Prolyl hydroxylase inhibitors and uses thereof

Abstract

The present invention discloses a prolyl hydroxylase inhibitor, which belongs to the field of pharmaceutical technology. The present invention provides a pyridinotriazole compound having the following structure: The compound has high prolyl hydroxylase inhibitory activity and EPO-inducing activity, and can effectively treat and prevent HIF-related diseases and / or EPO-related diseases, providing a new concept for treating diseases such as anemia, ischemia, and hypoxia. TIFF2025529533000075.tif42170

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to pyridinotriazole compounds having prolyl hydroxylase inhibitory activity and pharmaceutical compositions thereof, as well as to methods for preparing the same and their pharmaceutical uses. [Background technology]

[0002] Under conditions such as anemia, trauma, and tissue necrosis or loss, tissues and cells are often hypoxic. Hypoxia induces the expression of various transcription factors involved in angiogenesis, iron and glucose metabolism, and cell growth and proliferation. Among these, hypoxia-inducible factors (HIFs) are transcription factors initiated by hypoxic somatic cells and respond to cellular hypoxia by mediating a series of gene regulatory events in living cells. HIFs are heterodimers containing an oxygen-regulated α-subunit (HIFα) and a constitutively expressed β-subunit (HIFβ / ARNT). In oxygenated (normoxic) cells, the HIFα subunit is rapidly degraded by ubiquitination mediated by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Under hypoxic conditions, HIFα is not degraded, and the active HIFα / β complex accumulates in the cell nucleus, activating the expression of various genes, including glycolytic enzymes, glucose transport proteins, erythropoietin (EPO), and vascular endothelial growth factor (VEGF).

[0003] Erythropoietin (EPO) is a naturally occurring hormone produced in response to HIFα, stimulating the production of red blood cells (red blood cells), which carry oxygen throughout the body. EPO is normally secreted by the kidneys, and endogenous EPO production increases in conditions of reduced oxygen (hypoxia). All types of anemia are characterized by a decrease in the blood's oxygen-carrying capacity and have similar signs and symptoms, including pale skin and mucous membranes, weakness, dizziness, fatigue, and lethargy, leading to a reduced quality of life. Anemia is usually accompanied by a blood deficiency of red blood cells or hemoglobin. Common causes of anemia include iron, vitamin B12, and folate deficiency, and it can coexist with chronic diseases such as inflammatory disorders involving secondary bone marrow inhibition. Anemia is also associated with renal dysfunction, and the majority of patients with renal failure who undergo frequent dialysis suffer from chronic anemia.

[0004] Prolyl hydroxylase domain (PHD) is a key factor in the regulation of HIF. Under normoxia, PHD hydroxylates two key proline residues, Pro402 and Pro564, of HIFα, increasing its affinity for pVHL and accelerating its degradation. Under hypoxia and other pathological conditions, PHD-catalyzed HIF reactions are inhibited, slowing the rate of protease degradation, resulting in intracellular accumulation of HIFα and inducing a series of cellular adaptive responses to hypoxia. Inhibition of PHD with PHD inhibitors prolongs HIF activity and thereby increases the expression of genes such as EPO, effectively treating and preventing HIF- and / or EPO-related diseases, such as anemia, ischemia, and hypoxia.

[0005] For example, US Patent Application No. US 16757333 discloses crystalline forms of alkynylpyridine prolyl hydroxylase inhibitors and methods for their preparation, wherein the alkynylpyridine prolyl hydroxylase inhibitors have the following structural formula: [ka] It has.

[0006] Currently, prolyl hydroxylase inhibitors on the market include Roxadustat from AstraZeneca and Enarodustad from Japan Tobacco Inc.

[0007] Due to the limited variety of prolyl hydroxylase inhibitors available and the high demand, there is an urgent need to develop compounds that can treat diseases such as anemia, regional ischemia, and hypoxia. Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide pyridino-triazole compounds as HIF-PHD inhibitors and pharmaceutical compositions thereof, which can be used to treat various HIF- or EPO-related diseases, such as anemia. [Means for solving the problem]

[0009] In order to achieve the above invention objectives, the technical solutions of the present invention are as follows:

[0010] In one aspect, the present invention provides a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof, [ka] where: R is the unit of the following atoms or groups: [ka] is selected from L is -CH2- or -CH2O-; The value of n is an integer from 0 to 2, R 1 , R 2 , R 3are each independently selected from substituted or unsubstituted alkyl, cycloalkyl, aryl, and heterocyclic groups.

[0011] Preferably, the aryl comprises an aromatic heterocyclic group.

[0012] In some embodiments, L is -CH2- or -CH2O-; The value of n is 0 or 1, R 1 is a substituted or unsubstituted C 1~4 alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 at least one of haloalkyl, halogen, cyano, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R 2 is a substituted or unsubstituted C 1~4 alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 at least one of haloalkyl, halogen, cyano, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R 3 is a substituted or unsubstituted C 1~10 alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4It is at least one of haloalkyl, halogen, cyano, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen.

[0013] R 4 is selected from at least one of hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, and heterocyclic groups.

[0014] In some embodiments, L is -CH2- or -CH2O-; The value of n is 0 or 1, R 1 is a substituted or unsubstituted phenyl, said substituents being C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 at least one of haloalkyl, halogen, cyano, phenyl, or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R 2 is a substituted or unsubstituted phenyl, said substituents being C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 at least one of haloalkyl, halogen, cyano, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R 3 is a substituted or unsubstituted C 1~10 alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C 1~4 Alkyl, C 1~4 It is at least one of alkoxy, halogen, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen.

[0015] R 4is at least one of hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, and heterocyclic groups.

[0016] Or, R 4 is hydrogen, substituted or unsubstituted C 1~10 Alkyl, C 1~10 Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, wherein the substituent is C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 It is at least one of haloalkyl, halogen, cyano, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen.

[0017] Or, R 4 is hydrogen, substituted or unsubstituted C 1~10 Alkyl, C 1~10 Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, wherein the substituent is C 1~4 Alkyl, C 1~4 It is at least one of alkoxy, halogen, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen.

[0018] In some embodiments, The value of n is 0 or 1, R 1 is a substituted or unsubstituted phenyl, said substituents being C 1~4 Alkyl, C 1~4 A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~4 Alkyl, C 1~4the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is ortho-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 2 is a substituted or unsubstituted phenyl, said substituents being C 1~4 Alkyl, C 1~4 Alkoxy, halogen, or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably 1~4 Alkyl, C 1~4 the alkoxy and the 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen or the 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 3 is a substituted or unsubstituted C 1~5 alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituent is C 1~4 Alkyl, C 1~4 A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~4 Alkyl, C 1~4 The alkoxy, oxygen- and / or nitrogen-containing 5- or 6-membered aromatic heterocyclic group, or oxygen- and / or nitrogen-containing 5- or 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted, or para-substituted with respect to the core structure.

[0019] R 4 is hydrogen, substituted or unsubstituted C 1~5 Alkyl, C 1~5 Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituent is C1~4 Alkyl, C 1~4 A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~4 Alkyl, C 1~4 The alkoxy, oxygen- and / or nitrogen-containing 5- or 6-membered aromatic heterocyclic group, or oxygen- and / or nitrogen-containing 5- or 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted, or para-substituted with respect to the core structure.

[0020] In some embodiments, The value of n is 0 or 1, R 1 is a substituted or unsubstituted phenyl, said substituents being C 1~3 Alkyl, C 1~3 A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~3 Alkyl, C 1~3 the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is ortho-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 2 is a substituted or unsubstituted phenyl, said substituents being C 1~3 Alkyl, C 1~3 A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~3 Alkyl, C 1~3 the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is ortho-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 3 is a substituted or unsubstituted C1~5 alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituent is C 1~3 Alkyl, C 1~3 A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~3 Alkyl, C 1~3 The alkoxy, oxygen- and / or nitrogen-containing 5- or 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- or 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted, or para-substituted with respect to the core structure.

[0021] R 4 is hydrogen, substituted or unsubstituted C 1~5 Alkyl, C 1~5 Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituent is C 1~3 Alkyl, C 1~3 A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~3 Alkyl, C 1~3 The alkoxy, oxygen- and / or nitrogen-containing 5- or 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- or 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted, or para-substituted with respect to the core structure.

[0022] In some embodiments, The value of n is 0 or 1, R 1 is a substituted or unsubstituted phenyl, said substituents being C 1~2 Alkyl, C 1~2Alkoxy, F, Cl, Br, I, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably, 1~2 Alkyl, C 1~2 the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and F, Cl, Br, and I are ortho-, meta-, or para-substituted with respect to the core structure; R 2 is a substituted or unsubstituted phenyl, said substituents being C 1~2 Alkyl, C 1~2 Alkoxy, F, Cl, Br, I, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably, 1~2 Alkyl, C 1~2 the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and F, Cl, Br, and I are ortho-, meta-, or para-substituted with respect to the core structure; R 3 is a substituted or unsubstituted C 1~4 alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituent is C 1~2 Alkyl, C 1~2 Alkoxy, F, Cl, Br, I, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably, 1~2 Alkyl, C 1~2 The alkoxy, oxygen- and / or nitrogen-containing 5- or 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- or 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted, or para-substituted with respect to the core structure.

[0023] R 4is hydrogen, substituted or unsubstituted C 1~4 Alkyl, C 1~4 Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituent is C 1~2 Alkyl, C 1~2 Alkoxy, F, Cl, Br, I, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably, 1~2 Alkyl, C 1~2 The alkoxy, oxygen- and / or nitrogen-containing 5- or 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- or 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted, or para-substituted with respect to the core structure.

[0024] In some embodiments, The value of n is 0 or 1, R 1 is a substituted or unsubstituted phenyl, the substituent being a 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy, F, Cl, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy, oxygen and / or nitrogen is para-substituted with respect to the core structure, and F and Cl are ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 2 is a substituted or unsubstituted phenyl, the substituent being methyl, methoxy, F, Cl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, preferably the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy and oxygen and / or nitrogen is para-substituted with respect to the core structure, and F and Cl are ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 3 is a substituted or unsubstituted C 1~3The 5- to 6-membered aromatic heterocyclic group contains alkyl, phenyl, oxygen, and / or nitrogen, and the substituent on the phenyl is methyl, methoxy, F, Cl, or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen. Preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy, and oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted, or para-substituted with respect to the core structure.

[0025] R 4 is hydrogen, substituted or unsubstituted C 1~3 Alkyl, C 1~3 The substituent on the phenyl is a 5- to 6-membered aromatic heterocyclic group containing alkoxy, phenyl, oxygen, and / or nitrogen, and the substituent on the phenyl is methyl, methoxy, F, Cl, or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen. Preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy, and oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted, or para-substituted with respect to the core structure.

[0026] In some embodiments, The value of n is 0 or 1, R 1 is a substituted or unsubstituted phenyl, the substituent being methyl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and preferably the 5- to 6-membered aromatic heterocyclic group containing methyl, oxygen and / or nitrogen is para-substituted with respect to the core structure; R 2 is a substituted or unsubstituted phenyl, the substituent being methyl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and preferably the 5- to 6-membered aromatic heterocyclic group containing methyl, oxygen and / or nitrogen is para-substituted with respect to the core structure; R 3 is a substituted or unsubstituted C 1~3The substituent is a 5- to 6-membered aromatic heterocyclic group containing alkyl, phenyl, oxygen, and / or nitrogen, and the substituent is methyl, methoxy, F, Cl, or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen. Preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy, and oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted, or para-substituted with respect to the core structure.

[0027] R 4 is hydrogen, substituted or unsubstituted C 1~3 Alkyl, C 1~3 The substituent is a 5- to 6-membered aromatic heterocyclic group containing alkoxy, phenyl, oxygen and / or nitrogen, and the substituent is methyl, methoxy, F, Cl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen. Preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy and oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure.

[0028] In some embodiments, The value of n is 0 or 1, R 1 is phenyl, R 2 is phenyl, R 3 is a substituted or unsubstituted C 1~3 It is a 5- to 6-membered aromatic heterocyclic group containing alkyl, phenyl, oxygen and / or nitrogen, and the substituent is methyl, methoxy, halogen, or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen. Preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy, oxygen and / or nitrogen or the 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted, or para-substituted with respect to the core structure.

[0029] R 4 is hydrogen.

[0030] The term "core structure" refers to the remaining main structure of the compound of formula (I) other than the R group.

[0031] In some embodiments, the compound has the following structure: [ka] is selected from.

[0032] In some embodiments, the compound has the following structure: [ka] is selected from.

[0033] In some embodiments, the compound has the following structure: [ka] is selected from.

[0034] In some embodiments, the compound has the following structure: [ka] is selected from.

[0035] In some embodiments, the compound has the following structure: [ka] is selected from.

[0036] In some embodiments, the present invention provides a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof: [ka] where: The value of n is an integer from 0 to 3, R1 is selected from mono- or polysubstituted hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, heterocyclic groups on the aromatic ring.

[0037] In some embodiments, the aryl of a compound of Formula (II) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof comprises an aromatic heterocyclic group.

[0038] In some embodiments, the value of n in the compound of Formula (II) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof is an integer from 0 to 2, and R1 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, and heterocyclic groups.

[0039] In some embodiments, the value of n in the compound of Formula (II) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof is 0 or 1, and R is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, and heterocyclic groups.

[0040] In some embodiments, the value of n in the compound of Formula (II) or a stereoisomer, geometric isomer, tautomer, nitroxide hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof is 0 or 1, and R is hydrogen, substituted or unsubstituted C 1~10 Alkyl, C 1~10 Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, wherein the substituent is C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 It is at least one of haloalkyl, halogen, cyano, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen.

[0041] In some embodiments, the value of n in the compound of Formula (II) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof is 1 and R1 is hydrogen.

[0042] In some embodiments, the compound of Formula (II) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof has the following structure: [ka] is selected from.

[0043] In some embodiments, the method for preparing compounds of formula (II) can be carried out by the following synthetic route: [ka] The present invention is characterized by the use of:

[0044] In some embodiments, pharmaceutical compositions are provided that include a compound of Formula (II) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0045] In some embodiments, there is provided the use of a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a disease mediated by the inhibition of prolyl hydroxylase by inhibiting prolyl hydroxylase.

[0046] In some embodiments, the disease mediated by inhibition of prolyl hydroxylase is anemia, ischemia, or hypoxia.

[0047] In some embodiments, the disease mediated by inhibition of prolyl hydroxylase is renal anemia.

[0048] In the present invention, FG-4592 is roxarestat.

[0049] [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid showed excellent pharmacological effects when administered chronically. The data were significant, and it was able to significantly increase hemoglobin and EPO concentrations in SD rats. The overall effect was significantly superior to that of the active drug Enarodustadine.

[0050] Preferably, the purity of the intermediates obtained from the preparation of each step in the embodiments of the present invention can reach 95% or more.

[0051] Unless otherwise specified, the term "alkyl" as used herein refers to branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, including all isomers. Common abbreviations for alkyl may be used, such as methyl represented by "Me" or CH3, ethyl represented by "Et" or CH2CH3, propyl represented by "Pr" or CH2CH2CH3, and butyl represented by "Bu" or CH2CH2CH2CH3. For example, "C 1~4 "Alkyl" (or "C1-C4 alkyl") refers to straight or branched chain alkyl having the specified number of carbon atoms, including all isomers. 1~4 Alkyl includes n-, iso-, sec-, and tert-butyl, n- and iso-propyl, ethyl, and methyl. 1~10 "Alkyl" and the like have the same meaning.

[0052] The term "alkoxy" means straight chain and branched alkyls indicating the number of carbon atoms attached through the oxygen bridge.

[0053] The term "halogen" (or "halogenated") refers to fluorine, chlorine, bromine, and iodine (also referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)).

[0054] The term "aryl" refers to aromatic monocyclic and polycyclic ring systems in which the individual carbon rings in the polycyclic ring system are bonded to each other or are linked to each other by single bonds. Common aryls include phenyl, naphthyl, phenylidene, and the like.

[0055] The term "heterocyclic group" refers to a ring structure composed of carbon and non-carbon atoms, with non-carbon atoms such as nitrogen, oxygen, sulfur, etc. Common heterocyclic groups include pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone, pyrimidine, etc.

[0056] The term "aromatic heterocyclic group" refers to a 5- or 6-membered monocyclic aromatic ring or a 7- to 12-membered bicyclic ring, which consists of carbon atoms and one or more heteroatoms selected from N, O, and S. Aromatic heterocyclic groups include pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, azolyl, isoazolyl, diazolyl, thiazolyl, isothiazolyl and thiadiazolyl, benzotriazolyl, indolyl, isoindolyl, indolizolyl, dihydroindolyl, isodihydroindolyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dienyl, imidazo(2,1-b)(1,3)thiazole, and benzo-1,3-meta-dioxolanyl.

[0057] The aryl in the term "substituted aryl" is defined as above, and when no substituent is specified to substitute the aryl, the substituent can be halogen, C1-C20 Alkyl, CF3, NH2, N(C1-C6 alkyl)2, NO2, oxo, CN, N3, -OH, -O(C1-C6 alkyl), C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C6 alkyl)S(O) 0~2 -, aryl-S(O) 0~2 -, (C0-C6 alkyl)S(O) 0~2 (C0-C6 alkyl)-, (C0-C6 alkyl)C(O)NH-, H2N~C(NH)-, -O(C1-C6 alkyl)CF3, (C0-C6 alkyl)C(O)-, (C0-C6 alkyl)OC(O)-, (C0-C6 alkyl)2NC(O)-(C0-C6 alkyl)O(C1-C6 alkyl)-, (C0-C6 alkyl)C(O) 1-2 Selected from, but not limited to, (C0-C6 alkyl)-, (C0-C6 alkyl)OC(O)NH-, aryl, arylalkyl, heteroaryl, heterocycloalkyl, haloaryl, haloarylalkyl, haloheterocyclo, haloheterocycloalkyl, cyanoaryl, cyanoarylalkyl, cyanoheterocyclo, and cyanoheterocycloalkyl. The term "substituted phenyl" has an analogous definition.

[0058] Unless otherwise specified, all ranges described herein are inclusive. For example, "the value of n is an integer from 0 to 2" means that n is 0, 1, or 2.

[0059] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present invention is acidic, its corresponding salt can be easily prepared from an inorganic base or organic base. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (copper and cuprous), iron, ferrous, lithium, magnesium, manganese (manganese and manganese oxide), potassium, sodium, zinc, and the like salts. Preferred are ammonium, calcium, magnesium, potassium, and sodium salts. Salts prepared from organic bases include primary, secondary, and tertiary amines of natural and synthetic origin. Pharmaceutically acceptable organic non-toxic bases which can form salts include arginine, betaine, caffeine, choline, N,N'-dibenzylideneethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, aminoglucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, aminotriol, etc. When the compound of the present invention is basic, its corresponding salt can be readily prepared from inorganic or organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, nitric acid, paraffinic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.

[0060] The term "solvate" refers to a variable stoichiometric complex formed by a solute (i.e., a compound of formula (I)) or its pharmaceutically acceptable salt with a solvent that does not interfere with the biological activity of the solute. Examples of solvents include, but are not limited to, water, ethanol, and acetic acid. When the solvent is water, the solvate is called a hydrate. Hydrates include, but are not limited to, hemihydrate, monohydrate, 1.5-fold hydrate, dihydrate, and trihydrate.

[0061] The term "prodrug" refers to a functional derivative of a compound of the present invention that is readily converted in vivo into the desired compound.

[0062] On the other hand, the present invention provides a method for preparing the above compound, which comprises the following four synthetic routes: [ka] [ka] [ka] [ka] Includes: where R 1 , R 2 , R 3 , R 4 has the same definition as above.

[0063] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0064] In the context of pharmaceutical compositions, the term "composition" includes products containing an active ingredient and an inactive ingredient (a pharmaceutically acceptable excipient) that constitutes a carrier, as well as products obtained directly or indirectly by the combination, complexation, or aggregation of two or more ingredients, or by the decomposition of one or more ingredients, or by other types of reaction or interaction of one or more ingredients. Thus, the pharmaceutical compositions of the present invention include any composition prepared by mixing the compounds of formula (I) and / or formula (II), other active ingredients, and pharmaceutically acceptable excipients.

[0065] The pharmaceutical compositions of the present invention comprise a compound of Formula (I) and / or Formula (II) (or a pharmaceutically acceptable salt or solvate thereof) as an active ingredient, a pharmaceutically acceptable carrier, and any other therapeutic ingredient or adjuvant. Pharmaceutical compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular subject and the nature and severity of the condition for which the active ingredient is being administered. Pharmaceutical compositions can be prepared by any method known in the art of pharmacy.

[0066] The active ingredient can be administered orally in solid or liquid dosage forms, such as capsules, tablets, lozenges, sugar lozenges, granules, and powders, and in liquid dosage forms such as elixirs, syrups, emulsions, dispersions, and suspensions. The active ingredient can also be administered parenterally in sterile liquid dosage forms, such as dispersions, suspensions, or solutions. Other dosage forms that can be used to administer the active ingredient include ointments, creams, drops, transdermal patches, or powders for topical administration; eye drops or suspensions for ocular administration; spray or powder compositions for inhalation or nasal administration; or creams, ointments, sprays, or suppositories for rectal or vaginal administration. Gelatin capsules contain the active ingredient and a powdered carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, or stearic acid. Compressed tablets can also be prepared using similar diluents. Both tablets and capsules can be formulated as sustained-release formulations, releasing the drug continuously over several hours. Compressed tablets can be sugar-coated or film-coated to mask unpleasant tastes and protect the tablet from air, or enteric-coated to selectively disintegrate in the gastrointestinal tract. Liquid dosage forms for oral administration can contain colorants and flavors to enhance patient acceptance. Generally, water, a suitable oil, saline, aqueous dextrose (glucose), related sugar solutions, and diols such as propylene glycol and polyethylene glycol are suitable carriers for parenteral gastrointestinal solutions. Solutions for parenteral gastrointestinal administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizers, and, if necessary, buffers. 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. Additionally, parenteral gastrointestinal solutions may contain preservatives such as benzalkonium chloride, nipazine methyl ester or nipazine propyl ester, and chlorobutanol. For inhalation administration, the compounds of the present invention can be conveniently delivered as a spray from a pressurized package or nebulizer.The compound can also be delivered in the form of formulated powder, and the powder composition can be inhaled with the aid of an insufflation powder inhaler.The preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which can be formulated as a suspension or solution of the compound of formula (I) and / or formula (II) in a suitable propellant, such as a fluorocarbon or hydrocarbon.For ocular administration, the ophthalmic preparation can be formulated as a solution or suspension of the compound of formula (I) and / or formula (II) in a suitable ophthalmic vehicle at an appropriate weight percent, so as to maintain contact of the compound with the ocular surface for a sufficient time to allow the compound to penetrate the cornea and the inner region of the eye.

[0067] Useful pharmaceutical dosage forms for administering the compounds of the present invention include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injectables, oral suspensions, and the like.

[0068] When the compound of the present invention is administered gradually or in combination with other therapeutic agents, the same dosage form as described above can be used.When the drugs are administered in physical combination, dosage form and administration route should be selected based on the compatibility of the combined drugs.The compound of the present invention can be administered as a single active ingredient or in combination with a second active ingredient, and the second active ingredient is the active ingredient known to be used to increase erythropoietin level in patients.

[0069] On the other hand, the present invention provides the use of a compound represented by formula (I) or formula (II) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition, in the preparation of a medicament for treating a disease mediated by the inhibition of prolyl hydroxylase by inhibiting prolyl hydroxylase.

[0070] In some embodiments, the disease mediated by inhibition of prolyl hydroxylase is anemia, ischemia, or hypoxia.

[0071] In some embodiments, the anemia is renal anemia. [Effects of the Invention]

[0072] The present invention has the following beneficial effects.

[0073] By providing a new compound, it can be used as a prolyl hydroxylase inhibitor, has higher prolyl hydroxylase inhibitory activity and EPO-inducing activity, and can effectively treat and prevent HIF-related diseases and / or EPO-related diseases, providing a new approach to diseases such as anemia, ischemia, and hypoxia. [Brief explanation of the drawings]

[0074] [Figure 1] Micrograph of a single crystal sample of methyl acetate chiral isomer A. [Figure 2] Asymmetric unit diagram of the crystal structure of methyl acetate chiral isomer A. [Figure 3] Cell diagram of the crystal structure of methyl acetate chiral isomer A. [Figure 4] Stacking diagram of the crystal structure of methyl acetate chiral isomer A. [Figure 5] Comparison of the calculated XRPD with a single crystal sample of methyl acetate chiral isomer A. [Figure 6] Chemical structure of methyl acetate chiral isomer A. [Figure 7] Micrograph of a single crystal sample of methyl acetate chiral isomer B. [Figure 8] Asymmetric unit of the crystal structure of methyl acetate chiral isomer B. [Figure 9] Cell diagram of the crystal structure of methyl acetate chiral isomer B. [Figure 10] Stacking diagram of the crystal structure of methyl acetate chiral isomer B. [Figure 11] Comparative measured and calculated XRPD plots of a single crystal sample of methyl acetate chiral isomer B. [Figure 12]Chemical structure of methyl acetate chiral isomer B. DETAILED DESCRIPTION OF THE INVENTION

[0075] The following non-limiting examples may enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following are merely examples of the scope of protection claimed in the present application, and those skilled in the art can make various changes and modifications to the invention of the present application according to the disclosed content, which also shall fall within the scope of protection claimed in the present application.

[0076] The present invention will be further described below with reference to specific embodiments. Various chemical reagents used in the examples of the present invention are all obtained by conventional commercial means unless otherwise specified.

[0077] Example 1 Preparation of (7-hydroxy-5-(phenoxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid [ka]

[0078] Step 1. Preparation of 5-(phenoxy)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate 5-Iodo-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (1.0 g), phenol (310 mg), 2-pyridinecarboxylic acid (55 mg), cuprous iodide (42 mg), potassium phosphate (942 mg), and dimethyl sulfoxide (5.0 mL) were sequentially added to a reaction flask, and the atmosphere was purged with nitrogen three times. The mixture was heated to 65 °C and reacted overnight while monitoring by TLC until the reaction of the raw materials was complete. After cooling to room temperature, the mixture was extracted with ethyl acetate and washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 450 mg of a white solid.

[0079] MS m / z(ESI)[M+H] + :418.30

[0080] Step 2. Preparation of 5-(phenoxy)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid 5-(Phenoxy)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (450 mg) was dissolved in a 1:1 volumetric mixture of toluene and tetrahydrofuran (10 mL), followed by the addition of methanesulfonic acid (0.5 mL) and stirring at a reaction temperature of 60-70°C. The reaction was monitored by TLC until completion, at which point the reaction was stopped. The mixture was cooled to room temperature, a small amount of ethyl acetate was added, and the mixture was filtered to obtain 440 mg of a white solid.

[0081] MS m / z(ESI)[M+H] + :362.22

[0082] Step 3 Preparation of [(7-(benzyloxy)-5-(phenoxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate 5-(phenoxy)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (440 mg), EDCI (280 mg), HoBt (197 mg), N,N-dimethylformamide (5.0 mL), and triethylamine (247 mg) were added sequentially to a reaction flask and stirred at room temperature for 10 minutes. Glycine methyl ester hydrochloride (306 mg) was then added to the system, which was heated to 60°C and reacted for 1.5 hours. The reaction was stopped, cooled to room temperature, and quenched by adding saturated aqueous sodium bicarbonate solution. The reaction was then filtered to obtain 300 mg of a yellow solid.

[0083] MS m / z(ESI)[M+H] + :433.31

[0084] Step 4 Preparation of [(7-hydroxy-5-(phenoxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate [(7-(benzyloxy)-5-(phenoxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate (300 mg) and palladium on carbon (30 mg) were dissolved in a 1:1 volumetric ratio mixture of methanol and tetrahydrofuran (4.0 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere while monitoring by TLC until the reaction of the raw materials was complete, at which point the reaction was stopped. The mixture was concentrated under reduced pressure to remove the solvent, and the product (170 mg) was separated by column chromatography.

[0085] MS m / z(ESI)[M+H] + :343.22

[0086] Step 5 Preparation of [(7-hydroxy-5-(phenoxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid [(7-Hydroxy-5-(phenoxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate (170 mg) was dissolved in methanol (2.0 mL), and then 30% aqueous sodium hydroxide solution (1.0 mL) was added. The mixture was stirred at room temperature while monitoring by TLC until the reaction of the raw material was complete. The pH was adjusted to 1-2 with dilute hydrochloric acid, and the mixture was filtered to obtain 150 mg of the product.

[0087] 1 H 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

[0088] Example 2 Preparation of (5-(2-chlorophenoxy)-7-hydroxy-[1,2,4]triazolyl[1,5-a]pyridine-8-carbonyl)glycine [ka] Following the procedure of Example 1, substituting 428.1 mg of 2-chlorophenol for phenol, 108.9 mg of product was obtained.

[0089] 1 H 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

[0090] Example 3 Preparation of (5-(3-chlorophenoxy)-7-hydroxy-[1,2,4]triazolyl[1,5-a]pyridine-8-carbonyl)glycine [ka] Following the procedure of Example 1, substituting 428.1 mg of 3-chlorophenol for phenol, 201.6 mg of product was obtained.

[0091] 1 H 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

[0092] Example 4 Preparation of (5-(4-chlorophenoxy)-7-hydroxy-[1,2,4]triazolyl[1,5-a]pyridine-8-carbonyl)glycine [ka] Following the procedure of Example 1, substituting 428.1 mg of 4-chlorophenol for phenol, 182.1 mg of product was obtained.

[0093] 1 H 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

[0094] Example 5 Preparation of (5-(p-toluyloxy)-7-hydroxy-[1,2,4]triazolyl[1,5-a]pyridine-8-carbonyl)glycine [ka] Following the procedure of Example 1, substituting 356.9 mg of 4-methylphenol for phenol, 87.7 mg of product was obtained.

[0095] 1 H 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

[0096] Example 6 Preparation of (5-(p-methoxyphenoxy)-7-hydroxy-[1,2,4]triazolyl[1,5-a]pyridine-8-carbonyl)glycine [ka] Following the procedure of Example 1, substituting 409.2 mg of 4-methoxyphenol for phenol, 223.7 mg of product was obtained.

[0097] 1 H 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

[0098] Example 7 Preparation of (5-(3-morpholinophenoxy)-7-hydroxy-[1,2,4]triazolyl[1,5-a]pyridine-8-carbonyl)glycine [ka] Following the procedure of Example 1, substituting 590 mg of 3-morpholinophenol for phenol, 110.7 mg of product was obtained.

[0099] 1 H 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

[0100] Example 8 Preparation of (5-(4-fluorophenoxy)-7-hydroxy-[1,2,4]triazolyl[1,5-a]pyridine-8-carbonyl)glycine [ka] Following the procedure of Example 1, substituting 369.6 mg of 4-fluorophenol for phenol, 239.3 mg of product was obtained.

[0101] 1 H NMR(400MHz,d-DMSO)14.53(s,1H),12.98(brs,1H),9.71(s,1H),8.60(s,1 H),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

[0102] Example 9 Preparation of (5-(propoxy)-7-hydroxy-[1,2,4]triazolyl[1,5-a]pyridine-8-carbonyl)glycine [ka] Following the procedure of Example 1, (2 mL) n-propanol was substituted for phenol to give 20.1 mg of product.

[0103] 1 H 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

[0104] Example 10 Preparation of [(7-hydroxy-5-(phenylethynyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid [ka]

[0105] Step 1. Preparation of 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate In a reaction flask, 7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (15 g) was dissolved in a mixture of methanol and tetrahydrofuran (25 mL / 50 mL). The mixture was stirred at room temperature under a hydrogen atmosphere while monitoring by TLC until the reaction of the raw materials was complete. The solution was filtered to remove the palladium carbon, and the filtrate was concentrated under reduced pressure to obtain 11.7 g of crude product.

[0106] MS m / z(ESI):[M+H] + :236.24

[0107] Step 2. Preparation of 7-(pivaloyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate 7-Hydroxy-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (10.7 g) was placed in a reaction flask, and tetrahydrofuran (65 mL) was added. Then, triethylamine (8.0 mL) and pivaloyl chloride (9.1 g) were sequentially added. The atmosphere was purged with nitrogen three times, and the reaction flask was sealed. The reaction mixture was heated to 60 °C and stirred overnight. The reaction was stopped while monitoring by TLC until the reaction of the starting materials was complete. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride, and saturated brine, and then concentrated under reduced pressure to yield 12.0 g of a yellow solid.

[0108] MS m / z(ESI):[M+H] + :320.36

[0109] Step 3. Preparation of 5-iodo-7-(pivaloyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate 7-(Pivaloyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (10.0 g) was dissolved in tetrahydrofuran (50 mL), followed by the addition of iodine monomer (8.75 g), while maintaining the reaction temperature at -60 °C. After 5 min, lithium hexamethyldisilicate (62.7 mL, 1.0 M) was added in portions and stirred until the reaction of the starting material was complete, while monitoring by TLC. The reaction was then quenched by the addition of a solution of hydrochloric acid in ethyl acetate, extracted with ethyl acetate, and washed with aqueous sodium sulfite. The organic phase was separated and washed sequentially with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and saturated brine. The organic phase was separated, concentrated under reduced pressure, and purified by column chromatography to obtain 5.9 g of crude product.

[0110] 1 H 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

[0111] Step 4. Preparation of 5-(phenylethynyl)-7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate 5-Iodo-7-(pivaloyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (5.9 g), cuprous iodide (70 mg), Pd(dppf)Cl2 (285 mg), tetrahydrofuran (30 mL), triethylamine (6.6 g), and phenylacetylene (2.1 g) were sequentially added to a reaction flask. The atmosphere was purged with nitrogen three times, and the temperature was raised to 50 °C. The reaction was quenched by the addition of ammonia while monitoring by TLC until the reaction of the starting material was complete. The organic phase was extracted with ethyl acetate and separated. The ammonia layer was washed with hydrochloric acid and extracted with ethyl acetate. The combined organic phases were concentrated under reduced pressure and purified by column chromatography to yield 1.9 g of a red solid.

[0112] MS m / z(ESI):[M+H] + :336.36

[0113] Step 5. Preparation of 5-(phenylethynyl)-7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid 5-(Phenylethynyl)-7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (1.8 g) was dissolved in a 2:1 volumetric mixture of toluene and ethyl acetate (24 mL). Methanesulfonic acid (2.1 g) was then added and the mixture was stirred while maintaining the reaction temperature between 60 and 70 °C. The reaction was monitored by TLC until completion. After cooling the reaction mixture to room temperature, ethyl acetate (10 mL) was added. A large amount of solid precipitated, which was filtered to obtain a green solid. The solid was then dissolved in a small amount of N,N-dimethylacetamide, and ethyl acetate was added to the mixture. The solid precipitated, which was filtered to obtain 1.0 g of crude product.

[0114] MS m / z(ESI):[M+H] + :280.26

[0115] Step 6 Preparation of [(7-hydroxy-5-(phenylethynyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate In reaction flask A, 5-(phenylethynyl)-7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (0.8 g) was dissolved in dichloromethane (20 mL), and oxalyl chloride (0.76 g) was added dropwise and stirred at room temperature. Methyl glycinate hydrochloride (0.68 g), dichloromethane (20 mL), and triethylamine (3.0 mL) were added sequentially to reaction flask B and stirred at 0 °C. When complete reaction of the raw materials in reaction flask A was confirmed by TLC, stirring in reaction flask A was stopped, and the raw materials in reaction flask A were added to reaction flask B. The mixture was stirred at 0 °C while being monitored by TLC until the reaction of the raw materials was complete. The reaction was quenched with water. The organic phase was extracted with dichloromethane, washed sequentially with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate, and the organic phases were separated, combined, concentrated under reduced pressure, and separated by column chromatography to obtain 0.8 g of a yellow solid.

[0116] MS m / z(ESI):[M+H] + :351.33

[0117] Step 7 Preparation of [(7-hydroxy-5-(phenylethynyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid [(7-hydroxy-5-phenylethynyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate (0.8 g) was dissolved in ethanol (10 mL) and then added to aqueous sodium hydroxide solution (18 mL, 2.0 M). The mixture was stirred at room temperature while monitoring by TLC until the reaction of the raw materials was complete. The pH was adjusted to 4-5 with dilute hydrochloric acid, and the mixture was filtered to obtain 0.42 g of a pale yellow solid.

[0118] 1 H NMR(400MHz,d-DMSO)δ:14.33(s,1H),13.04(s,1H),9.90(s,1H),8.64(s,1 H),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

[0119] Example 11 Preparation of [(7-hydroxy-5-(phenylethynyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid [ka]

[0120] Step 1. Preparation of 5-(phenylethynyl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate 5-Iodo-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (500 mg), Pd(PPh3)2Cl2 (70.2 mg), sodium carbonate (360 mg), and styreneboronic acid (200 mg) were dissolved in a 1:1 volumetric ratio mixture of ethylene glycol dimethyl ether and degassed water (30 mL) and purged with nitrogen three times. The mixture was then stirred at 80 °C while monitoring by TLC until the reaction of the raw materials was complete, at which point heating was discontinued. The reaction mixture was cooled to room temperature, extracted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was separated, concentrated under reduced pressure, and purified by column chromatography to yield 340 mg of crude product.

[0121] Step 2. Preparation of 5-(phenylethynyl)-7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid 5-(Phenylethynyl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (290 mg) was dissolved in dichloromethane (10 mL) and cooled to -65 °C. Boron tribromide dichloromethane solution (3.4 mL, 1.0 M) was added to the reaction mixture and stirred until the reaction was complete, while monitoring by TLC. The reaction was stopped, and the solution was concentrated under reduced pressure to remove the starting material. The residue was then added to a mixture of water (10 mL) and methanol (3.0 mL), stirred at room temperature for 1 hour, and filtered to give 250 mg of a solid.

[0122] MS m / z(ESI):[M+H] + :282.04

[0123] Step 3 Preparation of [(7-hydroxy-5-(phenylethynyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate 5-(Phenylethynyl)-7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (143 mg), N,N-dimethylformamide (10 mL), DIPEA (329 mg), PyBOP (395 mg), and methyl glycinate hydrochloride (178 mg) were added sequentially to a reaction flask, stirred at room temperature overnight, and filtered to obtain a solid, yielding 50 mg of crude product.

[0124] MS m / z(ESI):[M+H] + :353.28

[0125] Step 4. Preparation of [(7-hydroxy-5-(phenylethynyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid [(7-hydroxy-5-(phenylethynyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate (50 mg) was dissolved in methanol (2.0 mL), followed by the addition of 30% aqueous sodium hydroxide (1.0 mL). The mixture was stirred at room temperature while monitoring by TLC until the reaction of the raw material was complete. The pH was adjusted to 1-2 with dilute hydrochloric acid, and the mixture was filtered to obtain 10 mg of the product.

[0126] 1 H NMR(400MHz,d-DMSO)δ:14.26(s,1H),12.98(s,1H),9.90(t,J=16.4Hz,1H),8.63(s,1 H),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

[0127] Example 12 Preparation of [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid [ka]

[0128] Step 1. Preparation of 5-(3,4-tetrahydronaphthalen-2-yl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate 5-Iodo-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (5.40 g), Pd(PPh3)2Cl2 (800 mg), potassium carbonate (4.20 g), and 3,4-dihydronaphthalenyl-2-boronic acid catalyzed ester (3.10 g) were dissolved in a 2:1 volume ratio mixture of ethylene glycol dimethyl ether and degassed water (30 mL) and purged with nitrogen three times. The mixture was then stirred at 80 °C while monitoring by TLC until the reaction of the raw materials was complete, at which point heating was discontinued. The reaction mixture was cooled to room temperature, extracted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was separated, concentrated under reduced pressure, and purified by column chromatography to obtain 3.30 g of crude product.

[0129] Step 2. Preparation of 5-(3,4-tetrahydronaphthalen-2-yl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid 5-(3,4-Tetrahydronaphthalen-2-yl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (3.30 g) was dissolved in a 3:1 volumetric ratio of toluene and ethyl acetate (28 mL). Methanesulfonic acid (2.80 g) was added to the reaction mixture and stirred. The reaction mixture was monitored by TLC until the reaction was complete. Ethyl acetate (20.0 mL) was added to the reaction mixture and stirred to precipitate crystals. The solid was collected by filtration. The mixture was then pulped with DMF / HO (20.0 mL / 40.0 mL), stirred to precipitate crystals, and collected by filtration to obtain 2.70 g of a pale blue solid.

[0130] Step 3 Preparation of [5-(3,4-tetrahydronaphthalen-2-yl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate 5-(3,4-Tetrahydronaphthalen-2-yl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (2.70 g), N,N-dimethylformamide (20.0 mL), HOBt (1.10 g), EDCI (1.40 g), glycine methyl ester hydrochloride (0.90 g), and triethylamine (1.50 g) were added sequentially to a reaction flask, and the mixture was stirred at room temperature while being monitored by TLC until the reaction of the raw materials was complete. Water (30.0 mL) was added to the reaction system, and the mixture was stirred to precipitate crystals. The mixture was filtered, the solid was collected, and dried to obtain an off-white solid (2.2 g).

[0131] Step 4 Preparation of [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate [5-(3,4-tetrahydronaphthalen-2-yl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid (1.0 g) was dissolved in tetrahydrofuran solution (8.0 mL), followed by the addition of palladium on carbon (300 mg), the hydrogen was replaced, and the mixture was stirred at room temperature while monitoring by TLC until the reaction of the raw material was complete. The mixture was then filtered through diatomaceous earth, concentrated under reduced pressure, and then pulped with isopropyl ether / hexane (1.5 mL / 1.5 mL) and filtered to obtain approximately 500 mg of an off-white solid.

[0132] Step 5. Preparation of [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate (0.20 g) was dissolved in ethanol (2.0 mL), and then aqueous sodium hydroxide solution (2.0 mL, 4.0 M) was added. The mixture was stirred at room temperature while monitoring by TLC until the reaction of the raw material was complete. The pH was adjusted to 6-7 with dilute hydrochloric acid, and the mixture was filtered to obtain 200 mg of a gray-white solid.

[0133] 1 H 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

[0134] Example 13 Preparation of [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid chiral isomer A

[0135] Step 1. Preparation of 5-(3,4-tetrahydronaphthalen-2-yl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate 5-Iodo-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (5.40 g), Pd(PPh3)2Cl2 (800 mg), sodium carbonate (4.20 g), and 3,4-dihydronaphthalenyl-2-boronic acid catalyzed ester (3.10 g) were dissolved in a 2:1 volumetric ratio mixture of ethylene glycol dimethyl ether and degassed water (30 mL). The mixture was then purged with nitrogen three times. The mixture was then stirred at 80 °C and monitored by TLC until the reaction of the starting material was complete. After cooling to room temperature, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was separated, concentrated under reduced pressure, and purified by column chromatography to obtain 3.30 g of crude product.

[0136] Step 2. Preparation of 5-(3,4-tetrahydronaphthalen-2-yl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid 5-(3,4-Tetrahydronaphthalen-2-yl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (3.30 g) was dissolved in a 3:1 volumetric ratio of toluene and ethyl acetate (28 mL). Methanesulfonic acid (2.80 g) was added to the reaction mixture and stirred. The reaction mixture was monitored by TLC until the reaction was complete. Ethyl acetate (20.0 mL) was added to the reaction mixture and stirred to precipitate crystals. The solid was then filtered and collected. The mixture was then pulped with DMF / HO (20.0 mL / 40.0 mL), stirred to precipitate crystals, and the solid was collected to give 2.70 g of a pale blue solid.

[0137] Step 3 Preparation of [5-(3,4-tetrahydronaphthalen-2-yl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate 5-(3,4-Tetrahydronaphthalen-2-yl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (2.70 g), N,N-dimethylformamide (20.0 mL), HoBt (1.10 g), EDCI (1.40 g), and methyl glycinate hydrochloride (0.90 g) were added sequentially to a reaction flask and stirred at room temperature. The reaction mixture was monitored by TLC until the reaction of the raw materials was complete. Water (30.0 mL) was added to the reaction mixture and stirred to precipitate crystals. The solid was collected by filtration and dried to obtain an off-white solid (2.2 g).

[0138] Step 4 Preparation of [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate [5-(3,4-tetrahydronaphthalen-2-yl)-7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid (1.0 g) was dissolved in tetrahydrofuran solution (8.0 mL), and then palladium on carbon (300 mg) was added. The mixture was stirred at room temperature and monitored by TLC until the reaction of the raw material was complete. The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and then pulped with isopropyl ether / hexane (1.5 mL / 1.5 mL) and filtered to obtain approximately 500 mg of a whitish solid.

[0139] Step 5 Preparation of [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]methyl acetate chiral isomer A (methyl acetate chiral isomer A) The product obtained in the previous synthesis was subjected to chiral resolution to separate 5 g of [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate. Separation conditions: (Chiral column: (S,S)Whelk-O1,5*25 cm, 10 μm, Mobile phase A: CO₂, Mobile phase B: ACN:IPA = 1:1, Flow rate: 200 mL / min, Gradient: 50% to 50%, 12 min run on B, Wavelength: 220 nm, Peak time: 8:50 min, Sample solution: Methanol: Dichloromethane = 1:1, Injection volume: 2 mL, Number of injection needles: 50). Chiral isomer A: White solid (2.060 g, Yield: 41.2%) was obtained.

[0140] Step 6. Preparation of [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid chiral isomer A Methyl [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate chiral isomer A (0.20 g) was dissolved in ethanol (2.0 mL), and then aqueous sodium hydroxide solution (1.0 mL, 4.0 M) was added. The mixture was stirred at room temperature and monitored by TLC until the reaction of the raw material was complete. The pH was adjusted to 1-2 with dilute hydrochloric acid, and the mixture was filtered to obtain 200 mg of a gray-white solid.

[0141] 1 H 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]D 20 =+37.384(c1.01,DMF).

[0142] Example 14 Preparation of [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid chiral isomer B

[0143] Step 1 Preparation of [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]methyl acetate chiral isomer B 5 g of the synthesized [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetate was subjected to chiral separation. Separation conditions: (Chiral column: (S,S)Whelk-O1, 5*25 cm, 10 μm, Mobile phase A: CO₂, Mobile phase B: ACN:IPA = 1:1, Flow rate: 200 mL / min, Gradient: 50% to 50%, 12 min run on B, Wavelength: 220 nm, (OB peak time): 10.09 min, Sample solution: methanol:dichloromethane = 1:1, Injection volume: 2 mL, Number of injection needles: 50). Chiral isomer B (methyl acetate chiral isomer B): 1.997 g, 39.94% yield, was obtained as a white solid.

[0144] Step 2 Preparation of [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid chiral isomer B [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]methyl acetate chiral isomer B (0.20 g) was dissolved in ethanol (2.0 mL), and then aqueous sodium hydroxide solution (1.0 mL, 4.0 M) was added. The mixture was stirred at room temperature and monitored by TLC until the reaction of the raw material was complete. The pH was adjusted to 1-2 with dilute hydrochloric acid, and the mixture was filtered to obtain 200 mg of a gray-white solid.

[0145] 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]D 20 =-36.601(c1.01,DMF).

[0146] Example 15 Biological Testing 1. Detection of PHD2 enzyme activity inhibition 1.1 Reagents and Consumables PHD2 enzyme: purchased from Active motif, α-Ketoglutaric acid sodium salt: purchased from Sigma; FITC-HIF1α: Purchased from GL, Nunc Multiwell Plate TM 384: Purchased from Thermo Scientific.

[0147] 1.2 Test Method (1) Prepare 1x Assay buffer. (2) Preparation of compound concentration gradient: The test compound concentration started from 10 μM, then diluted 3-fold to 10 concentrations, and tested in multiple wells. The compound was diluted to a 100-fold final concentration in a 384-well plate, and then 100 nL was transferred to a 384-well reaction plate using the non-contact sonic pipetting system Echo550. 100 nL of 100% DMSO was added to the negative control wells and the positive control wells, respectively. (3) Prepare an enzyme solution with 1x Assay buffer at a final concentration of 2x. (4) Add 5 μL of enzyme solution at twice the final concentration to the compound wells and the positive control wells. (5) Add 5 μL of 1× Assay buffer to the negative control well. (6) Centrifuge at 1000 rpm for 30 seconds, shake to mix well, and then incubate for 15 minutes. (7) Prepare a tracer solution with 1x Assay buffer at a final concentration of 2x, add 5.0 μL of the tracer solution at a final concentration of 2x, and start the reaction. (8) The 384-well plate was centrifuged at 1000 rpm for 30 seconds, then shaken for 60 minutes to mix well. The mP values ​​were read from the Envision multifunction enzyme marker (Multimode PlateReader, Perkin Elmer), and the data was exported to determine the inhibition rates of the test compounds. Compound numbers 1 to 12 correspond to the compounds prepared in Examples 1 to 12, respectively. The results are shown in the table below.

[0148] [Table 1]

[0149] As can be seen from the above table, the compounds of the examples of the present invention have good HIF-prolyl hydroxylase inhibitory activity, and therefore, compounds 1 to 12 have good inhibitory activity.

[0150] 2. In vitro erythropoietin (EPO) induction activity test of the compound of the present invention The in vitro erythropoietin (EPO)-inducing activity of the compounds of Examples 10 to 12 of the present invention was evaluated using Hep3B (ATCC), a cell line derived from human hepatocellular carcinoma. Hep3B cells were cultured in EMEM (Eagle's minimum essential medium) at 37°C in the presence of 10% fetal bovine serum (FBS). The experimental steps were as follows: (1) Cell preparation: Cells were seeded into a 96-well plate, with 2 x 10 cells per well. 4 Spread 100 μL per well. (2) Preparation of compound concentration gradient: 100 μM, 20 μM, 2 multi-well detection. A 200-fold final concentration solution was placed in a 96-well plate, and the compound was diluted 200 / 3 times using cell culture medium. 50 μL was then aspirated and administered to the cells. 50 μL of DMSO-containing culture medium was added to the negative control wells to achieve a final concentration of 5‰ DMSO. 50 μL of the highest concentration positive compound was added to the positive control wells and incubated at 37°C for 24 hours. (3) Wash the reaction plate twice with approximately 400 μL of 1X Wash Buffer per well. (4) Add 100 μL of diluted standard (including standard blank control) to the appropriate wells; (5) Add 50 μL of sample and 50 μL of sample diluent to the sample well. (6) Add 50 μL of 1X Biotin Conjugated Antibody to all wells and incubate at room temperature for 1 hour. (7) Wash the reaction plate six times with approximately 400 μL of 1X Wash Buffer per well. (8) 100 μL of 1X Streptavidin-HRP was added to each well. The plate was incubated at room temperature for 15 minutes. (9) Wash the reaction plate six times with approximately 400 μL of 1X Wash Buffer per well. (10) Add 100 μL of TMB Substrate Solution to one well. Incubate at room temperature for 10 minutes. (11) Add 100 μL of Stop Solution to each well. (12) OD450 was read using EnSight. The EPO-inducing activity of each compound was expressed as the half-maximal effective concentration (EC50). The experimental results are shown in the table below.

[0151] [Table 2-1]

[0152] As can be seen from the above table, the compounds of the present invention have higher EPO-inducing activity, and therefore the inducing activity of the compounds obtained in Examples 10 to 14 is good.

[0153] Example 16 Pharmacokinetic evaluation of compounds 1. Purpose of the test After intravenous or oral administration of the compounds to SD rats, the concentrations of related compounds in plasma were measured by LC-MS / MS to preliminarily evaluate the pharmacokinetics and absolute bioavailability of the compounds prepared in Examples 13 and 14 in rats. 2. Breed: Sprague Dawley rat, Sex: Male, Weight: 200-250g Source: Zhejiang Wetong Lihua Experimental Animal Technology Co., Ltd.

[0154] 3. Experimental Procedure The pharmacokinetic characteristics of compounds in rodents were measured after intravenous injection and oral administration using standard methods. During the experiment, candidate compounds were prepared into clear solutions and administered to rats via a single intravenous injection and oral administration. The intravenous vehicle was a fixed ratio of N,N-dimethylacetamide (DMA) to 10% Solutol HS15 solution, while the oral vehicle was a fixed ratio of sodium carboxymethylcellulose (CMC) suspension. Blood samples were collected into K2EDTA anticoagulant tubes at 5, 15, and 30 minutes, 1, 2, 4, 6, 8, 10, and 24 hours after administration and stored on ice until centrifugation.

[0155] [Table 2-2]

[0156] As can be seen from the above table, the compounds prepared in Examples 13 and 14 of the present invention have good PK properties, and therefore the compounds prepared in Examples 13 and 14 have significantly longer half-lives and higher body exposure.

[0157] Example 17 Pharmacological evaluation of compounds 1. Purpose of the experiment The purpose of this experiment was to evaluate the effect of continuous administration of the compounds prepared in Examples 12, 13 and 14 on EPO (erythropoietin) in SD rats. 2.Animals Species: Rat Variety: SD (Sprague Dawley) Age and weight: 8 weeks, weight 200-220g Gender: Male Animal source: Beijing Wetong Lihua Experimental Animal Technology Co., Ltd. 3. Test compound and positive control information Positive drug: Enarodustat Description: Pharmaceuticals approved for manufacturing and sales in Japan Specifications and contents: 2mg JTZ-951 (Enarodustat), 140 tablets / box 4. Experimental Method: After one week of acclimation, SD rats were randomly divided into three groups of six rats each: a blank group, a positive drug group (Enarodustat), and a compound group prepared in Example 12. For Enarodustat, tablets were crushed using a mortar and pestle, followed by the addition of a quantitative amount of 0.5% methylcellulose and magnetic stirring. The compound prepared in Example 12 was weighed, followed by the addition of a quantitative amount of 0.5% methylcellulose and magnetic stirring. The final concentration of all compounds was 0.3 mg / mL, and the administration volume was 10 mL / kg. The rats were administered once daily for 14 consecutive days. On the 14th day, blood samples were collected and EPO levels were measured 4 hours after administration.

[0158] 5. Results and Analysis As can be seen from the results, after 14 days of administration, the EPO levels in the serum of rats treated with the positive drug Enarodustat and the compound group prepared in Examples 12, 13, and 14 were significantly increased, and the EPO levels in the plasma after administration of the compounds prepared in Examples 12, 13, and 14 were significantly higher than that of the positive drug Enarodustat.

[0159] [Table 3]

[0160] As described above, the compounds prepared in Examples 12, 13, and 14 significantly increased EPO levels in SD rats, and the overall effect was significantly superior to that of the active drug Enarodustat, demonstrating excellent pharmacological effects.

[0161] Example 18: Determination of the chiral configuration of compound A of methyl acetate chiral isomer A of Example 13 1. Compound preparation Referring to the preparation method of [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]methyl acetate chiral isomer A (Step 5) in Example 13, methyl acetate chiral isomer A was obtained by chiral resolution, and this isomer is the precursor compound of the final product of Example 13 (the product of Step 5). 2. Single crystal culture Approximately 3-7 mg of methyl acetate chiral isomer A was weighed into a vial, and acetonitrile was gradually added at 50°C. The mixture was stirred until the solution was clear or nearly clear. The filtrate was filtered while still hot, transferred to a clean vial, and programmed using a Crystal 16 device to cool the mixture from 50°C to 30°C at a rate of 0.01°C / min, and then maintained at 30°C for approximately 2 days. Needle-shaped single crystals were obtained from acetonitrile by cooling crystallization and used for X-ray single crystal diffraction analysis, as shown in Figure 1. 3. Equipment and parameters Single-crystal data for methyl acetate chiral isomer A were collected on a Rigaku XtaLAB Synergy DW diffractometer at 180 K using Cu Kα radiation (λ = 1.54184 Å). The diffraction data were reduced and corrected using the CrysAlisPro program, and the structure was analyzed using the SHELXT program using a dyadic space algorithm. All non-hydrogen atoms were localized directly from the difference Fourier plot, and hydrogen atoms were placed on parent atoms. The SHELXL program was used to complete the final structure refinement based on the F2 full-matrix least-squares method. 4. X-ray diffraction analysis The single crystal structure of methyl acetate chiral isomer A is monoclinic and belongs to the P21 space group, and the molecular formula of the single crystal is C 20 H 20 N4O4. There is one methyl acetate chiral isomer A molecule in each asymmetric unit, and each cell contains two asymmetric units. The absolute configuration of the chiral carbon is "R."

[0162] 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 angles, hydrogen bonds, bond lengths, and bond angles are detailed in Tables 5 to 11. The XRPD plot calculated from the single crystal structure is in close agreement with the test results for the single crystal sample, but there are some discrepancies in the peak positions. This is thought to be due to the fact that the single crystal data was collected under 180 K conditions, whereas the experimentally measured XRPD pattern was obtained at room temperature (Figure 5).

[0163] [Table 4]

[0164] [Table 5]

[0165] [Table 6]

[0166] [Table 7]

[0167] [Table 8]

[0168] [Table 9]

[0169] [Table 10]

[0170] [Table 11]

[0171] 5. Analysis method 5.1 Polarized Light Microscope (PLM) PLM analysis was performed using an ECLIPSE LV100POL (Nikon, JPN) polarizing microscope. A small amount of sample was spread flat on a slide, and a drop of cedar oil was added to disperse the sample. A coverslip was then added, and the sample was then placed under the microscope and observed with a 10x objective. 5.2 X-ray powder diffraction (XRPD) The solid samples were examined using an X-ray diffractometer. The samples were placed flat on a zero-background single crystal silicon sample disk, and after spreading the samples with light pressure, they were analyzed according to the parameters in Table 12.

[0172] [Table 12]

[0173] As can be seen from the above single crystal structure analysis, the chiral configuration of the methyl acetate chiral isomer A is the "R" configuration, as shown in Figure 6. As can be seen from this, in Example 13, when the methyl ester is removed using aqueous sodium hydroxide to obtain the carboxylic acid product, the chiral configuration of the product does not change, so it can be assumed that the chiral configuration of the product in Example 13, [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid chiral isomer A, is the "R" configuration.

[0174] Example 19: Determination of the chiral configuration of compound B of methyl acetate chiral isomer of Example 14 1. Preparation of Compounds Referring to the preparation method of [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]methyl acetate chiral isomer B (Step 1) in Example 14, methyl acetate chiral isomer B was obtained by chiral resolution, which is the precursor compound of the final product in Example 14. 2. Single crystal culture An appropriate amount of methyl acetate chiral isomer B sample was weighed into a vial, and dimethyl sulfoxide was added and stirred at room temperature until the solution was just clear or nearly clear. The mixture was filtered, and the filtrate was transferred to a clean vial, capped, punctured, and left at room temperature to slowly evaporate. By slow evaporation, needle-like single crystals were obtained from dimethyl sulfoxide as shown in Figure 7 and used for X-ray single crystal diffraction analysis. 3. Equipment and parameters Single-crystal data for methyl acetate chiral isomer B were collected on a Rigaku XtaLAB Synergy DW diffractometer at 180 K using Cu Kα radiation (λ = 1.54184 Å). The diffraction data were reduced and corrected using the CrysAlisPro program, and the structure was analyzed using the SHELXT program with a dyadic space algorithm. All non-hydrogen atoms were localized directly from the difference Fourier plot, and hydrogen atoms were placed on parent atoms. The SHELXT program was used to complete the final structure refinement based on the F2 full-matrix least-squares method. 4. X-ray diffraction analysis The single crystal structure of methyl acetate chiral isomer B is monoclinic and belongs to the P21 space group, and the molecular formula of the single crystal is C 20 H 20 N4O4. There is one methyl acetate chiral isomer B molecule in each asymmetric unit, and each cell contains two asymmetric units. The absolute configuration of the 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 angles, hydrogen bonds, bond lengths, and bond angle parameters are summarized in Tables 14 to 20. The XRPD pattern measured in the single crystal sample experiment had more peaks than the calculated XRPD pattern, which may be because the solvent was almost completely evaporated after the single crystal test, and other crystalline forms were precipitated during the solvent evaporation process (Figure 11).

[0175] [Table 13]

[0176] [Table 14]

[0177] [Table 15]

[0178] [Table 16]

[0179] [Table 17]

[0180] [Table 18]

[0181] [Table 19]

[0182] [Table 20]

[0183] 5. Analysis method 5.1 Polarized Light Microscope (PLM) PLM analysis was performed using an ECLIPSE LV100POL (Nikon, JPN) polarizing microscope. A small amount of sample was spread flat on a slide, and a drop of cedar oil was added to disperse the sample. A coverslip was then added. The sample was then placed under the microscope and observed through an objective lens. 5.2 X-ray powder diffraction (XRPD) The solid samples were detected using an X-ray diffractometer. The samples were flattened onto a zero-background single crystal silicon sample disk, and after spreading the sample with light pressure, they were analyzed according to the parameters in Table 21.

[0184] [Table 21]

[0185] As can be seen from the above single crystal structure analysis, the chiral configuration of the methyl acetate chiral isomer B is the "S" configuration, as shown in Figure 12. As can be seen from this, in Example 14, when the methyl ester is removed using aqueous sodium hydroxide to obtain the carboxylic acid product, the chiral configuration of the product does not change, so the chiral configuration of the product in Example 14, [(7-hydroxy-5-(1,2,3,4-tetrahydronaphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic acid chiral isomer B, is the "S" configuration.

[0186] Example 20 Subacute toxicity test of the compounds of Examples 13 and 14 1. Experimental Materials 1.1 Test Subject

[0187] [Table 22]

[0188] 1.2 Recipe preparation Weigh out appropriate amounts of the compound of Example 13 and the compound of Example 14 on a balance and place them in appropriate glass vials. Then, DMSO, Solutol HS-15, and 0.9% saline (v:v:v = 5%:10%:85%) were added to the glass vials in sequence, followed by vortex mixing. The drug dissolution status was monitored during mixing until complete dissolution / suspension. Finally, a test solution for administering the compound of Example 13 and the compound of Example 14 at a concentration of 0.67 mg / mL was prepared and made ready-to-use.

[0189] 2. Experimental Animals The source and number of experimental animals are shown in Table 23. The animal room was well ventilated and equipped with an air-conditioning system, with a temperature maintained at 20-25°C and humidity at 40-70%, and light and dark cycles of 12 hours each. Food and water were provided ad libitum. SD rats were selected for this experiment after acclimation for at least 3 days prior to drug administration and in good physical condition as determined by veterinary examination.

[0190] [Table 23]

[0191] 3. Experimental plan 3.1 Test cycle and dosage setting All animal manipulations in this study complied with the requirements of the "Regulations for the Management of Experimental Animals" issued by the Ministry of Science and Technology of the People's Republic of China. In this study, a vehicle control group, a group administered with the compound of Example 13, and a group administered with the compound of Example 14 were set up. The compounds of Example 13 and Example 14 were administered at a dose of 10 mg / kg once daily for 14 consecutive days. The blank control group received an equal volume of blank vehicle at a volume of 15 mL / kg. After each administration, the animals were observed for signs and severity of toxicity. Observation resumed for 7 days after the final administration. Water was allowed ad libitum throughout the experiment. Details are shown in Table 24.

[0192] [Table 24]

[0193] After weighing, the theoretical administration volume for each SD rat was calculated according to the following formula: The actual administration volume and sample collection time for each SD rat should be recorded in detail in the corresponding table.

[0194]

number

[0195] 3.2 Experimental observation During the experiment, the experimenter and veterinarian were required to continuously monitor the signs and health of the experimental animals. Any abnormal animal behavior, such as pain, depression, or decreased activity, must be recorded in the original experiment record. If the abnormal behavior of the experimental animals exceeds the animal welfare requirements documented by the IACUC, the veterinarian can decide whether to terminate the experiment and notify the experimental project leader.

[0196] 3.3 Cageside observations During the experiment, all animals were observed at least twice daily, with continuous observation for two hours after the end of administration. If any animals showed severe toxic side effects or died during administration, the observation results were recorded on the appropriate form. Observation indicators included the animals' appearance, behavior, secretions, excretions, feeding, and mortality (number of deaths, time of death, and pre-mortem reactions). In the case of clinical symptoms, the number of observations should be increased to closely observe the symptoms, onset time, severity, duration, and reversibility of the animal's toxic reactions. If an animal was found dead or moribund, it should be promptly dissected and observed according to regulations.

[0197] 3.4 Weight Before administration, the body weight was measured every day for 14 consecutive days, and the body weight was recorded in the corresponding table. Also, the body weight was recorded in the corresponding table. During the test period, the food intake of the test animals was examined.

[0198] 3.5 Clinical Pathology Approximately 1.8-2.0 mL of whole blood was collected for hematological and blood biochemistry tests before the first administration and 24 hours after the end of the final administration. An additional blood sample was collected for coagulation tests 24 hours after the end of the final administration. If the animal's condition was abnormal during administration, the times for hematological, coagulation, and blood biochemistry tests were advanced. The animals were fasted for at least 12 hours before blood samples were collected. Approximately 500 μL of whole blood was placed in an anticoagulated tube containing EDTA-K2 and subjected to hematological analysis. White blood cell count (WBC) Neutrophil categorization (absolute count, NEUT, percentage, %NEUT) Lymphocyte differential count (absolute count, LYM, percentage, %LYM) Monocyte classification count (absolute count, MONO, percentage, %MONO) Eosinophil differential count (absolute count, EOS, percentage, %EOS) Basophil count (absolute count, BASO, percentage, %BASO) Red blood cell count (RBC) Hemoglobin (HGB) Red blood cell compaction (HCT) Mean corpuscular volume (MCV) Mean corpuscular hemoglobin (MCH) Mean corpuscular hemoglobin concentration (MCHC) Red blood cell coefficient of variation (RDW-CV) Red blood cell distribution width standard deviation (RDW-SD) Platelet count (PLT) Platelet mean distribution width (MPV) Platelet mean volume (PDW) Platelet pressure (PCT) Approximately 1.5 mL of whole blood was placed in a split gel blood tube (without anticoagulant) and blood biochemistry analysis was performed. Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Alkaline Phosphatase (ALP) Albumin (ALB) Total cholesterol (Cholesterol, TC) Creatinine (CRE) Urea Creatine Phosphokinase (CK) Triglycerides (TG) Total Bilirubin (TBIL) Total Protein (TP) Aspartate aminotransferase / alanine aminotransferase (AST / ALT) Globulin (Glo II) Albumin / Globulin (A / G II) Electrolyte Class (K + / Na + / Cl - / Ca 2+ )

[0199] 4. Conclusion Under the present experimental conditions, the compounds of Examples 13 and 14 did not show obvious gastrointestinal necrotic hair, black stomach bleeding spots, or flatulence, and their toxicity was lower than that of Enarodustat, indicating good safety.

[0200] The above are only preferred embodiments of the present invention, and are not intended to limit the present invention. As long as they do not deviate from the spirit and principles of the present invention, any modifications, equivalent replacements, improvements, etc. shall all fall within the scope of protection of the present invention.

[0201] (Addendum) (Appendix 1) A compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof. [ka] (where, R is the unit of the following atoms or groups: [ka] is selected from L is -CH2- or -CH2O-; The value of n is an integer from 0 to 2, R 1 , R 2 , R 3 are each independently selected from substituted or unsubstituted alkyl, cycloalkyl, aryl, and heterocyclic groups; R 4 is selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, and heterocyclic groups.

[0202] (Appendix 2) 10. The compound of claim 1, wherein the aryl comprises an aromatic heterocyclic group, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof.

[0203] (Appendix 3) L is -CH2- or -CH2O-; The value of n is 0 or 1, R 1 is a substituted or unsubstituted C 1~4 alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 at least one of haloalkyl, halogen, cyano, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R 2 is a substituted or unsubstituted C 1~4 alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C 1~4 Alkyl, C 1~4Alkoxy, C 1~4 at least one of haloalkyl, halogen, cyano, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R 3 is a substituted or unsubstituted C 1~10 alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 at least one of haloalkyl, halogen, cyano, phenyl, or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R 4 is hydrogen, substituted or unsubstituted C 1~10 Alkyl, C 1~10 Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, wherein the substituent is C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof.

[0204] (Appendix 4) L is -CH2- or -CH2O-; The value of n is 0 or 1, R 1 is a substituted or unsubstituted phenyl, said substituents being C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4at least one of haloalkyl, halogen, cyano, phenyl, or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R 2 is a substituted or unsubstituted phenyl, said substituents being C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 at least one of haloalkyl, halogen, cyano, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R 3 is a substituted or unsubstituted C 1~10 alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C 1~4 Alkyl, C 1~4 at least one of alkoxy, halogen, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, R 4 is hydrogen, substituted or unsubstituted C 1~10 Alkyl, C 1~10 Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, wherein the substituent is C 1~4 Alkyl, C 1~4 The compound according to Appendix 2, wherein the compound is at least one of alkoxy, halogen, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof.

[0205] (Appendix 5) The value of n is 0 or 1, R 1 is a substituted or unsubstituted phenyl, said substituents being C 1~4 Alkyl, C 1~4A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~4 Alkyl, C 1~4 the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is ortho-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 2 is a substituted or unsubstituted phenyl, said substituents being C 1~4 Alkyl, C 1~4 Alkoxy, halogen, or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably 1~4 Alkyl, C 1~4 the alkoxy and the 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen or the 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 3 is a substituted or unsubstituted C alkyl, phenyl, 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C 1~4 Alkyl, C 1~4 A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~4 Alkyl, C 1~4 the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group, or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted with respect to the core structure; R 4 is hydrogen, substituted or unsubstituted C 1~5 Alkyl, C 1~5Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituent is C 1~4 Alkyl, C 1~4 A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~4 Alkyl, C 1~4 the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group, or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted with respect to the core structure; Preferably, The value of n is 0 or 1, R 1 is a substituted or unsubstituted phenyl, said substituents being C 1~3 Alkyl, C 1~3 A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~3 Alkyl, C 1~3 the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is ortho-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted; R 2 is a substituted or unsubstituted phenyl, said substituents being C 1~3 Alkyl, C 1~3 A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~3 Alkyl, C 1~3the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is ortho-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 3 is a substituted or unsubstituted C 1~5 alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituent is C 1~3 Alkyl, C 1~3 A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~3 Alkyl, C 1~3 the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted with respect to the core structure; R 4 is hydrogen, substituted or unsubstituted C 1~5 Alkyl, C 1~5 Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituent is C 1~3 Alkyl, C 1~3 A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the C 1~3 Alkyl, C 1~3 the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted with respect to the core structure; or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof according to Appendix 3.

[0206] (Appendix 6) The value of n is 0 or 1, R 1 is a substituted or unsubstituted phenyl, said substituents being C 1~2 Alkyl, C 1~2 Alkoxy, F, Cl, Br, I, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably, 1~2 Alkyl, C 1~2 the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and F, Cl, Br, and I are ortho-, meta-, or para-substituted with respect to the core structure; R 2 is a substituted or unsubstituted phenyl, said substituents being C 1~2 Alkyl, C 1~2 Alkoxy, F, Cl, Br, I, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably, 1~2 Alkyl, C 1~2 the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and F, Cl, Br, and I are ortho-, meta-, or para-substituted with respect to the core structure; R 3 is a substituted or unsubstituted C 1~4 alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituent is C 1~2 Alkyl, C 1~2 Alkoxy, F, Cl, Br, I, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably, 1~2 Alkyl, C 1~2the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted with respect to the core structure; R 4 is hydrogen, substituted or unsubstituted C 1~4 Alkyl, C 1~4 Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituent is C 1~2 Alkyl, C 1~2 Alkoxy, F, Cl, Br, I, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably, 1~2 Alkyl, C 1~2 the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted with respect to the core structure; Preferably, The value of n is 0 or 1, R 1 is a substituted or unsubstituted phenyl, the substituent being a 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy, F, Cl, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy, oxygen and / or nitrogen is para-substituted with respect to the core structure, and F and Cl are ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 2is a substituted or unsubstituted phenyl, the substituent being methyl, methoxy, F, Cl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, preferably the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy and oxygen and / or nitrogen is para-substituted with respect to the core structure, and F and Cl are ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 3 is a substituted or unsubstituted C 1~3 a 5- to 6-membered aromatic heterocyclic group containing alkyl, phenyl, oxygen and / or nitrogen, wherein the substituent on the phenyl is methyl, methoxy, F, Cl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy and oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 4 is hydrogen, substituted or unsubstituted C 1~3 Alkyl, C 1~3 a 5- to 6-membered aromatic heterocyclic group containing alkoxy, phenyl, oxygen and / or nitrogen, wherein the substituent on the phenyl is methyl, methoxy, F, Cl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy and oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; More preferably, The value of n is 0 or 1, R 1 is a substituted or unsubstituted phenyl, the substituent being methyl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and preferably the 5- to 6-membered aromatic heterocyclic group containing methyl, oxygen and / or nitrogen is para-substituted with respect to the core structure; R 2is a substituted or unsubstituted phenyl, the substituent being methyl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and preferably the 5- to 6-membered aromatic heterocyclic group containing methyl, oxygen and / or nitrogen is para-substituted with respect to the core structure; R 3 is a substituted or unsubstituted C 1~3 a 5- to 6-membered aromatic heterocyclic group containing alkyl, phenyl, oxygen and / or nitrogen, wherein the substituent is methyl, methoxy, F, Cl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy and oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 4 is hydrogen, substituted or unsubstituted C 1~3 Alkyl, C 1~3 a 5- to 6-membered aromatic heterocyclic group containing alkoxy, phenyl, oxygen and / or nitrogen, wherein the substituent is methyl, methoxy, F, Cl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy and oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; More preferably, The value of n is 0 or 1, R 1 is phenyl, R 2 is phenyl, R 3 is a substituted or unsubstituted C 1~3a 5- to 6-membered aromatic heterocyclic group containing alkyl, phenyl, oxygen and / or nitrogen, wherein the substituent is methyl, methoxy, halogen or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy, oxygen and / or nitrogen or the 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R 4 is hydrogen, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof.

[0207] (Appendix 7) The compound has the following structure: [ka] is selected from Preferably, the compound has the following structure: [ka] is selected from More preferably, the compound has the following structure: [ka] is selected from More preferably, the compound has the following structure: [ka] Selected from: 7. The compound of claim 6, wherein:

[0208] (Appendix 8) A method for preparing a compound according to any one of claims 1 to 7, comprising the following four synthetic routes: [ka] [ka] [ka] [ka] Including, where R 1 , R 2 , R 3 has the same definition as in the cited appendix.

[0209] (Appendix 9) A pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0210] (Appendix 10) Use of a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition as described above, in the preparation of a medicament for treating a disease mediated by the inhibition of prolyl hydroxylase, by inhibiting prolyl hydroxylase, wherein the disease mediated by the inhibition of prolyl hydroxylase is preferably anemia, ischemia or hypoxia, more preferably renal anemia.

Claims

1. A compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof. 【Chemical 1】 (where, R is a unit of the following atoms or groups: 【Chemistry 2】 is selected from L is -CH ２ - or -CH ２ O-, the value of n is an integer from 0 to 2; R １ , R ２ , R ３ are each independently selected from substituted or unsubstituted alkyl, cycloalkyl, aryl, and heterocyclic groups; R ４ is selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxy, aryl, and heterocyclic groups.

2. 2. The compound of claim 1, wherein the aryl comprises an aromatic heterocyclic group, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof.

3. L is -CH ２ - or -CH ２ O-, the value of n is 0 or 1; R １ is a substituted or unsubstituted C １～４ alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C １～４ Alkyl, C １～４ Alkoxy, C １～４ at least one of haloalkyl, halogen, cyano, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R ２ is a substituted or unsubstituted C １～４ alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C １～４ Alkyl, C １～４ Alkoxy, C １～４ at least one of haloalkyl, halogen, cyano, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R ３ is a substituted or unsubstituted C １～１０ alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C １～４ Alkyl, C １～４ Alkoxy, C １～４ at least one of haloalkyl, halogen, cyano, phenyl, or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R ４ is hydrogen, substituted or unsubstituted C １～１０ Alkyl, C １～１０ Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, wherein the substituent is C １～４ Alkyl, C １～４ Alkoxy, C １～４ The compound according to claim 1, wherein the compound is at least one of haloalkyl, halogen, cyano, phenyl, or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof.

4. L is -CH ２ - or -CH ２ O-, the value of n is 0 or 1; R １ is a substituted or unsubstituted phenyl, said substituents being C １～４ Alkyl, C １～４ Alkoxy, C １～４ at least one of haloalkyl, halogen, cyano, phenyl, or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R ２ is a substituted or unsubstituted phenyl, said substituents being C １～４ Alkyl, C １～４ Alkoxy, C １～４ at least one of haloalkyl, halogen, cyano, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R ３ is a substituted or unsubstituted C １～１０ alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C １～４ Alkyl, C １～４ at least one of alkoxy, halogen, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen; R ４ is hydrogen, substituted or unsubstituted C １～１０ Alkyl, C １～１０ Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, wherein the substituent is C １～４ Alkyl, C １～４ The compound according to claim 2, wherein the compound is at least one of alkoxy, halogen, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof.

5. the value of n is 0 or 1; R １ is a substituted or unsubstituted phenyl, said substituents being C １～４ Alkyl, C １～４ A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably １～４ Alkyl, C １～４ the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is ortho-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R ２ is a substituted or unsubstituted phenyl, said substituents being C １～４ Alkyl, C １～４ Alkoxy, halogen, or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably １～４ Alkyl, C １～４ the alkoxy and the 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen or the 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R ３ is a substituted or unsubstituted C １ - ５ alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are １～４ Alkyl, C １～４ A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably １～４ Alkyl, C １～４ the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group, or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted with respect to the core structure; R ４ is hydrogen, substituted or unsubstituted C １～５ Alkyl, C １～５ Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituent is C １～４ Alkyl, C １～４ A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably １～４ Alkyl, C １～４ the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group, or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted with respect to the core structure; Preferably, the value of n is 0 or 1; R １ is a substituted or unsubstituted phenyl, said substituents being C １～３ Alkyl, C １～３ A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably １～３ Alkyl, C １～３ the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is ortho-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted; R ２ is a substituted or unsubstituted phenyl, said substituents being C １～３ Alkyl, C １～３ A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably １～３ Alkyl, C １～３ the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is ortho-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R ３ is a substituted or unsubstituted C １～５ alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are １～３ Alkyl, C １～３ A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably １～３ Alkyl, C １～３ the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted with respect to the core structure; R ４ is hydrogen, substituted or unsubstituted C １～５ Alkyl, C １～５ Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are C １～３ Alkyl, C １～３ A 5- to 6-membered aromatic heterocyclic group containing alkoxy, halogen, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably １～３ Alkyl, C １～３ The compound according to claim 3, wherein the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or the oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted with respect to the core structure, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

6. the value of n is 0 or 1; R １ is a substituted or unsubstituted phenyl, said substituents being C １～２ Alkyl, C １～２ Alkoxy, F, Cl, Br, I, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably the C １～２ Alkyl, C １～２ the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and F, Cl, Br, and I are ortho-, meta-, or para-substituted with respect to the core structure; R ２ is a substituted or unsubstituted phenyl, said substituents being C １～２ Alkyl, C １～２ Alkoxy, F, Cl, Br, I, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably the C １～２ Alkyl, C １～２ the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and F, Cl, Br, and I are ortho-, meta-, or para-substituted with respect to the core structure; R ３ is a substituted or unsubstituted C １～４ alkyl, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituents are １～２ Alkyl, C １～２ Alkoxy, F, Cl, Br, I, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably the C １～２ Alkyl, C １～２ the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted with respect to the core structure; R ４ is hydrogen, substituted or unsubstituted C １～４ Alkyl, C １～４ Alkoxy, phenyl, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and the substituent is C １～２ Alkyl, C １～２ Alkoxy, F, Cl, Br, I, a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, and preferably the C １～２ Alkyl, C １～２ the alkoxy, oxygen- and / or nitrogen-containing 5- to 6-membered aromatic heterocyclic group or oxygen- and / or nitrogen-containing 5- to 6-membered heterocyclic group is para-substituted with respect to the core structure, and the halogen is ortho-, meta- or para-substituted with respect to the core structure; Preferably, the value of n is 0 or 1; R １ is a substituted or unsubstituted phenyl, the substituent being a 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy, F, Cl, oxygen and / or nitrogen, or a 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen, preferably the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy, oxygen and / or nitrogen is para-substituted with respect to the core structure, and F and Cl are ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R ２ is a substituted or unsubstituted phenyl, the substituent being methyl, methoxy, F, Cl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, preferably the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy and oxygen and / or nitrogen is para-substituted with respect to the core structure, and F and Cl are ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R ３ is a substituted or unsubstituted C １～３ a 5- to 6-membered aromatic heterocyclic group containing alkyl, phenyl, oxygen and / or nitrogen, wherein the substituent for the phenyl is methyl, methoxy, F, Cl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy and oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R ４ is hydrogen, substituted or unsubstituted C １～３ Alkyl, C １～３ a 5- to 6-membered aromatic heterocyclic group containing alkoxy, phenyl, oxygen and / or nitrogen, wherein the substituent for the phenyl is methyl, methoxy, F, Cl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy and oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; More preferably, the value of n is 0 or 1; R １ is a substituted or unsubstituted phenyl, the substituent being methyl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and preferably the 5- to 6-membered aromatic heterocyclic group containing methyl, oxygen and / or nitrogen is para-substituted with respect to the core structure; R ２ is a substituted or unsubstituted phenyl, the substituent being methyl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and preferably the 5- to 6-membered aromatic heterocyclic group containing methyl, oxygen and / or nitrogen is para-substituted with respect to the core structure; R ３ is a substituted or unsubstituted C １～３ a 5- to 6-membered aromatic heterocyclic group containing alkyl, phenyl, oxygen and / or nitrogen, wherein the substituent is methyl, methoxy, F, Cl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy and oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R ４ is hydrogen, substituted or unsubstituted C １～３ Alkyl, C １～３ a 5- to 6-membered aromatic heterocyclic group containing alkoxy, phenyl, oxygen and / or nitrogen, wherein the substituent is methyl, methoxy, F, Cl or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy and oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; More preferably, the value of n is 0 or 1; R １ is phenyl, R ２ is phenyl, R ３ is a substituted or unsubstituted C １～３ a 5- to 6-membered aromatic heterocyclic group containing alkyl, phenyl, oxygen and / or nitrogen, wherein the substituent is methyl, methoxy, halogen or a 5- to 6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, preferably, the 5- to 6-membered aromatic heterocyclic group containing methyl, methoxy, oxygen and / or nitrogen or the 5- to 6-membered heterocyclic group containing oxygen and / or nitrogen is para-substituted with respect to the core structure, and the halogen is ortho-substituted, meta-substituted or para-substituted with respect to the core structure; R ４ is hydrogen, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof.

7. The compound has the following structure: 【Chemistry 3】 is selected from Preferably, the compound has the following structure: 【Chemistry 4】 is selected from More preferably, the compound has the following structure: 【Chemistry 5】 is selected from More preferably, the compound has the following structure: 【Chemistry 6】 Selected from:

7. The compound of claim 6, or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

8. A method for preparing the compound according to any one of claims 1 to 7, comprising the following four synthetic routes: 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 Including, Here, R １ , R ２ , R ３ has the same definition as in the cited claims.

9. A pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

10. Use of a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition as described above, in the preparation of a medicament for treating a disease mediated by the inhibition of prolyl hydroxylase, by inhibiting prolyl hydroxylase, wherein the disease mediated by the inhibition of prolyl hydroxylase is preferably anemia, ischemia or hypoxia, more preferably renal anemia.

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