 1 is hydrogen, substituted or unsubstituted C 1-10 alkyl, C 1-10 alkoxy, phenyl, oxygen- and/or nitrogen-containing 5-6-membered aromatic heterocyclic group, 5-6-membered heterogeneous compounds containing oxygen and/or nitrogen Ring group, the substituent is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, cyano, phenyl or 5-6 yuan aromatic containing oxygen and/or nitrogen At least one of a heterocyclyl group and a 5-6 membered heterocyclyl group containing oxygen and/or nitrogen.
  • n of the compound of formula (II) or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug The value of is 1; R 1 is hydrogen.
  • the compound of formula (II) or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from The following structure:
  • the preparation method of the compound of formula (II) is characterized by using the following synthetic route:
  • a pharmaceutical composition including a compound represented by formula (II) or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, Pharmaceutically acceptable salts or prodrugs, and one or more pharmaceutically acceptable carriers, diluents, and excipients.
  • the compound represented by formula (II) or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the above-mentioned pharmaceutical compositions are used in the preparation of drugs for treating diseases mediated by the inhibition of co-aminoacyl hydroxylases by inhibiting co-aminoacyl hydroxylases.
  • the disease mediated by inhibition of coenzyme A hydroxylase is anemia, ischemia, or hypoxia.
  • the disease mediated by inhibition of coamyl hydroxylase is renal anemia.
  • FG-4592 is roxadustat.
  • Acetic acid in continuous chronic administration, shows excellent pharmacological effects, the data is significant, it can significantly increase the hemoglobin level and EPO level of SD rats, and the overall effect is significantly better than the positive drug Enarodustat (enarodustat) .
  • the purity of the intermediate prepared in each step in the embodiment of the present invention can be above 95%.
  • alkyl as used herein includes branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, including all isomers. Common abbreviations for alkyl groups include “Me” or CH 3 for methyl, “Et” or CH 2 CH 3 for ethyl, “Pr” or CH 2 CH 2 CH 3 for propyl, and “Pr” or CH 2 CH 3 for propyl. It can be represented by “Bu” or CH 2 CH 2 CH 2 CH 3 , etc.
  • C 1-4 alkyl refers to a straight or branched chain alkyl group having a specified number of carbon atoms, including all isomers.
  • C 1-4 alkyl includes n-, iso-, sec- and tert-butyl, n- and isopropyl, ethyl and methyl.
  • C 1-10 alkyl and the like have similar meanings.
  • alkoxy refers to straight and branched chain alkyl groups of the indicated number of carbon atoms linked through an oxygen bridge.
  • halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro(F), chloro(Cl), bromo(Br) and iodo(I)).
  • aryl refers to aromatic mono- and polycarbocyclic ring systems in which the individual carbocyclic rings are fused or linked to each other by single bonds.
  • Typical aryl groups include phenyl, naphthyl and biphenylene.
  • heterocycle refers to a cyclic structure composed of carbon atoms and non-carbon atoms. Examples of non-carbon atoms in the ring include nitrogen, oxygen, and sulfur. Typical heterocyclyl groups include pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone and pyrimidine.
  • aromatic heterocycle refers to a 5- or 6-membered monocyclic aromatic ring or a 7-12-membered bicyclic ring, which is composed of carbon atoms and one or more heteroatoms selected from N, O and S.
  • aromatic heterocycles include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furyl, imidazolyl, pyrazolyl, triazolyl, Tetrazolyl, azolyl, isoxazolyl, diazolyl, thiazolyl, isothiazolyl and thiadiazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, indoline base, isoindolyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isochromanyl Quinolyl, 2,3-dihydrobenzo
  • the aryl group in the term "substituted aryl" is as defined above.
  • the substituent may be selected from the following groups, including but not limited to: halogen, C 1 -C 20 alkyl, CF 3.
  • n is an integer between 0 and 2
  • n can be 0, 1, or 2.
  • salts refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
  • inorganic or organic bases include aluminum, ammonium, calcium, copper (copper and cuprous), iron, ferrous, lithium, magnesium, manganese (manganese and manganese), potassium, sodium, zinc, and the like. Preferred are ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts prepared from organic bases include primary, secondary and tertiary amines derived from natural and synthetic sources.
  • Organic non-toxic bases that can form salts include arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylamino Ethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, bicyclic Hexylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine wait.
  • acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid , maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, acetic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc.
  • acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid , maleic
  • solvate refers to a complex of variable stoichiometry formed by a solute (i.e., a compound of formula (I)) or a pharmaceutically acceptable salt thereof and a solvent that does not interfere with the biological activity of the solute.
  • solvents include, but are not limited to, water, ethanol, and acetic acid.
  • the solvent is water, the solvate is referred to as a hydrate. Hydrates include, but are not limited to, hemihydrates, monohydrates, one and a half hydrates, dihydrates, and trihydrates.
  • prodrug is a functional derivative of a compound of the invention that is readily converted to the desired compound in the body.
  • the present invention provides a preparation method for the above compound, including the following four synthetic routes:
  • R 1 , R 2 , R 3 and R 4 have the same definitions as mentioned above.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (I) or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, Pharmaceutically acceptable salts or prodrugs, and one or more pharmaceutically acceptable carriers, diluents, and excipients.
  • composition includes products containing an active ingredient and inert ingredients constituting a carrier (pharmaceutically acceptable excipients), as well as any combination, complexation or aggregation of two or more ingredients, or products resulting directly or indirectly from the decomposition of one or more ingredients, or other types of reactions or interactions of one or more ingredients.
  • pharmaceutical compositions of the present invention include any composition prepared by mixing a compound of formula (I) and/or formula (II), other active ingredients and pharmaceutically acceptable excipients.
  • composition of the present invention contains as an active ingredient a compound represented by formula (I) and/or formula (II) (or a pharmaceutically acceptable salt or solvate thereof), a pharmaceutically acceptable carrier and optional other treatments sexual ingredients or adjuvants.
  • Pharmaceutical compositions include compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most appropriate route in any particular case will depend on the particular subject to whom it is administered. The nature and severity of the condition of the active ingredient. Pharmaceutical compositions may be prepared by any method known in the pharmaceutical art.
  • the active ingredients may be administered orally in solid dosage forms, such as capsules, tablets, lozenges, dragees, granules and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions and suspension.
  • the active ingredients may also be administered parenterally in sterile liquid dosage forms such as dispersions, suspensions or solutions.
  • Other dosage forms that may be used to administer the active ingredients are ointments, creams, drops, transdermal patches or powders for topical administration; ophthalmic solutions or suspension forms for administration to the eye, i.e.
  • Gelatin capsules contain active ingredients and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be formulated as extended-release products to provide sustained release of the drug over several hours. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from air, or may be enteric-coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration may contain coloring and flavoring agents to increase patient acceptance.
  • water, suitable oils, saline, aqueous dextrose (glucose) solutions, and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizers and, if necessary, buffer substances.
  • Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid alone or in combination are suitable stabilizers.
  • Citric acid and its salts and sodium EDTA can also be used.
  • parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propylparaben, and chlorobutanol.
  • the compounds of the present invention are conveniently delivered as a spray from a pressurized pack or nebulizer.
  • the compounds may also be delivered in powder form formulated for inhalation with the aid of an insufflation powder inhaler device.
  • a preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of formula (I) and/or formula (II) in a suitable propellant, Propellants such as fluorocarbons or hydrocarbons.
  • MDI metered dose inhalation
  • ophthalmic preparations may be formulated with suitable weight percent solutions or suspensions of the compounds of formula (I) and/or formula (II) in a suitable ophthalmic carrier to maintain contact of the compounds with the ocular surface. Allow sufficient time for the compound to penetrate the cornea and interior areas of the eye.
  • Useful pharmaceutical dosage forms for administering the compounds of this invention include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections, and oral suspensions.
  • the same dosage forms as described above may be used.
  • the dosage form and route of administration should be selected based on the compatibility of the combined drugs.
  • the compounds of the present invention may be administered as the sole active ingredient or in combination with a second active ingredient, including active ingredients known to be useful for increasing erythropoietin levels in patients.
  • the present invention provides compounds represented by formula (I), formula (II) or their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutical Acceptable salts or prodrugs, or the use of pharmaceutical compositions as described above in the preparation of medicaments for the treatment of diseases mediated by inhibition of coamyl hydroxylase by inhibiting coamyl hydroxylase.
  • the disease mediated by inhibition of coamyl hydroxylase is anemia, ischemia, and hypoxia.
  • the anemia is renal anemia.
  • Propose a new compound that can be used as a coamyl hydroxylase inhibitor, has high coamyl hydroxylase inhibitory activity and EPO-inducing activity, and can effectively treat and prevent HIF-related and/or EPO-related diseases, Provide new ideas for diseases such as anemia, ischemia and hypoxia.
  • Figure 1 is a microscope photo of a single crystal sample of chiral isomer A of methyl acetate
  • FIG2 is an asymmetric unit diagram of the crystal structure of chiral isomer A of methyl acetate
  • Figure 3 is a unit cell diagram of the crystal structure of chiral isomer A of methyl acetate
  • FIG4 is a stacking diagram of the crystal structure of chiral isomer A of methyl acetate
  • Figure 5 is a comparison chart of the single crystal sample of methyl acetate chiral isomer A and the calculated XRPD;
  • Figure 6 is a chemical structure diagram of chiral isomer A of methyl acetate
  • Figure 7 is a microscope photo of a single crystal sample of chiral isomer B of methyl acetate
  • Figure 8 shows the asymmetric unit of the crystal structure of chiral isomer B of methyl acetate
  • Figure 9 is a unit cell diagram of the crystal structure of chiral isomer B of methyl acetate
  • Figure 10 is a stacking diagram of the crystal structure of chiral isomer B of methyl acetate
  • Figure 11 is the XRPD comparison chart obtained from actual measurement and calculation of methyl acetate chiral isomer B single crystal sample
  • Figure 12 is a chemical structure diagram of chiral isomer B of methyl acetate.
  • reaction solution was cooled to room temperature, the reaction solution was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution, and saturated brine in sequence, and then concentrated under reduced pressure to obtain 12.0 g of a yellow solid.
  • reaction bottle A dissolve 5-(phenylethynyl)-7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (0.8g) in dichloromethane (20 mL), add oxalyl chloride (0.76 g) dropwise, and stir at room temperature.
  • reaction bottle B add glycinate methyl ester hydrochloride (0.68g), dichloromethane (20 mL), and triethylamine (3.0 mL) in sequence, and stir at 0°C. TLC monitors that the raw materials in reaction bottle A are completely reacted. Stop stirring in reaction bottle A, and add the materials in reaction bottle A to reaction bottle B.
  • reaction solution was cooled to room temperature, it was extracted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was separated, concentrated under reduced pressure, and analyzed by column chromatography to obtain 3.30 g of crude product.
  • reaction solution was cooled to room temperature, it was extracted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was separated, concentrated under reduced pressure, and analyzed by column chromatography to obtain 3.30 g of crude product.
  • PHD2 enzyme purchased from Active motif
  • ⁇ -ketoglutarate sodium salt purchased from Sigma;
  • FITC-HIF1 ⁇ purchased from GL;
  • Multiwell plate Nunc TM 384 purchased from Thermo Scientific.
  • test compound test concentration is 10 ⁇ M starting from 10 ⁇ M, diluted 3 times, 10 concentrations, and tested in multiple holes; dilute it into a solution with a final concentration of 100 times in a 384-well plate, and then use a non-contact
  • the sonic pipetting system Echo550 transfers 100nL to the 384 reaction plate for later use.
  • EPO erythropoietin
  • Cell preparation seed cells in a 96-well plate, plate at 2*10 ⁇ 4 per well, 100 ⁇ L per well;
  • the EPO-inducing activity of each compound was expressed as the half-maximum effect concentration (EC50).
  • EC50 half-maximum effect concentration
  • Candidate compounds in the experiment The substance was mixed into a clear solution and given to rats through a single intravenous injection and intragastric administration.
  • the intravenous vehicle is a certain proportion of N,N-dimethylacetamide (DMA) and 10% Solutol HS15 solution
  • the oral vehicle is a certain proportion of sodium carboxymethyl cellulose (CMC) suspension.
  • Blood samples were collected into K2EDTA anticoagulant tubes at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h and 24 h after the animals were administered, and temporarily stored on ice until centrifugation.
  • DMA N,N-dimethylacetamide
  • CMC sodium carboxymethyl cellulose
  • the purpose of this experiment is to evaluate the effect of continuous administration of the compounds prepared in Examples 12, 13, and 14 on EPO (erythropoietin) in SD rats.
  • Age and weight 8 weeks, weight 200-220g
  • the SD rats were randomly divided into 3 groups, with 6 rats in each group, which were respectively the blank group, the positive drug group (Enarodustat) and the compound group of Example 12.
  • Enarodustat crushes the tablets in a mortar
  • 0.5% methylcellulose is added quantitatively, and magnetic stirring is used to mix.
  • 0.5% methylcellulose is quantitatively added.
  • Mix with magnetic stirrer The final concentration of all compounds was 0.3 mg/mL, and the administration volume was 10 mL/kg.
  • the drug was administered once a day for 14 consecutive days. On the 14th day, blood was taken 4 hours after administration to measure the EPO level.
  • the compounds prepared in Examples 12, 13, and 14 can significantly increase the EPO level of SD rats, and the overall effect is significantly better than the positive drug Enarodustat, showing excellent pharmacological effects.
  • Example 18 Determination of the chiral configuration of the chiral isomer A compound of methyl acetate in Example 13
  • the single crystal structure of chiral isomer A of methyl acetate belongs to the monoclinic crystal system, P21 space group, and the molecular formula of the single crystal is C 20 H 20 N 4 O 4 .
  • the absolute configuration of a chiral carbon is "R".
  • the refined single crystal structure is shown in Figures 2, 3 and 4.
  • the crystal structure parameters are summarized in Table 4, and the atomic coordinates, anisotropic displacement parameters, torsion angle, hydrogen bonding, bond length and bond angle data are detailed in Tables 5 to 11.
  • the XRPD pattern calculated based on the single crystal structure is basically consistent with the test results of the single crystal sample, but there is a certain shift in the peak position. This may be because the single crystal data was collected at 180K, and the experimentally measured XRPD pattern was obtained at room temperature ( Figure 5).
  • PLM analysis was performed using ECLIPSE LV100POL (Nikon, JPN) polarizing microscope. Spread a small amount of sample onto a glass slide, drop in cedar oil to disperse the sample, and then add a coverslip. Subsequently, the sample was placed under a microscope and observed with a 10x objective lens.
  • Example 19 Determination of the chiral configuration of the chiral isomer B compound of methyl acetate in Example 14
  • needle-shaped single crystals were obtained from dimethyl sulfoxide, as shown in Figure 7, and were used for X-ray single crystal diffraction analysis.
  • the single crystal structure of chiral isomer B of methyl acetate belongs to the monoclinic crystal system, P21 space group, and the molecular formula of the single crystal is C 20 H 20 N 4 O 4 .
  • the absolute configuration of a chiral carbon is "S".
  • the refined single crystal structure is shown in Figures 8, 9 and 10.
  • the crystal structure parameters are summarized in Table 13, and the atomic coordinates, anisotropic displacement parameters, torsion angle, hydrogen bonding, bond length and bond angle parameters are summarized in Tables 14 to 20.
  • the XRPD pattern obtained from the experimental measurement of the single crystal sample is more peaked than the calculated XRPD pattern; it is possible that the solvent has nearly evaporated after the single crystal test, which is caused by the precipitation of other crystal forms during the solvent evaporation process ( Figure 11).
  • PLM analysis was performed using ECLIPSE LV100POL (Nikon, JPN) polarizing microscope. Spread a small amount of sample onto a glass slide, drop in cedar oil to disperse the sample, and then add a coverslip. Subsequently, the sample was placed under a microscope and observed with an objective lens.
  • the chiral configuration of the chiral isomer B of methyl acetate is the "S" configuration, as shown in Figure 12. It can be seen from this that in Example 14, when using sodium hydroxide aqueous solution to remove the methyl ester to obtain the carboxylic acid product, the generated chiral configuration will not be changed. Therefore, it can be inferred that the product [(7-hydroxy-5) in Example 14 -(1,2,3,4-tetralin-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid chiral isomer
  • the chiral configuration of B is the "S" configuration.
  • Example 20 Subacute toxicity test of compounds of Examples 13 and 14
  • mice The sources and numbers of experimental animals are shown in Table 23.
  • the animal room was well ventilated and equipped with air conditioning, with the temperature maintained at 20-25°C, the humidity maintained at 40%-70%, the light and dark lighting at 12 hours each, and the animals were free to eat and drink.
  • SD rats that were adaptively fed for at least 3 days before administration and were in good physical condition after veterinary examination were selected for this experiment.
  • experimenters and veterinarians need to continuously observe the physical signs and health status of the experimental animals. Any abnormal performance of the animal, such as pain, depression, reduced activity, etc., must be recorded in the original experimental record. If the abnormal performance of experimental animals exceeds the requirements of IACUC-related animal welfare documents, the veterinarian can determine whether to terminate the experiment and notify the person in charge of the experimental project.
  • Observation indicators include: animal appearance, behavioral activities, secretions, excretions, diet, death conditions (number of deaths, time of death, pre-death reaction), etc. If clinical symptoms occur, the number of observations needs to be increased to observe in detail the symptoms of the animal's poisoning reaction, its onset time, severity, duration and whether it is reversible. If an animal is found dead or dying, follow the regulations Carry out anatomical observations on animals promptly.
  • the animals need to be weighed before daily administration for 14 consecutive days, and the weight is recorded in the corresponding form. And record the weight in the corresponding table. And during the test period, the food intake of the test animals was detected.
  • WBC White blood cell count
  • Neutrophil differential count absolute count, NEUT; percentage, %NEUT
  • Lymphocyte differential count absolute count, LYM; percentage, %LYM
  • Basophil differential count absolute count, BASO; percentage, % BASO
  • HGB Hemoglobin
  • HCT Hematocrit
  • MCH Mean corpuscular hemoglobin content
  • MCHC Mean corpuscular hemoglobin concentration
  • Red blood cell coefficient of variation (RDW-CV)
  • Red blood cell distribution width standard deviation (RDW-SD)
  • PKT Platelet Count
  • PCT Platelet count
  • TBIL Total Bilirubin

Abstract

本发明公开了一种脯氨酰羟化酶抑制，属于医药技术领域。本发明提供了一种吡啶并***类化合物，结构如下式所示，具有较高的脯氨酰羟化酶抑制活性和EPO诱导活性，可以有效治疗和预防HIF相关和/或EPO相关的病症，为贫血、局部缺血和缺氧等病症提供新思路。

Description

一种脯氨酰羟化酶抑制剂及其用途 技术领域
本发明属于医药技术领域，具体涉及一种具有脯氨酰羟化酶抑制作用的吡啶并***类化合物及其药物组合物，进一步涉及其制备方法及其制药用途。
背景技术
在贫血、外伤、组织坏死及缺损等情况下，组织或细胞常处于低氧状态。低氧导致一系列转录诱导因子的表达，它们参与了血管形成，铁、糖代谢及细胞的生长和增殖。其中，缺氧诱导性因子(hypoxia inducible factor,HIF)是体细胞在缺氧状态下启动的一种转录因子，在生物细胞内通过介导一系列基因调节来响应细胞缺氧状态。HIF是含有氧调控的α-亚单位(HIFα)和组成型表达的β-亚单位(HIFβ/ARNT)的杂二聚体。在含氧(含氧量正常的)细胞中，HIFα亚单位通过逢希伯-林道肿瘤抑制因子(von Hippel-Lindau tumor suppressor，pVHL)E3连接酶复合物泛素化(ubiquitination)的机制被快速降解。在缺氧条件下，HIFα不被降解，且活性HIFα/β复合物在细胞核内积累，并活化各种基因的表达，包括糖酵解酶，葡萄糖转运蛋白，***(EPO)和血管内皮生长因子(VEGF)。
***(EPO)是随HIFα而产生的一种自然存在的激素，其剌激运载氧气贯穿全身的红细脂(红血球)的产生。EPO通常由肾分泌，且内源性EPO在氧减少(缺氧)的条件下增加。所有类型贫血的特征在于血液运载氧的能力减少，并因而伴有类似体征与症状，包括皮肤及粘膜苍白、虚弱、头晕、易疲劳和嗜睡，导致生活质量的下降。贫血通常与红细胞中或血红蛋白中血液缺乏的病况有关。贫血的普遍原因包括铁、维生素B12和叶酸缺乏，也会与慢性疾病并发，例如炎性疾病，包括具有继发骨髓炎性抑制的疾病等。贫血也与肾功能障碍有关，经常透析的大多数肾衰竭患者患有慢性贫血。
脯氨酰羟化酶(prolyl hydroxylase domain,PHD)是调节HIF的关键因子。在常氧状态下，PHD可以羟基化HIFα的两个关键脯氨酸残基Pro402和Pro564，增加其与pVHL的亲和力，加速降解的过程。在缺氧及其他病理状态下，PHD催化的HIF反应受阻，蛋白酶降解速度减慢，造成HIFα在细胞内积聚，进而引起细胞对低氧的一系列适应性反应。通过PHD抑制剂抑制PHD，延长HIF的作用，进而增加EPO等基因的表达，可以有效治疗和预防HIF相关和/或EPO相关的病症，如贫血、局部缺血和缺氧的病症。
例如，美国专利申请US16757333公开了一种炔基吡啶类辅氨酰羟化酶抑制剂的晶型及其制备方法，所述炔基吡啶类辅氨酰羟化酶抑制剂结构式如下：
目前，已有辅氨酰羟化酶抑制剂上市销售，包括阿斯利康的Roxadustat(罗沙司他)及日本烟草产业株式会社的Enarodustat(恩那司他)。
由于辅氨酰羟化酶抑制剂种类开发有限以及需求较高，因此，迫切需要研发此类化合物，进而治疗贫血、局部缺血和缺氧等病症。
发明内容
本发明的目的是提供一种作为HIF-PHD抑制剂吡啶并***类化合物及其药物组合物，可用于治疗各种HIF相关或EPO相关的疾病，如贫血等。
为实现上述发明目的，本发明技术方案如下：
一方面，本发明提供一种式(I)所示的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药；
其中，
R选自以下原子或基团的单元：
L为-CH2-或-CH2O-；
n的数值为0-2之间的整数；
R1、R2、R3各自独立的选自为取代或未取代的烷基、环烷基、芳基、杂环基。
优选地，所述芳基包括芳杂环。
在一些实施例中，
L为-CH2-或-CH2O-；
n的数值为0或1；
R1为取代或未取代的C1-4烷基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、C1-4卤代烷基、卤素、氰基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种；
R2为取代或未取代的C1-4烷基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、C1-4卤代烷基、卤素、氰基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种；
R3为取代或未取代的C1-10烷基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、C1-4卤代烷基、卤素、氰基、苯基或含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种。
R4选自为氢、取代或未取代的烷基、环烷基、烷氧基、芳基、杂环基中的至少一种。
在一些实施例中，
L为-CH2-或-CH2O-；
n的数值为0或1；
R1为取代或未取代的苯基，所述取代基为C1-4烷基、C1-4烷氧基、C1-4卤代烷基、卤素、氰基、苯基或含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种；
R2为取代或未取代的苯基，所述取代基为C1-4烷基、C1-4烷氧基、C1-4卤代烷基、卤素、氰基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种；
R3为取代或未取代的C1-10烷基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、卤素、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种。
R4为氢、取代或未取代的烷基、环烷基、烷氧基、芳基、杂环基中的至少一种。
或，R4为氢、取代或未取代的C1-10烷基、C1-10烷氧基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、C1-4卤代烷基、卤素、氰基、苯基或含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种。
或，R4为氢、取代或未取代的C1-10烷基、C1-10烷氧基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、卤素、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种。
在一些实施例中，
n的数值为0或1；
R1为取代或未取代的苯基，所述取代基为C1-4烷基、C1-4烷氧基、卤素、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-4烷基、C1-4烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基为相对于母核结构对位取代，卤素相对于母核结构为邻位、间位或对位取代；
R2为取代或未取代的苯基，所述取代基为C1-4烷基、C1-4烷氧基、卤素或含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-4烷基、C1-4烷氧基和含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代；
R3为取代或未取代的C1-5烷基、苯基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、卤素、含氧和/或氮的5-6元芳杂环或含氧和/或氮的5-6元杂环基；优选地，所述C1-4烷基、C1-4烷氧基、含氧和/或氮的5-6元芳杂环、或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代。
R4为氢、取代或未取代的C1-5烷基、C1-5烷氧基、苯基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、卤素、含氧和/或氮的5-6元芳杂环或含氧和/或氮的5-6元杂环基；优选地，所述C1-4烷基、C1-4烷氧基、含氧和/或氮的5-6元芳杂环、或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代。
在一些实施例中，
n的数值为0或1；
R1为取代或未取代的苯基，所述取代基为C1-3烷基、C1-3烷氧基、卤素、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-3烷基、C1-3烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基为相对于母核结构对位取代，卤素相对于母核结构为邻位、间位或对位取代；
R2为取代或未取代的苯基，所述取代基为C1-3烷基、C1-3烷氧基、卤素、含氧和/或氮的 5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-3烷基、C1-3烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基为相对于母核结构对位取代，卤素相对于母核结构为邻位、间位或对位取代；
R3为取代或未取代的C1-5烷基、苯基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基，所述取代基为C1-3烷基、C1-3烷氧基、卤素、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-3烷基、C1-3烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代。
R4为氢、取代或未取代的C1-5烷基、C1-5烷氧基、苯基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基，所述取代基为C1-3烷基、C1-3烷氧基、卤素、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-3烷基、C1-3烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代。
在一些实施例中，
n的数值为0或1；
R1为取代或未取代的苯基，所述取代基为C1-2烷基、C1-2烷氧基、F、Cl、Br、I、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-2烷基、C1-2烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，F、Cl、Br、I相对于母核结构为邻位、间位或对位取代；
R2为取代或未取代的苯基，所述取代基为C1-2烷基、C1-2烷氧基、F、Cl、Br、I、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-2烷基、C1-2烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，F、Cl、Br、I相对于母核结构为邻位、间位或对位取代；
R3为取代或未取代的C1-4烷基、苯基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基，所述取代基为C1-2烷基、C1-2烷氧基、F、Cl、Br、I、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-2烷基、C1-2烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代。
R4为氢、取代或未取代的C1-4烷基、C1-4烷氧基、苯基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基，所述取代基为C1-2烷基、C1-2烷氧基、F、Cl、Br、I、含氧 和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-2烷基、C1-2烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代。
在一些实施例中，
n的数值为0或1；
R1为取代或未取代的苯基，所述取代基为甲基、甲氧基、F、Cl、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述甲基、甲氧基、含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代，F、Cl相对于母核结构为邻位、间位或对位取代；
R2为取代或未取代的苯基，所述取代基为甲基、甲氧基、F、Cl或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、甲氧基和含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代，F、Cl相对于母核结构为邻位、间位或对位取代；
R3为取代或未取代的C1-3烷基、苯基、含氧和/或氮的5-6元芳杂环，所述取代苯基的取代基为甲基、甲氧基、F、Cl或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、甲氧基和含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代。
R4为氢、取代或未取代的C1-3烷基、C1-3烷氧基、苯基、含氧和/或氮的5-6元芳杂环，所述取代苯基的取代基为甲基、甲氧基、F、Cl或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、甲氧基和含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代。
在一些实施例中，
n的数值为0或1；
R1为取代或未取代的苯基，所述取代基为甲基或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代；
R2为取代或未取代的苯基，所述取代基为甲基或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代；
R3为取代或未取代的C1-3烷基、苯基、含氧和/或氮的5-6元芳杂环，所述取代基为甲基、甲氧基、F、Cl或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、甲氧基和含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代。
R4为氢、取代或未取代的C1-3烷基、C1-3烷氧基、苯基、含氧和/或氮的5-6元芳杂环，所述取代基为甲基、甲氧基、F、Cl或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、甲 氧基和含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代。
在一些实施例中，
n的数值为0或1；
R1为苯基；
R2为苯基；
R3为取代或未取代的C1-3烷基、苯基、含氧和/或氮的5-6元芳杂环，所述取代基为甲基、甲氧基、卤素或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、甲氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代。
R4为氢。
术语“母核结构”是指式(I)所示的化合物结构中除R基团以外的剩余主体结构。
在一些实施例中，所述化合物选自以下结构：

在一些实施例中，所述化合物选自以下结构：
在一些实施例中，所述化合物选自以下结构：
在一些实施例中，所述化合物选自以下结构：
在一些实施例中，所述化合物选自以下结构：
在一些实施例中，本发明提供一种式(Ⅱ)所示的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药；
其中，
n的数值为0-3之间的整数；
R1选自芳环上单取代或多取代的氢、卤素、取代或未取代的烷基、环烷基、烷氧基、芳基、杂环基。
在一些实施例中，式(Ⅱ)化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药的芳基包括芳杂环。
在一些实施例中，式(Ⅱ)化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药的n的数值为0-2之间的整数；R1选自氢、卤素、取代或未取代的烷基、环烷基、烷氧基、芳基、杂环基。
在一些实施例中，式(Ⅱ)化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药的n的数值为0或1；R1选自氢、卤素、取代或未取代的烷基、环烷基、烷氧基、芳基、杂环基。
在一些实施例中，式(Ⅱ)化合物或其立体异构体、几何异构体、互变异构体、氮氧化物水合物、溶剂化物、药学上可接受的盐或前药的n的数值为0或1；R1为氢、取代或未取代的C1-10烷基、C1-10烷氧基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂 环基，所述取代基为C1-4烷基、C1-4烷氧基、C1-4卤代烷基、卤素、氰基、苯基或含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种。
在一些实施例中，式(Ⅱ)化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药的n的数值为1；R1为氢。
在一些实施例中，式(Ⅱ)化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药选自以下结构：
在一些实施例中，式(Ⅱ)化合物的制备方法，其特征在于，使用以下合成路线：
在一些实施例中，包括一种药物组合物，包含式(Ⅱ)所示的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，以及一种或多种可药用载体、稀释剂、赋形剂。
在一些实施例中，式(Ⅱ)所示的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，或者上述药物组合物在制备用于通过抑制辅氨酰羟化酶来治疗抑制辅氨酰羟化酶介导的疾病的药物中的用途。
在一些实施例中，所述抑制辅氨酰羟化酶介导的疾病为贫血、局部缺血、缺氧。
在一些实施例中，所述抑制辅氨酰羟化酶介导的疾病为肾性贫血。
本发明中FG-4592为罗沙司他。
[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸，在持续慢性给药中，表现出优秀的药理学作用，数据具有显著性，能够显著增加SD大鼠血红蛋白水平和EPO水平，且整体效果显著优于阳性药Enarodustat(恩那司他)。
优选地，本发明实施例中各步制备得到的中间体纯度可95％以上。
除非有说明，本文所用的术语“烷基”包括具有特定数目碳原子的支链和直链饱和的脂肪烃基团，包括所有异构体。烷基的常用缩写例如甲基可以用“Me”或CH3表示，乙基可以用“Et”或CH2CH3表示，丙基可以用“Pr”或CH2CH2CH3表示，丁基可以用“Bu”或CH2CH2CH2CH3表示等。例如“C1-4烷基”(或“C1-C4烷基”)是指具有特定数目碳原子的直链或支链烷基，包括所有异构体。C1-4烷基包括正、异、仲和叔丁基、正和异丙基，乙基和甲基。术语“C1-10烷基”等具有类似的含义。
术语“烷氧基”表示通过氧桥连接的标明数目碳原子的直链和支链烷基。
术语“卤素”(或“卤代”)是指氟、氯、溴和碘(或者称为氟代(F)、氯代(Cl)、溴代(Br)和碘代(I))。
术语“芳基”是指芳香的单和多碳环***，其中在多环***中各个碳环是稠合的或通过单键相互连接。一般芳基包括苯基、萘基和亚联苯基。
术语“杂环”是指碳原子及非碳原子构成的环状结构，环中的非碳原子举例如氮、氧和硫等。一般杂环基包括吡啶、喹啉、托烷、吩噻嗪、苯并二氮杂卓、呋喃、吡唑酮和嘧啶。
术语“芳杂环”是指5或6元单环芳香环或7-12元双环，其由碳原子和一个或多个选自N、O和S的杂原子构成。芳杂环举例包括吡啶基、吡咯基、吡嗪基、嘧啶基、哒嗪基、噻吩基(或噻吩基(thiophenyl))、噻唑基、呋喃基、咪唑基、吡唑基、***基、四唑基、唑基、异唑基、二唑基、噻唑基、异噻唑基和噻二唑基、苯并***基、吲哚基、异吲哚基、吲唑基、二氢吲哚基、异二氢吲哚基、喹喔啉基、喹唑啉基、噌啉基、色满基、异色满基、四氢喹啉基、喹啉基、四氢异喹啉基、异喹啉基、2，3-二氢苯并呋喃基、2，3-二氢苯并-1，4-二烯基、咪唑并(2，1-b)(1，3)噻唑和苯并-1，3-间二氧杂环戊烯基。
术语“取代芳基”中的芳基如前定义，当未指定取代芳基的取代基时，取代基可选自下列基团，包括但不限于：卤素、C1-C20烷基、CF3、NH2、N(C1-C6烷基)2、NO2、氧代、CN、N3、-OH、-O(C1-C6烷基)、C3-C10环烷基、C2-C6烯基、C2-C6炔基、(C0-C6烷基)S(O)0-2-、芳 基-S(O)0-2-、(C0-C6烷基)S(O)0-2(C0-C6烷基)-、(C0-C6烷基)C(O)NH-、H2N-C(NH)-、-O(C1-C6烷基)CF3、(C0-C6烷基)C(O)-、(C0-C6烷基)OC(O)-、(C0-C6烷基)2NC(O)-(C0-C6烷基)O(C1-C6烷基)-、(C0-C6烷基)C(O)1-2(C0-C6烷基)-、(C0-C6烷基)OC(O)NH-、芳基、芳烷基、杂芳基、杂环基烷基、卤素-芳基、卤素-芳烷基、卤素-杂环、卤素-杂环基烷基、氰基-芳基、氰基-芳烷基、氰基-杂环和氰基-杂环基烷基。术语“取代苯基”具有类似的定义。
除非明确说明，本文列出的所有范围是包含性的。例如，“n的数值为0-2之间的整数”是指n可以是0、1或2。
术语“药学上可接受的盐”是指由药学可接受的无毒碱或酸制备的盐。当本发明的化合物是酸性时，其相应的盐可以容易地由无机碱或有机碱制备。衍生自这种无机碱的盐包括铝、铵、钙、铜(铜和亚铜)、铁、亚铁、锂、镁、锰(锰和亚锰)、钾、钠、锌等盐。优选的为铵、钙、镁、钾和钠等盐。由有机碱制备的盐包括来源于天然和合成来源的伯胺、仲胺和叔胺。可以形成盐的药学可接受的有机无毒碱包括精氨酸、甜菜碱、咖啡因、胆碱、N，N′-二苄基亚乙基二胺、二乙基胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、哈胺(hydrabamine)、异丙胺、二环己基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤类、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。当本发明的化合物是碱性时，其相应的盐可以容易地由无机酸或有机酸制备。这种酸包括例如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙基磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。
术语“溶剂化物”是指由溶质(即式(I)化合物)或其药学可接受的盐和不妨碍溶质生物活性的溶剂形成的可变化学计量的复合物。溶剂的实例包括但不限于水、乙醇和乙酸。当溶剂是水时，该溶剂化物称为水合物。水合物包括但不限于半、一、一倍半、二和三水合物。
术语“前药”是本发明化合物的功能性衍生物，其在体内容易转化为需要的化合物。
另一方面，本发明提供上述化合物的制备方法，包括以下四种合成路线：
路线1：
路线2：
路线3：
路线4：
其中，R1、R2、R3、R4具有与前述相同的定义。
再一方面，本发明提供一种药物组合物，包含式(I)所示的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，以及一种或多种可药用载体、稀释剂、赋形剂。
在药物组合物中，术语“组合物”包括包含活性成分和组成载体的惰性成分(药学可接受的赋形剂)的产品，以及任何由两种或多种成分的组合、络合或者聚集、或一种或多种成分的分解、或由一种或多种成分的其它类型反应或相互作用直接或间接地得到的产品。因此，本发明的药物组合物包括任何通过混合式(I)和/或式(Ⅱ)化合物、其它活性成分和药学可接受的赋形剂制备的组合物。
本发明的药物组合物包含作为活性成分的式(I)和/或式(Ⅱ)所示的化合物(或其药学可接受的盐或溶剂化物)、药学可接受的载体和任选的其它治疗性成分或佐剂。药物组合物包括适合口服、直肠、局部和胃肠外(包括皮下、肌内和静脉内)给药的组合物，虽然在任何特定的情况下最合适的途径取决于特定的主体、对其给予活性成分的病症的性质和严重度。药物组合物可以通过药剂学领域公知的任何方法制备。
活性成分可以以固体剂型或液体剂型口服给药，所述固体剂型例如胶囊、片剂、锭剂、糖锭剂、颗粒和粉剂，所述液体剂型例如酏剂、糖浆剂、乳剂、分散体和混悬液。活性成分还可以以无菌液体剂型例如分散体、混悬液或溶液胃肠外给药。可以用于将活性成分进行给药的其它剂型还有用于局部给药的软膏、乳膏、滴剂、经皮贴剂或粉剂；用于眼睛给药的眼用溶液或混悬液形式，即滴眼液；用于吸入或鼻内给药的喷雾剂或粉末组合物，或用于直肠或***给药的乳膏、软膏、喷雾剂或栓剂。明胶胶囊包含活性成分和粉状载体，例如乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸等。可以使用类似的稀释剂来制备压制片剂。片剂和胶囊都可以被制备成缓释产品以在数小时内提供药物的持续释放。压制片剂可以包糖衣或包膜衣以掩盖任何令人不愉快的味道和保护该片剂不受空气影响，或者可以包肠溶衣用于在胃肠道内选择性崩解。用于口服给药的液体剂型可包含着色剂和矫味剂以增加患者的接受性。 一般而言，水、合适的油、盐水、右旋糖(葡萄糖)水溶液、以及相关的糖溶液和二醇类如丙二醇或聚乙二醇是合适的胃肠外溶液的载体。用于胃肠外给药的溶液优选包含活性成分的水溶性盐、合适的稳定剂和根据需要使用的缓冲物质。抗氧化剂例如单独或组合的亚硫酸氢钠、亚硫酸钠或抗坏血酸是合适的稳定剂。还可以使用柠檬酸及其盐和EDTA钠。此外，胃肠外溶液还可以包含防腐剂，例如苯扎氯铵、尼泊金甲酯或尼泊金丙酯和氯丁醇。对于吸入给药而言，本发明的化合物可以方便地从加压包装或喷雾器中以喷雾剂形式递送。该化合物还可以以进行配制的粉末形式递送，该粉末组合物可以在吹入粉末吸入器装置的帮助下吸入。优选的用于吸入的递送***是定量吸入(MDI)气雾剂，其可以配制成式(I)和/或式(Ⅱ)的化合物在合适的推进剂中的混悬液或溶液，所述推进剂例如碳氟化合物或烃。对于眼睛给药而言，眼用制剂可以用式(I)和/或式(Ⅱ)化合物在合适眼用载体中的合适重量百分比的溶液或混悬液进行配制，从而保持化合物与眼睛表面接触足够的时间以使化合物渗透到眼睛的角膜和内部区域。
用于给予本发明化合物的有用的药物剂型包括但不限于硬和软明胶胶囊、片剂、胃肠外注射液和口服混悬液。
当本发明的化合物逐步给药或与其它治疗剂结合给药时，可以使用和前述相同的剂型。当药物以物理组合给药时，剂型和给药途径应根据组合药物的相容性选择。本发明的化合物可以作为唯一活性成分或与第二活性成分组合给药，所述第二活性成分包括其已知可用于提高患者***水平的活性成分。
再一方面，本发明提供式(I)、式(Ⅱ)所示的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，或者上述药物组合物在制备用于通过抑制辅氨酰羟化酶来治疗抑制辅氨酰羟化酶介导的疾病的药物中的用途。
在一些实施例中，所述抑制辅氨酰羟化酶介导的疾病为贫血、局部缺血、缺氧。
在一些实施例中，所述贫血为肾性贫血。
本发明的有益效果为：
提出一种新的化合物，可以作为辅氨酰羟化酶抑制剂，具有较高的辅氨酰羟化酶抑制活性和EPO诱导活性，可以有效治疗和预防HIF相关和/或EPO相关的病症，为贫血、局部缺血和缺氧等病症提供新思路。
附图说明
图1为乙酸甲酯手性异构体A单晶样品的显微镜照片；
图2为乙酸甲酯手性异构体A晶体结构的不对称单元图；
图3为乙酸甲酯手性异构体A晶体结构的晶胞图；
图4为乙酸甲酯手性异构体A晶体结构的堆积图；
图5为乙酸甲酯手性异构体A单晶样品和计算所得的XRPD对比图；
图6为乙酸甲酯手性异构体A的化学结构图；
图7为乙酸甲酯手性异构体B单晶样品的显微镜照片；
图8为乙酸甲酯手性异构体B晶体结构的不对称单元；
图9为乙酸甲酯手性异构体B晶体结构的晶胞图；
图10为乙酸甲酯手性异构体B晶体结构的堆积图；
图11为乙酸甲酯手性异构体B单晶样品实际测定和计算所得的XRPD对比图；
图12为乙酸甲酯手性异构体B的化学结构图。
具体实施方式
以下非限制性实施例可以使本领域的普通技术人员更全面的理解本发明，但不以任何方式限制本发明。下述内容仅仅是对本申请要求保护的范围的示例性说明，本领域技术人员可以根据所公开的内容对本申请的发明作出多种改变和修饰，而其也应当属于本申请要求保护的范围之中。
下面以具体实施例的方式对本发明作进一步的说明。本发明实施例中所使用的各种化学试剂如无特殊说明均通过常规商业途径获得。
实施例1
(7-羟基-5-(苯氧基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸的制备
步骤1制备5-(苯氧基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯
将5-碘-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(1.0g)，苯酚(310mg)，2-吡啶甲酸(55mg)，碘化亚铜(42mg)，磷酸钾(942mg)，二甲亚砜(5.0mL)依次加入反应瓶中，并置换氮气三次。升温至65℃，反应过夜，直至TLC监测原料反应完全。待冷却至室温，乙酸乙酯萃取，饱和食盐水洗涤，分离有机相，无水硫酸钠干燥，减压浓缩，柱层析得白色固体450mg。
MS m/z(ESI)[M+H]+:418.30
步骤2制备5-(苯氧基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-甲酸
将5-(苯氧基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(450mg)溶于体积比为1：1的甲苯和四氢呋喃的混合溶液中(10mL)，然后加入甲磺酸(0.5mL)并搅拌，保持反应温度在60-70℃之间。直至TLC监测原料反应完全，停止反应。冷却至室温，加入少量乙酸乙酯，过滤，得到白色固体440mg。
MS m/z(ESI)[M+H]+:362.22
步骤3制备[(7-(苄氧基)-5-(苯氧基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯
将5-(苯氧基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-甲酸(440mg)，EDCI(280mg)，HoBt(197mg)，N,N-二甲基甲酰胺(5.0mL)，三乙胺(247mg)依次加入反应瓶中，室温下搅拌10分钟，然后将甘氨酸甲酯盐酸盐(306mg)加入体系中，并升温至60℃反应1.5小时。停止反应，冷却至室温，加入饱和碳酸氢钠水溶液淬灭反应，抽滤得到黄色固体300mg。
MS m/z(ESI)[M+H]+:433.31
步骤4制备[(7-羟基-5-(苯氧基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯
将[(7-(苄氧基)-5-(苯氧基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯(300mg)，钯碳(30mg)溶于体积比为1:1的甲醇和四氢呋喃混合溶剂(4.0mL)，在氢气环境下，室温搅拌，直至TLC监测原料反应完全，停止反应。减压浓缩除去溶剂，柱层析分离，得到产物170mg。
MS m/z(ESI)[M+H]+:343.22
步骤5制备[(7-羟基-5-(苯氧基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸
将[(7-羟基-5-(苯氧基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯(170mg)溶于甲醇(2.0mL)中，随后加入30％氢氧化钠水溶液(1.0mL)，室温搅拌，直至TLC监测原料反应完全，用稀盐酸调节pH至1-2之间，过滤，得到产物150mg。
1H NMR(400MHz,d-DMSO)δ：14.52(s,1H),12.95(brs,1H),9.71(s,1H),8.59(s,1H),7.59–7.53(m,2H),7.44–7.41(m,3H),5.83(s,1H),4.20(d,J＝5.6Hz,2H)
MS m/z(ESI):329.09
实施例2
(5-(2-氯苯氧基)-7-羟基-[1,2,4]***基[1,5-a]吡啶-8-羰基)甘氨酸的制备
按实施例1的方法，用428.1mg的2-氯苯酚替换苯酚，得到产物108.9mg。
1H NMR(400MHz,d-DMSO)δ：14.58(s,1H),12.97(brs,1H),9.71(t,J＝5.6Hz,1H),8.63(s,1H),7.75(d,J＝7.6Hz,1H),7.61(d,J＝8.0Hz,1H),7.54(t,J＝8.0Hz,1H),7.47(t,J＝7.2Hz,1H),5.89(s,1H),4.21(d,J＝5.6Hz,2H)
MS m/z(ESI)[M+H]+:363.17
实施例3
(5-(3-氯苯氧基)-7-羟基-[1,2,4]***基[1,5-a]吡啶-8-羰基)甘氨酸的制备
按实施例1的方法，用428.1mg的3-氯苯酚替换苯酚，得到产物201.6mg。
1H NMR(400MHz,d-DMSO)14.54(s,1H),12.97(brs,1H),9.72(s,1H),8.58(s,1H),7.62(s,1H),7.57(t,J＝8.4Hz,1H),7.47(d,J＝8.4Hz,1H),7.41(d,J＝8.4Hz,1H),6.10(s,1H),4.21(d,J＝5.6Hz,2H)
MS m/z(ESI)[M+H]+:363.14
实施例4
(5-(4-氯苯氧基)-7-羟基-[1,2,4]***基[1,5-a]吡啶-8-羰基)甘氨酸的制备
按实施例1的方法，用428.1mg的4-氯苯酚替换苯酚，得到产物182.1mg。
1H NMR(400MHz,d-DMSO)δ：14.54(s,1H),12.96(s,1H),9.72(t,J＝5.6Hz,1H),8.60(s,1H),7.62(d,J＝8.4Hz,2H),7.48(d,J＝8.4Hz,2H),6.02(s,1H),4.21(d,J＝5.6Hz,2H)
MS m/z(ESI)[M+H]+:363.14
实施例5
(5-(对甲苯氧基)-7-羟基-[1,2,4]***基[1,5-a]吡啶-8-羰基)甘氨酸的制备
按实施例1的方法，用356.9mg的4-甲基苯酚替换苯酚，得到产物87.7mg。
1H NMR(400MHz,d-DMSO)δ：14.51(s,1H),12.95(s,1H),9.69(t,J＝5.6Hz,1H),8.59(s,1H),7.37(d,J＝8.4Hz,2H),7.31(d,J＝8.4Hz,2H),5.77(s,1H),4.20(d,J＝5.6Hz,2H),2.37(s,3H)
MS m/z(ESI)[M+H]+:343.16
实施例6
(5-(对甲氧基苯氧基)-7-羟基-[1,2,4]***基[1,5-a]吡啶-8-羰基)甘氨酸的制备
按实施例1的方法，用(409.2mg)4-甲氧基苯酚替换苯酚，得到产物223.7mg。
1H NMR(400MHz,d-DMSO)δ：14.51(s,1H),12.96(s,1H),9.70(t,J＝5.6Hz,1H),8.60(s,1H),7.39(d,J＝8.8Hz,2H),7.11(d,J＝8.8Hz,2H),5.72(s,1H),4.21(d,J＝5.6Hz,2H),3.82(s,3H)
MS m/z(ESI)[M+H]+:359.22
实施例7
(5-(3-吗啉苯氧基)-7-羟基-[1,2,4]***基[1,5-a]吡啶-8-羰基)甘氨酸的制备
按实施例1的方法，用(590mg)3-吗啉苯酚替换苯酚，得到产物110.7mg。
1H NMR(400MHz,d-DMSO)δ：14.51(s,1H),12.95(brs,1H),9.70(t,J＝5.2Hz,1H),8.59(s,1H),7.39(d,J＝8.0Hz,2H),6.99(d,J＝12.0Hz,2H),6.80(d,J＝7.6Hz,2H),5.82(s,1H),4.21(d,J＝5.6Hz,2H),3.73(t,J＝4.8Hz,4H),3.18(t,J＝4.8Hz,4H)
MS m/z(ESI)[M+H]+:414.23
实施例8
(5-(4-氟苯氧基)-7-羟基-[1,2,4]***基[1,5-a]吡啶-8-羰基)甘氨酸的制备
按实施例1的方法，用(369.6mg)4-氟苯酚替换苯酚，得到产物239.3mg。
1H NMR(400MHz,d-DMSO)14.53(s,1H),12.98(brs,1H),9.71(s,1H),8.60(s,1H),7.53–7.49(m,2H),7.43–7.38(m,2H),5.86(s,1H),4.20(d,J＝5.6Hz,2H)
MS m/z(ESI)[M+H]+:347.14
实施例9
(5-(丙氧基)-7-羟基-[1,2,4]***基[1,5-a]吡啶-8-羰基)甘氨酸的制备
按实施例1的方法，用(2ml)正丙醇替换苯酚，得到产物20.1mg。
1H NMR(400MHz,d-DMSO)14.51(s,1H),12.92(brs,1H),9.65(t,J＝5.6Hz,1H),8.47(s,1H),6.44(s,1H),4.39(t,J＝6.4Hz,2H),4.18(d,J＝5.6Hz,2H),1.91–1.82(m,2H),1.03(t,J＝7.2Hz,3H)
MS m/z(ESI)[M+H]+:295.12
实施例10
[(7-羟基-5-(苯乙炔基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸的制备
步骤1制备7-羟基-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯
在反应瓶中，将7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(15g)溶于甲醇和四氢呋喃的混合溶液中(25mL/50mL)，并在氢气的环境下室温搅拌，直至TLC监测原料反应完全，停止反应。过滤除去溶液中的钯碳，然后将滤液减压浓缩，得到粗产物11.7g。
MS m/z(ESI):[M+H]+:236.24
步骤2制备7-(特戊酰氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯
将7-羟基-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(10.7g)置于反应瓶中并加入四氢呋喃(65mL)，然后依次加入三乙胺(8.0mL)，特戊酰氯(9.1g)。置换三次氮气并密封反应瓶。将反应混合物加热至60℃并搅拌过夜。直至TLC监测原料反应完全，停止反应。待反应液冷却至室温后，反应液用乙酸乙酯萃取，饱和碳酸氢钠水溶液，饱和氯化铵水溶液，饱和食盐水依次冲洗，而后减压浓缩，得到黄色固体12.0g。
MS m/z(ESI):[M+H]+:320.36
步骤3制备5-碘-7-(特戊酰氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯
将7-(特戊酰氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(10.0g)溶于四氢呋喃(50mL)溶液中，然后加入碘单质(8.75g)，并将反应温度保持在-60℃之下。5分钟后分批加入六甲基二硅基锂(62.7mL，1.0M)，并搅拌直至TLC监测原料反应完全。随后加入盐酸乙酸乙酯溶液淬灭反应，乙酸乙酯萃取，亚硫酸钠水溶液洗涤。分离有机相，并使用饱和氯化铵水溶液，饱和碳酸氢钠水溶液，饱和食盐水依次洗涤。分离有机相并减压浓缩，粗产物柱层析得产物5.9g。
1H NMR(400MHz,CDCl3)δ：8.36(d,J＝5.2Hz,1H),7.45(d,J＝5.2Hz,1H),2.31(s,6H)
MS m/z(ESI):[M+H]+:446.26
步骤4制备5-(苯乙炔基)-7-羟基-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯
将5-碘-7-(特戊酰氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(5.9g)，碘化亚铜(70mg)， Pd(dppf)Cl2(285mg)，四氢呋喃(30mL)，三乙胺(6.6g)，苯乙炔(2.1g)依次加入反应瓶中。置换氮气三次，升温至50℃反应，直至TLC监测原料反应完全，加入氨水猝灭反应。乙酸乙酯萃取，分离有机相。氨水层用盐酸洗涤，乙酸乙酯萃取，随后合并有机相，减压浓缩，柱层析纯化，得红色固体1.9g。
MS m/z(ESI):[M+H]+:336.36
步骤5制备5-(苯乙炔基)-7-羟基-[1,2,4]***并[1,5-a]吡啶-8-甲酸
将5-(苯乙炔基)-7-羟基-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(1.8g)溶于体积比为2：1的甲苯和乙酸乙酯的混合溶液中(24mL)，然后加入甲磺酸(2.1g)并搅拌，保持反应温度在60-70℃之间。直至TLC监测原料反应完全，停止反应。待反应液冷却至室温后，加入乙酸乙酯(10mL)，析出大量固体，过滤得到绿色固体。随后将固体用少量N,N-二甲基乙酰胺溶解，并往体系中加入乙酸乙酯，析出固体，过滤得粗产物1.0g。
MS m/z(ESI):[M+H]+:280.26
步骤6制备[(7-羟基-5-(苯乙炔基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯
在反应瓶A中，将5-(苯乙炔基)-7-羟基-[1,2,4]***并[1,5-a]吡啶-8-甲酸(0.8g)溶于二氯甲烷(20mL)中，滴加草酰氯(0.76g)，室温搅拌。在反应瓶B中，将甘胺酸甲酯盐酸盐(0.68g)，二氯甲烷(20mL)，三乙胺(3.0mL)依次加入，并在0℃下搅拌。TLC监测反应瓶A中得原料反应完全，停止反应瓶A中的搅拌，并将反应瓶A中的物料加入反应瓶B中，0℃下搅拌直至TLC监测原料反应完全，用水淬灭反应。二氯甲烷萃取，饱和氯化铵水溶液，饱和碳酸氢钠水溶液依次洗涤有机相，分离合并有机相，减压浓缩后，柱层析分离，得黄色固体0.8g。
MS m/z(ESI):[M+H]+:351.33
步骤7制备[(7-羟基-5-(苯乙炔基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸
将[(7-羟基-5-苯乙炔基[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯(0.8g)溶于乙醇(10mL)中，随后加入氢氧化钠水溶液(18mL,2.0M)，室温搅拌，直至TLC监测原料反应完全，用稀盐酸调节pH至4-5，过滤得淡黄色固体0.42g。
1H NMR(400MHz,d-DMSO)δ：14.33(s,1H),13.04(s,1H),9.90(s,1H),8.64(s,1H),7.74–7.72(m,2H),7.61–7.53(m,3H),7.37(s,1H),4.24(d,J＝5.6Hz,2H)
MS m/z(ESI):[M+H]+:337.31
实施例11
[(7-羟基-5-(苯乙烯基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸的制备
步骤1制备5-(苯乙烯基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯
将5-碘-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(500mg)，Pd(PPh3)2Cl2(70.2mg)，碳酸钠(360mg)，苯乙烯硼酸(200mg)溶于体积比为1:1的乙二醇二甲醚和脱气水的混合溶剂(30mL)中，并置换氮气三次。随后在80℃下搅拌，直至TLC监测原料反应完全，停止加热。待反应液冷却至室温后，用乙酸乙酯萃取，饱和食盐水洗涤有机相。分离有机相，减压浓缩，柱层析分，得到粗产物340mg。
步骤2制备5-(苯乙烯基)-7-羟基-[1,2,4]***并[1,5-a]吡啶-8-甲酸
将5-(苯乙烯基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(290mg)溶于二氯甲烷(10mL)溶液中，并冷却至-65℃，然后将三溴化硼二氯甲烷溶液(3.4mL,1.0M)加入反应体系中并搅拌，直至TLC监测原料反应完全。停止反应，将溶液减压浓缩除去，随后将残留物加入水(10mL)和甲醇(3.0mL)得混合溶剂中室温搅拌1小时，过滤得到固体250mg。
MS m/z(ESI):[M+H]+:282.04
步骤3制备[(7-羟基-5-(苯乙烯基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯
将5-(苯乙烯基)-7-羟基-[1,2,4]***并[1,5-a]吡啶-8-甲酸(143mg),N,N-二甲基甲酰胺(10mL)，DIPEA(329mg),PyBOP(395mg),甘胺酸甲酯盐酸盐(178mg)依次加入反应瓶中，室温搅拌过夜，过滤出固体，得到粗产物50mg。
MS m/z(ESI):[M+H]+:353.28
步骤4制备[(7-羟基-5-(苯乙烯基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸
将[(7-羟基-5-(苯乙烯基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯(50mg)溶于甲醇(2.0mL)中，随后加入30％氢氧化钠水溶液(1.0mL)，室温搅拌，直至TLC监测原料反应完全，用稀盐酸调节pH至1-2之间，过滤，得到产物10mg。
1H NMR(400MHz,d-DMSO)δ：14.26(s,1H),12.98(s,1H),9.90(t,J＝16.4Hz,1H),8.63(s,1H),8.22(d,J＝16.4Hz,1H),7.76–7.71(m,3H),7.50–7.40(m,4H),4.23(d,J＝5.6Hz,2H)
MS m/z(ESI):[M+H]+:339.21
实施例12
[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸的制备
步骤1制备5-(3,4-二氢萘-2-基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯
将5-碘-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(5.40g)，Pd(PPh3)2Cl2(800mg)，碳酸钾(4.20g)，3,4-二氢萘基-2-硼酸片呐醇酯(3.10g)溶于体积比为2:1的乙二醇二甲醚和脱气水的混合溶剂(30mL)中，并置换氮气三次。随后在80℃下搅拌，直至TLC监测原料反应完全，停止加热。待反应液冷却至室温后，用乙酸乙酯萃取，饱和食盐水洗涤有机相。分离有机相，减压浓缩，柱层析分，得到粗产物3.30g。
步骤2制备5-(3,4-二氢萘-2-基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-甲酸
将5-(3,4-二氢萘-2-基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(3.30g)溶于体积比为3:1的甲苯与乙酸乙酯的混合溶液(28mL)，然后将甲磺酸(2.80g)加入反应体系中并搅拌，直至TLC监测原料反应完全，向反应体系中加入乙酸乙酯(20.0mL)搅拌析晶，抽滤、收集固体。随后用DMF/H2O(20.0mL/40.0mL)打浆，搅拌析晶，抽滤、收集固体，得到淡青色固体2.70g。
步骤3制备[5-(3,4-二氢萘-2-基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯
将5-(3,4-二氢萘-2-基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(2.70g),N,N-二甲基甲酰胺(20.0mL)，HOBt(1.10g),EDCI(1.40g),甘氨酸甲酯盐酸盐(0.90g)，三乙胺(1.50g)依次加入反应瓶中，室温搅拌，直至TLC监测原料反应完全，向反应体系中加入水(30.0mL)搅拌析晶，抽滤、收集固体、干燥得类白色固体(2.2g)。
步骤4制备[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯
将[5-(3,4-二氢萘-2-基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸(1.0g)溶于四氢呋喃溶液(8.0mL)中，随后加入钯碳(300mg)，置换氢气，室温搅拌，直至TLC监测原料反应完全，硅藻土过滤，减压浓缩，随后用异丙醚/正己烷(1.5mL/1.5mL)打浆，过滤，得类似白色固体约500mg。
步骤5制备[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸
将[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯(0.20g)溶于乙醇溶液(2.0mL)中，随后加入氢氧化钠水溶液(2.0mL,4.0M)，室温搅拌，直至TLC监测原料反应完全，用稀盐酸调节pH至6-7之间，过滤，得到灰白色固体200mg。
1H NMR(400MHz,d-DMSO)δ：14.37(brs,1H),9.93(s,1H),8.56(s,1H),7.13(s,4H),6.78(s,1H),4.12(d,J＝4.0Hz,2H),3.81–3.76(m,1H),3.26–2.86(m,4H),2.26–2.05(m,2H),
MS m/z(ESI):[M+H]+:367.32
实施例13[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸手性异构体A的制备
步骤1制备5-(3,4-二氢萘-2-基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯
将5-碘-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(5.40g)，Pd(PPh3)2Cl2(800mg)，碳酸钠(4.20g)，3,4-二氢萘基-2-硼酸片呐醇酯(3.10g)溶于体积比为2:1的乙二醇二甲醚和脱气水的混合溶剂(30mL)中，并置换氮气三次。随后在80℃下搅拌，直至TLC监测原料反应完全，停止加热。待反应液冷却至室温后，用乙酸乙酯萃取，饱和食盐水洗涤有机相。分离有机相，减压浓缩，柱层析分，得到粗产物3.30g。
步骤2制备5-(3,4-二氢萘-2-基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-甲酸
将5-(3,4-二氢萘-2-基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(3.30g)溶于体积比为3:1的甲苯与乙酸乙酯的混合溶液(28mL)，然后将甲磺酸(2.80g)加入反应体系中并搅拌，直至TLC监测原料反应完全，向反应体系中加入乙酸乙酯(20.0mL)搅拌析晶，抽滤、收集固体。随后用DMF/H2O(20.0mL/40.0mL)打浆，搅拌析晶，抽滤、收集固体，得到淡青色固体2.70g。
步骤3制备[5-(3,4-二氢萘-2-基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯
将5-(3,4-二氢萘-2-基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羧酸叔丁酯(2.70g),N,N-二甲基甲酰胺(20.0mL)，HoBt(1.10g),EDCI(1.40g),甘胺酸甲酯盐酸盐(0.90g)依次加入反应瓶中，室温搅拌，直至TLC监测原料反应完全，向反应体系中加入水(30.0mL)搅拌析晶，抽滤、收集固体、干燥得类白色固体(2.2g)。
步骤4制备[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯
将[5-(3,4-二氢萘-2-基)-7-(苄氧基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸(1.0g)溶于四氢呋喃溶液(8.0mL)中，随后加入钯碳(300mg)，室温搅拌，直至TLC监测原料反 应完全，硅藻土过滤，减压浓缩，随后用异丙醚/正己烷(1.5mL/1.5mL)打浆，过滤，得类似白色固体约500mg。
步骤5制备[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯手性异构体A(乙酸甲酯手性异构体A)
将前一步合成得到的产物进行手性拆分，拆分5g[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯。拆分条件：(手性柱：(S,S)Whelk-O1,5*25厘米,10微米；流动相A:CO2，流动相B:ACN:IPA＝1:1；流速：200毫升/分钟；梯度：50％-50％；B走12分钟；波长220纳米；出峰时间：8.50分钟；样品溶液：甲醇：二氯甲烷＝1:1；进样体积：2ML；进样针数：50)得到手性异构体A:白色固体(2.060克，收率41.2％)
步骤6制备[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸手性异构体A
将[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯手性异构体A(0.20g)溶于乙醇溶液(2.0mL)中，随后加入氢氧化钠水溶液(1.0mL,4.0M)，室温搅拌，直至TLC监测原料反应完全，用稀盐酸调节pH至1-2之间，过滤，得到灰白色固体200mg。
1H NMR(400MHz,d-DMSO)δ：14.37(brs,1H),9.93(s,1H),8.56(s,1H),7.13(s,4H),6.78(s,1H),4.12(d,J＝4.0Hz,2H),3.81–3.76(m,1H),3.26–2.86(m,4H),2.26–2.05(m,2H),
MS m/z(ESI):[M+H]+:367.32
[α]D20＝+37.384(c 1.01,DMF)。
实施例14[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸手性异构体B的制备
步骤1制备[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯手性异构体B
将合成得到的[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯进行手性拆分，拆分5g。拆分条件：(手性柱：(S,S)Whelk-O1,5*25厘米,10微米；流动相A:CO2，流动相B:ACN:IPA＝1:1；流速：200毫升/分钟；梯度：50％-50％；B走12分钟；波长220纳米；(OB出峰时间)：10.09分钟；样品溶液：甲醇：二氯甲烷＝1:1；进样体积：2ML；进样针数：50)得到手性异构体B(乙酸甲酯手性异构体B):白色固体(1.997克，收率39.94％)
步骤2制备[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸手性异构体B
将[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯手性异构体B(0.20g)溶于乙醇溶液(2.0mL)中，随后加入氢氧化钠水溶液(1.0mL,4.0M)，室温搅拌，直至TLC监测原料反应完全，用稀盐酸调节pH至1-2之间，过滤，得到灰白色固体200mg。
1H NMR(400MHz,d-DMSO)δ：14.37(brs,1H),9.93(s,1H),8.56(s,1H),7.13(s,4H),6.78(s,1H),4.12(d,J＝4.0Hz,2H),3.81–3.76(m,1H),3.26–2.86(m,4H),2.26–2.05(m,2H),
MS m/z(ESI):[M+H]+:367.32
[α]D20＝–36.601(c 1.01,DMF)。
实施例15生物学测试
1、PHD2酶活抑制检测
1.1试剂及耗材
PHD2酶：从Active motif处购买；
α-酮戊二酸钠盐：从Sigma处购买；
FITC-HIF1α：从GL处购买；
多孔板NuncTM384：从Thermo Scientific处购买。
1.2试验方法
(1)配制1×Assay buffer(分析缓冲液)；
(2)化合物浓度梯度的配制：受试化合物测试浓度为10μM起始，3倍稀释，10个浓度，复孔测试；在384孔板中稀释成100倍终浓度的溶液，然后用非接触式声波移液***Echo550转移100nL到384反应板中备用。阴性对照孔和阳性对照孔中分别加100nL的100％DMSO；
(3)用1×Assay buffer配制2倍终浓度的酶溶液；
(4)在化合物孔和阳性对照孔分别加5μL的2倍终浓度的酶溶液；
(5)在阴性对照孔中加5μL的1×Assay buffer；
(6)1000rpm离心30秒，振荡混匀后孵育15min；
(7)用1×Assay buffer配制2倍终浓度的tracer溶液，加入5.0μL的2倍终浓度的tracer溶液，起始反应；
(8)将384孔板1000rpm离心30秒，振荡混匀60min，从Envision多功能酶标仪(Multimode  PlateReader，Perkin Elmer)上读数得到mP值，导出数据并进行处理，得到待测化合物的抑制率，化合物编号1-12分别对应实施例1-12制备的化合物，结果如下表所示：
表1
由上表可知，本发明实施例化合物具有良好的HIF-脯氨酰羟化酶抑制活性，可见，化合物1-12抑制活性好。
2、本发明化合物的体外***(EPO)诱导活性实验
使用来自人肝癌的细胞株Hep3B(ATCC)，对本发明实施例10-12的化合物的体外***(EPO)诱导活性进行评价。将Hep3B细胞在37℃，10％胎牛血清(FBS)的存在下，在EMEM培养基(Eagle's Minimum Essential Medium)中培养。实验步骤如下：
(1)细胞准备：在96孔板中接种细胞，以每孔2*10^4，每孔100μL的量进行铺板；
(2)化合物浓度梯度的配制：100μM,20μM,2复孔检测。在96孔板中配置200倍终浓度的溶液，使用细胞培养基再将化合物稀释200/3倍，然后吸取50μL对细胞进行给药。阴性对照孔加50μL含DMSO的培养液使其终浓度含5‰DMSO，阳性对照孔加50μL的最高浓度阳性化合物，37℃孵育24小时；
(3)以每孔约400μL的1X Wash Buffer清洗反应板两次；
(4)向适当的孔中加入100μL稀释好的的standard(包括标准空白对照)；
(5)向样品孔中加入50μL样品和50μL Sample Diluent；
(6)向所有孔中加入50μL 1X Biotin Conjugated Antibody，室温孵育1小时；
(7)以每孔约400μL 1X Wash Buffer清洗6次反应板；
(8)每孔加入100μL 1X Streptavidin-HRP。室温孵育15分钟；
(9)以每孔约400μL 1X Wash Buffer清洗6次反应板；
(10)每孔加入100μL TMB Substrate Solution。室温孵育10分钟；
(11)每孔加入100μL Stop Solution；
(12)用EnSight读取OD450。
各化合物的EPO诱导活性表示为半数最大效应浓度(EC50)。实验结果如下表所示：
表2
由上表可知，本发明的化合物具有较高的EPO诱导活性，可见，实施例10-14得到化合物的诱导活性好。
实施例16化合物药代动力学评价
1.试验目的
测定SD大鼠静注或灌胃给予化合物后，采用LC-MS/MS方法检测血浆中相关化合物的浓度，初步评价实施例13及14制备得到的化合物在大鼠体内药动学及其绝对生物利用度。
2.品系：Sprague Dawley大鼠，性别：雄，体重：200-250g
来源：浙江维通利华实验动物技术有限公司
3.实验操作
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征，实验中候选化合 物配成澄清溶液，给予大鼠单次静脉注射及灌胃给药。静注溶媒为一定比例的N,N-二甲基乙酰胺(DMA)与10％Solutol HS15溶液，口服溶媒为一定比例的羧甲基纤维素钠(CMC)混悬液。动物给药后5min、15min、30min、1h、2h、4h、6h、8h、10h和24h各采集血样至K2EDTA抗凝管中，于冰上暂存至离心。
实验结果：
由上表可知，本发明实施例13和14制备得到的化合物具有良好的PK性质，可见，实施例13和14制备得到的化合物半衰期明显更长，体内暴露量更高。
实施例17化合物药理学评价
1.实验目的
本实验的目的是评价实施例12、13、14制备得到的化合物持续给药对SD大鼠EPO(***)的影响。
2.动物
种属：大鼠
品系：SD(Sprague Dawley)
周龄及体重：8周，体重200-220g
性别：雄性
动物来源：北京维通利华实验动物技术有限公司
3.受试化合物和阳性对照药信息
阳性药：Enarodustat
描述：日本批准上市的商品化药物
规格和含量：2mg JTZ-951(Enarodustat)，140粒/盒
4.实验方案：
SD大鼠经过适应性饲养一周后，随机分为3组，每组6只，分别为空白组、阳性药组(Enarodustat)和实施例12化合物组。Enarodustat使用研钵碾碎药片后，定量加入0.5％的甲基纤维素，磁力搅拌混匀；实施例12制备得到的化合物称量后定量加入0.5％的甲基纤维 素，磁力搅拌混匀。所有化合物的终浓度均为0.3mg/mL，给药体积为10mL/kg。每日给药一次，连续14天，第14天给药后4h取血测EPO水平。
5.结果及分析
结果显示，给药14天后阳性药Enarodustat和实施例12、13、14制备得到的化合物组大鼠血清中EPO的水平显著增加，且实施例12、13、14制备得到的化合物给药后血浆中的EPO水平显著高于阳性药Enarodustat。
表3给药14天后EPO水平(pg/mL)
备注：2904.6pg/mL为测量上限。
综上所述，实施例12、13、14制备得到的化合物能够显著增加SD大鼠EPO水平，且整体效果显著优于阳性药Enarodustat，表现出优秀的药理学作用。
实施例18实施例13的乙酸甲酯手性异构体A化合物手性构型测定
1、化合物制备
参照实施例13中，[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯手性异构体A(步骤五)的制备方法，通过手性拆分的方法得到乙酸甲酯手性异构体A，该异构体为实施例13中最终产物的前一步化合物(步骤五产物)。
2、单晶培养
称取约3-7mg乙酸甲酯手性异构体A于小瓶中，在50℃条件下，边搅拌边逐步加入乙腈，直至药液刚好澄清或接近澄清。趁热过滤，将滤液置于干净的小瓶中，通过Crystal 16仪器进行程序降温，先以0.01℃/min的速率从50℃降至30℃，然后在30℃条件下保持约2天。
通过降温结晶的方法，从乙腈中得到了针状单晶，如图1所示，并将其用于X射线单晶衍射分析。
3、仪器和参数
乙酸甲酯手性异构体A的单晶数据是通过Rigaku XtaLAB Synergy DW衍射仪，在180K条件下，使用Cu Kα射线收集得到的。衍射数据使用CrysAlisPro程序进行数据还原和吸收校正，并使用SHELXT程序通过对偶空间算法解析该结构。所有非氢原子从差值傅里叶图直接定位，氢原子被填充在母原子上。使用SHELXL程序，基于F2全矩阵最小二乘法来完成对最终结构的精修。
4、X射线衍射分析
乙酸甲酯手性异构体A的单晶结构属于单斜晶系，P21空间群，单晶的分子式为C20H20N4O4。每个不对称单元中有一个乙酸甲酯手性异构体A分子，每个晶胞中包含两个不对称单元。手性碳的绝对构型为“R”。
精修的单晶结构如图2、图3和图4所示。晶体结构参数总结在表4中，原子坐标、各向异性位移参数、扭转角、氢键、键长和键角数据详见表5至表11。根据单晶结构计算得到的XRPD图与单晶样品的测试结果基本一致，但峰位置有一定偏移，这可能是由于单晶数据的收集是在180K条件下进行的，而实验测定的XRPD图谱是在室温下得到的所致(图5)。
表4.乙酸甲酯手性异构体A的晶体结构参数

表5.乙酸甲酯手性异构体A的原子坐标(×104)和等效各向同性位移参数
表6.乙酸甲酯手性异构体A的各向异性位移参数

表7.乙酸甲酯手性异构体A的键长

表8.乙酸甲酯手性异构体A的键角
表9.乙酸甲酯手性异构体A的扭转角

表10.乙酸甲酯手性异构体A的氢键
表1.乙酸甲酯手性异构体A的原子坐标(×104)和各向同性位移参数

5、分析方法
5.1偏光显微镜(PLM)
采用ECLIPSE LV100POL(Nikon,JPN)偏光显微镜进行PLM分析。将少量的样品平铺至载玻片上，滴入香柏油将样品分散后，加上盖玻片。随后，将样品置于显微镜下用10倍物镜观察。
5.2 X射线粉末衍射(XRPD)
使用X射线衍射仪对固体样品进行检测。将样品平铺于零背景单晶硅样品盘上，将样品轻压铺平后，根据表12中的参数进行分析。
表12.XRPD测试参数
通过上述单晶结构解析可知，该乙酸甲酯手性异构体A的手性构型为“R”构型，如图6所示。由此可知，实施例13中，使用氢氧化钠水溶液脱除甲酯得到羧酸产物时，不改变已产生的手性构型，故推测可知，实施例13中产物[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸手性异构体A的手性构型为“R”构型。
实施例19实施例14的乙酸甲酯手性异构体B化合物手性构型测定
1、化合物制备
参照实施例14中，[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸甲酯手性异构体B(步骤一)的制备方法，通过手性拆分的方法得到乙酸甲酯手性异构体B，该异构体为实施例14中最终产物的前一步化合物。
2、单晶培养
称取适量的乙酸甲酯手性异构体B样品于小瓶中，在室温条件下，边搅拌边逐步加入二甲基亚砜，直至药液刚好澄清或接近澄清。过滤，将滤液置于干净的小瓶中，加盖扎孔，将小瓶静置于室温条件下缓慢挥发。
通过缓慢挥发的方法，从二甲基亚砜中得到了针状单晶，如图7所示，并将其用于X射线单晶衍射分析。
3、仪器和参数
乙酸甲酯手性异构体B的单晶数据是通过Rigaku XtaLAB Synergy DW衍射仪，在180K条件下，使用Cu Kα射线收集得到的。衍射数据使用CrysAlisPro程序进行数据还原和吸收校正，并使用SHELXT程序通过对偶空间算法解析该结构。所有非氢原子从差值傅里叶图直接定位，氢原子被填充在母原子上。使用SHELXL程序，基于F2全矩阵最小二乘法来完成对最终结构的精修。
4、X射线衍射分析
乙酸甲酯手性异构体B的单晶结构属于单斜晶系，P21空间群，单晶的分子式为C20H20N4O4。每个不对称单元中有一个乙酸甲酯手性异构体B分子，每个晶胞中包含两个不对称单元。手性碳的绝对构型为“S”。
精修的单晶结构如图8、图9和图10所示。晶体结构参数总结在表13中，原子坐标、各向异性位移参数、扭转角、氢键、键长和键角参数总结于表14至表20。单晶样品实验测定所得的XRPD式样比计算所得的XRPD图谱多峰；可能单晶测试后溶剂已接近挥干，是溶剂挥发的过程中又有其他晶型析出所致(图11)。
表13.乙酸甲酯手性异构体B的晶体结构参数

表14.乙酸甲酯手性异构体B的原子坐标(×104)和等效各向同性位移参数

表15.乙酸甲酯手性异构体B的各向异性位移参数
表16.乙酸甲酯手性异构体B的键长
表17.乙酸甲酯手性异构体B的键角

表18.乙酸甲酯手性异构体B的扭转角
表19.乙酸甲酯手性异构体B的氢键
表20.乙酸甲酯手性异构体B的氢原子坐标(×104)和各向同性位移参数

5、分析方法
5.1偏光显微镜(PLM)
采用ECLIPSE LV100POL(Nikon,JPN)偏光显微镜进行PLM分析。将少量的样品平铺至载玻片上，滴入香柏油将样品分散后，加上盖玻片。随后，将样品置于显微镜下用物镜观察。
5.2 X射线粉末衍射(XRPD)
使用X射线衍射仪对固体样品进行检测。将样品平铺于零背景单晶硅样品盘上，将样品轻压铺平后，根据表21中的参数进行分析。
表21.XRPD测试参数

通过上述单晶结构解析可知，该乙酸甲酯手性异构体B的手性构型为“S”构型，如图12所示。由此可知，实施例14中，使用氢氧化钠水溶液脱除甲酯得到羧酸产物时，不改变已产生的手性构型，故推测可知，实施例14中产物[(7-羟基-5-(1,2,3,4-四氢萘-2-基)-[1,2,4]***并[1,5-a]吡啶-8-羰基)氨基]乙酸手性异构体B的手性构型为“S”构型。
实施例20实施例13及14化合物亚急性毒性试验
1.实验材料
1.1供试品
表22样品信息
1.2处方配制
用天平称取适量实施例13化合物、实施例14化合物分别置于合适的玻璃瓶中，然后在玻璃瓶中依次加入DMSO、Solutol HS-15和0.9％的生理盐水(比例为v：v：v＝5％：10％：85％)，再进行涡旋、搅拌，在搅拌过程中持续关注药物溶解情况，直至完全溶解/混悬。最后配制成浓度为0.67mg/mL的实施例13化合物实施例14化合物给药试液，现配现用。
2.实验动物
实验动物来源及数量见表23。动物房通风良好，装备空调，温度保持在20～25℃，湿度保持在40％～70％，明暗照明各12小时，动物自由进食和饮水。给药前至少适应性饲养3天，经兽医检验，体征状况良好的SD大鼠可入选本实验。
表23实验动物来源及数量
3.实验方案
3.1试验周期和剂量设置
该实验中对实验动物的任何操作均符合中华人民共和国科学技术部颁布的《实验动物管理条例》的要求。本试验设置溶媒对照组、实施例13化合物给药组、实施例14化合物给药组。实施例13化合物给药组、实施例14化合物给药组给药剂量为(10mg/kg)，每天1次，连续14天给药，空白对照组给予等量空白溶媒，给药体积均为15mL/kg，每次给药后观察动物的毒性反应症状及程度。末次给药后恢复观察7天。实验过程中自由饮水。详见表24。
表24试验剂量及分组设计
称量体重后，按以下公式计算每只SD大鼠的理论给药体积。每只SD大鼠的实际给药量和样品采集时间需详细记录在相应表格中。
3.2实验观察
在实验过程中，实验人员和兽医需对实验动物的体征和健康状况进行持续观察。动物的任何异常表现，例如疼痛、抑郁、活动减少等，需记录在实验原始记录中。如果实验动物的异常表现超过IACUC相关动物福利的文件规定，可经由兽医判断是否中止实验，并通报实验项目负责人。
3.3笼边观察
实验期间所有动物每天至少进行2次笼边观察，且在给药结束后连续观察2小时，给药过程中，若动物出现严重毒副作用或动物死亡，都应将观察结果记录在相应的表格中。观察指标包括：动物外观、行为活动、分泌物、***物、饮食情况、死亡情况(死亡数量、死亡时间、濒死前反应)等。如出现临床症状，需增加观察次数，以便详细观察动物中毒反应的症状，起始时间、严重程度、持续时间以及是否可逆。如发现动物死亡或濒死，应按照规定 及时对动物进行解剖观察。
3.4体重
每日给药前需对动物进行体重称量，连续称重14天，并将体重记录在相应表格中。并将体重记录在相应表格中。并在试验期间检测试验动物的摄食量。
3.5临床病理学
于首次给药前及末次给药结束后24小时采集约1.8～2.0mL全血进行血液学及血液生化检查，此外于末次给药结束后24小时采集血样进行凝血检查，若给药期间动物状态出现异常，血液学、凝血及血液生化检查时间则提前。采血前禁食12小时以上。
大约500μL全血置于含有EDTA-K2的抗凝管用于血液学分析：
白细胞计数(WBC)
中性粒细胞分类计数(绝对计数，NEUT；百分比，％NEUT)
淋巴细胞分类计数(绝对计数，LYM；百分比，％LYM)
单核细胞分类计数(绝对计数，MONO；百分比，％MONO)
嗜酸性粒细胞分类计数(绝对计数，EOS；百分比，％EOS)
嗜碱性粒细胞分类计数(绝对计数，BASO；百分比，％BASO)
红细胞计数(RBC)
血红蛋白(HGB)
红细胞压积(HCT)
红细胞平均体积(MCV)
平均红细胞血红蛋白含量(MCH)
平均红细胞血红蛋白浓度(MCHC)
红细胞变异系数(RDW-CV)
红细胞分布宽度标准差(RDW-SD)
血小板计数(PLT)
血小板平均分布宽度(MPV)
血小板平均体积(PDW)
血小板压积(PCT)
大约1.5mL全血置于分离胶采血管(无抗凝剂)用于血液生化学分析：
丙氨酸氨基转移酶(Alanine Aminotransferase，ALT)
天门冬氨酸氨基转移酶(Aspartate Aminotransferase，AST)
碱性磷酸酶(Alkaline Phosphatase，ALP)
白蛋白(Albumin，ALB)
总胆固醇(Cholesterol，TC)
肌酐(Creatinine，CRE)
尿素(UREA)
肌酸激酶(Creatine Phosphokinase，CK)
甘油三酯(Triglyceride，TG)
总胆红素(Total Bilirubin，TBIL)
总蛋白(Total Protein，TP)
天门冬氨酸氨基转移酶/丙氨酸氨基转移酶(AST/ALT)
球蛋白(GloⅡ)
白蛋白/球蛋白(A/GⅡ)
电解质类(K+/Na+/Cl－/Ca2+)
4.结论
本实验条件下，实施例13及14化合物未见明显胃肠道坏死发、黑胃部有出血点或胀气，该毒性低于恩那司他(Enarodustat)，具有较好的安全性。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种式(I)所示的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药:
    其中，
    R选自以下原子或基团的单元：
    L为-CH2-或-CH2O-；
    n的数值为0-2之间的整数；
    R1、R2、R3各自独立的选自为取代或未取代的烷基、环烷基、芳基、杂环基；R4选自为氢、取代或未取代的烷基、环烷基、烷氧基、芳基、杂环基。
  2. 根据权利要求1所述的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述芳基包括芳杂环。
  3. 根据权利要求1所述的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，
    L为-CH2-或-CH2O-；
    n的数值为0或1；
    R1为取代或未取代的C1-4烷基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、C1-4卤代烷基、卤素、氰基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种；
    R2为取代或未取代的C1-4烷基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、C1-4卤代烷基、卤素、氰基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种；
    R3为取代或未取代的C1-10烷基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、C1-4卤代烷基、卤素、氰基、苯基或含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种；
    R4为氢、取代或未取代的C1-10烷基、C1-10烷氧基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、C1-4卤代烷基、卤素、氰基、苯基或含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种。
  4. 根据权利要求2所述的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，
    L为-CH2-或-CH2O-；
    n的数值为0或1；
    R1为取代或未取代的苯基，所述取代基为C1-4烷基、C1-4烷氧基、C1-4卤代烷基、卤素、氰基、苯基或含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种；
    R2为取代或未取代的苯基，所述取代基为C1-4烷基、C1-4烷氧基、C1-4卤代烷基、卤素、氰基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种；
    R3为取代或未取代的C1-10烷基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、卤素、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种；
    R4为氢、取代或未取代的C1-10烷基、C1-10烷氧基、苯基、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、卤素、含氧和/或氮的5-6元芳杂环基、含氧和/或氮的5-6元杂环基中的至少一种。
  5. 根据权利要求3所述的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，
    n的数值为0或1；
    R1为取代或未取代的苯基，所述取代基为C1-4烷基、C1-4烷氧基、卤素、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-4烷基、C1-4烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基为相对于母核结构对位取代，卤素相对于母核结构为邻位、间位或对位取代；
    R2为取代或未取代的苯基，所述取代基为C1-4烷基、C1-4烷氧基、卤素或含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-4烷基、C1-4烷氧基和含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对 于母核结构为邻位、间位或对位取代；
    R3为取代或未取代的C1-5烷基、苯基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、卤素、含氧和/或氮的5-6元芳杂环或含氧和/或氮的5-6元杂环基；优选地，所述C1-4烷基、C1-4烷氧基、含氧和/或氮的5-6元芳杂环、或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代；
    R4为氢、取代或未取代的C1-5烷基、C1-5烷氧基、苯基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基，所述取代基为C1-4烷基、C1-4烷氧基、卤素、含氧和/或氮的5-6元芳杂环或含氧和/或氮的5-6元杂环基；优选地，所述C1-4烷基、C1-4烷氧基、含氧和/或氮的5-6元芳杂环、或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代；
    优选地，
    n的数值为0或1；
    R1为取代或未取代的苯基，所述取代基为C1-3烷基、C1-3烷氧基、卤素、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-3烷基、C1-3烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基为相对于母核结构对位取代，卤素为邻位、间位或对位取代；
    R2为取代或未取代的苯基，所述取代基为C1-3烷基、C1-3烷氧基、卤素、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-3烷基、C1-3烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基为相对于母核结构对位取代，卤素相对于母核结构为邻位、间位或对位取代；
    R3为取代或未取代的C1-5烷基、苯基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基，所述取代基为C1-3烷基、C1-3烷氧基、卤素、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-3烷基、C1-3烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代；
    R4为氢、取代或未取代的C1-5烷基、C1-5烷氧基、苯基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基，所述取代基为C1-3烷基、C1-3烷氧基、卤素、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-3烷基、C1-3烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对 于母核结构为邻位、间位或对位取代。
  6. 根据权利要求5所述的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，
    n的数值为0或1；
    R1为取代或未取代的苯基，所述取代基为C1-2烷基、C1-2烷氧基、F、Cl、Br、I、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-2烷基、C1-2烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，F、Cl、Br、I相对于母核结构为邻位、间位或对位取代；
    R2为取代或未取代的苯基，所述取代基为C1-2烷基、C1-2烷氧基、F、Cl、Br、I、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-2烷基、C1-2烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，F、Cl、Br、I相对于母核结构为邻位、间位或对位取代；
    R3为取代或未取代的C1-4烷基、苯基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基，所述取代基为C1-2烷基、C1-2烷氧基、F、Cl、Br、I、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-2烷基、C1-2烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代；
    R4为氢、取代或未取代的C1-4烷基、C1-4烷氧基、苯基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基，所述取代基为C1-2烷基、C1-2烷氧基、F、Cl、Br、I、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述C1-2烷基、C1-2烷氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代；
    优选地，
    n的数值为0或1；
    R1为取代或未取代的苯基，所述取代基为甲基、甲氧基、F、Cl、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基；优选地，所述甲基、甲氧基、含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代，F、Cl相对于母核结构为邻位、间位或对位取代；
    R2为取代或未取代的苯基，所述取代基为甲基、甲氧基、F、Cl或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、甲氧基和含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代，F、Cl相对于母核结构为邻位、间位或对位取代；
    R3为取代或未取代的C1-3烷基、苯基、含氧和/或氮的5-6元芳杂环，所述取代苯基的取代基为甲基、甲氧基、F、Cl或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、甲氧基和含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代；
    R4为氢、取代或未取代的C1-3烷基、C1-3烷氧基、苯基、含氧和/或氮的5-6元芳杂环，所述取代苯基的取代基为甲基、甲氧基、F、Cl或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、甲氧基和含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代；
    进一步优选地，
    n的数值为0或1；
    R1为取代或未取代的苯基，所述取代基为甲基或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代；
    R2为取代或未取代的苯基，所述取代基为甲基或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代；
    R3为取代或未取代的C1-3烷基、苯基、含氧和/或氮的5-6元芳杂环，所述取代基为甲基、甲氧基、F、Cl或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、甲氧基和含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代；
    R4为氢、取代或未取代的C1-3烷基、C1-3烷氧基、苯基、含氧和/或氮的5-6元芳杂环，所述取代基为甲基、甲氧基、F、Cl或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、甲氧基和含氧和/或氮的5-6元芳杂环相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代；
    更进一步优选地，
    n的数值为0或1；
    R1为苯基；
    R2为苯基；
    R3为取代或未取代的C1-3烷基、苯基、含氧和/或氮的5-6元芳杂环，所述取代基为甲基、甲氧基、卤素或含氧和/或氮的5-6元芳杂环；优选地，所述甲基、甲氧基、含氧和/或氮的5-6元芳杂环基或含氧和/或氮的5-6元杂环基相对于母核结构为对位取代，卤素相对于母核结构为邻位、间位或对位取代；
    R4为氢。
  7. 根据权利要求6所述的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物选自以下结构：
    优选地，所述化合物选自以下结构：

    进一步优选地，所述化合物选自以下结构：
    更进一步优选地，所述化合物选自以下结构：
  8. 权利要求1-7任一项所述化合物的制备方法，其特征在于，包括以下四种合成路线：
    路线1：
    路线2：
    路线3：
    路线4：
    其中，R1、R2、R3具有与所引用权利要求相同的定义。
  9. 一种药物组合物，其特征在于，包含式(I)所示的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，以及一种或多种可药用载体、稀释剂、赋形剂。
  10. 式(I)所示的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，或者上述药物组合物在制备用于通过抑制辅氨酰 羟化酶来治疗抑制辅氨酰羟化酶介导的疾病的药物中的用途；优选地，所述抑制辅氨酰羟化酶介导的疾病为贫血、局部缺血、缺氧；进一步优选为肾性贫血。
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