CN108069952B

CN108069952B - Quinolinone compound and application thereof in medicines

Info

Publication number: CN108069952B
Application number: CN201610978312.9A
Authority: CN
Inventors: 左应林; 王晓军; 张英俊; 吴方园; 劳锦花
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2016-11-08
Filing date: 2016-11-08
Publication date: 2022-09-27
Anticipated expiration: 2036-11-08
Also published as: CN108069952A

Abstract

The invention relates to quinolinone compounds and application thereof in medicaments, and also relates to a pharmaceutical composition containing the compounds and application of the compounds or the pharmaceutical composition in preparation of medicaments for preventing, treating or relieving HIF (HIF-associated) and/or EPO (erythropoietin) related diseases of patients.

Description

Quinolinone compound and application thereof in medicines

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a novel quinolinone compound and a pharmaceutical composition thereof, and further relates to an application of the compound or the pharmaceutical composition in preparation of medicines.

Background

In the case of anemia, trauma, tissue necrosis and defects, the tissue or cells are often in a hypoxic state. Hypoxia results in the expression of a series of transcription inducible factors that are involved in angiogenesis, iron, sugar metabolism, and cell growth and proliferation. Among them, HIF (hypoxia inducible factor) is a transcription factor that is activated by somatic cells under reduced oxygen, and is widely distributed in various parts of the body, particularly, vascular intima, heart, brain, kidney, liver, and the like. HIF is a heterodimer comprising an oxygen-regulated α -subunit (HIF α) and a constitutively expressed β -subunit (HIF β/ARNT). In oxygenated (normoxic) cells, the HIF α subunit is rapidly degraded by the ubiquitination (ubiquitination) mechanism of the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Under hypoxic conditions, HIF α is not reduced, and active HIF α/β complexes accumulate in the nucleus and activate the expression of various genes, including glycolytic enzymes, glucose transporters, Erythropoietin (EPO) and Vascular Endothelial Growth Factor (VEGF).

Erythropoietin (EPO) is a naturally occurring hormone produced by HIF α that stimulates the production of red blood lipids (red blood cells) that carry oxygen throughout the body. EPO is normally secreted by the kidney, and endogenous EPO is increased under conditions of reduced oxygen (hypoxia). All types of anemia are characterized by a reduced capacity of the blood to carry oxygen and are therefore accompanied by similar signs and symptoms, including pale skin and mucous membranes, weakness, dizziness, fatigue and lethargy, leading to a reduction in quality of life. Anemia is often associated with conditions of blood deficiency in erythrocytes or in hemoglobin. The common causes of anemia include iron and vitamin B ₁₂ And folate deficiency, and also in association with chronic diseases, such as inflammatory diseases, including diseases with secondary myeloinflammatory suppression, and the like. Anemia is also associated with renal dysfunction, and most renal failure patients who are constantly dialyzing suffer from chronic anemia.

Prolyl Hydroxylase (PHD) is a key factor in the regulation of HIF. Under normoxic conditions, PHD can hydroxylate two key proline residues Pro402 and Pro564 of HIF α, increasing its affinity for pVHL, accelerating the degradation process. Under hypoxia and other pathological conditions, the HIF reaction catalyzed by PHD is blocked, the degradation speed of protease is reduced, HIF alpha is accumulated in cells, and a series of adaptive responses of the cells to hypoxia are caused. By inhibiting PHD through a PHD inhibitor, the action of HIF is prolonged, and the expression of genes such as EPO is increased, so that HIF-related and/or EPO-related symptoms, such as anemia, ischemia and hypoxia, can be effectively treated and prevented.

The invention relates to quinolinone compounds as HIF-PHD inhibitors, which can be used for treating various HIF-related and/or EPO-related diseases, such as anemia and the like.

Summary of the invention

In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, metabolic precursor, pharmaceutically acceptable salt or prodrug of a compound of formula (I),

wherein the content of the first and second substances,

R ¹ is- (CR) ¹⁰ R ¹¹ ) _m -M ¹ -M ² ；

Wherein each R is ¹⁰ And R ¹¹ Independently is H, halogen, cyano, hydroxy, mercapto, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

M ¹ is cycloalkyl, heterocyclyl, aryl or heteroaryl;

M ² is- (CR) ¹² R ¹³ ) _p -O-R ¹⁴ 、-(CR ¹² R ¹³ ) _p -NR ¹⁵ R ¹⁶ 、-(CR ¹² R ¹³ ) _p -C(＝X)R ¹⁷ 、-(CR ¹² R ¹³ ) _p -S(＝O) _n R ¹⁸ Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;

provided that M is ¹ 、M ² Is not phenyl at the same time;

wherein each X is independently O or S;

each R ¹² And R ¹³ Independently is H, halogen, cyano, hydroxy, mercapto, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

R ¹⁴ is haloalkyl, acyl, sulfonyl, sulfinyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;

R ¹⁵ is H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

R ¹⁶ is alkyl, haloalkyl, acyl, sulfonyl, sulfinyl,Cycloalkyl, heterocyclyl, aryl or heteroaryl;

each R ¹⁷ And R ¹⁸ Independently is H, -Y-R ¹⁹ Hydroxyl, mercapto, amino, alkyl, haloalkyl, acyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein each R is ¹⁹ Independently is H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

each R ² 、R ³ 、R ⁴ And R ⁵ Independently is H, -Y-R ²⁰ Halogen, nitro, cyano, alkyl, haloalkyl, amino, acyl, sulfonyl, sulfinyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

wherein each Y is independently O or S;

each R ²⁰ Independently is H, alkyl, haloalkyl, acyl, sulfonyl, sulfinyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R ⁶ is H, hydroxyl, sulfhydryl, amino or alkyl;

R ⁷ is hydrogen or alkyl;

each R ⁸ And R ⁹ Independently is H or alkyl;

each k is independently 1,2, 3 or 4;

each m is independently 1,2, 3, 4,5 or 6;

each n is independently 0, 1 or 2;

each p is independently 0, 1,2, 3 or 4;

wherein M is ¹ 、M ² 、R ² ～R ²⁰ The hydroxy, mercapto, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, acyl, sulfonyl, sulfinyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl groups recited in (a) can be independently optionally substituted with one or more substituents selected from the group consisting of H, oxo (═ O), halogen, hydroxy, nitro, cyano, mercapto, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, acyl, sulfonyl, sulfinyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkylOxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, or heterocyclyloxy.

In some embodiments, the invention relates to a compound that is a compound of formula (II) or a stereoisomer, geometric isomer, nitroxide, solvate, metabolite, metabolic precursor, or pharmaceutically acceptable salt of a compound of formula (II),

wherein R is ¹ 、R ² 、R ³ 、R ⁴ And R ⁵ Have the meaning described in the present invention.

In some embodiments, each R is ¹⁰ And R ¹¹ Independently H, fluorine, chlorine, bromine, cyano, hydroxyl, mercapto, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radical, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-14 Aryl or C _1-9 A heteroaryl group; wherein R is ¹⁰ And R ¹¹ C as described in (1) _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radical, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-14 Aryl and C _1-9 Heteroaryl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, mercapto, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl or sulfonyl.

In some embodiments, M ¹ Is C _3-12 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-14 Aryl or C _1-9 A heteroaryl group; wherein M is ¹ Optionally substituted with one or more groups selected from H, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, mercapto, nitro, cyano, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl, sulfonyl, sulfinyl, C _3-10 Cycloalkyl radical, C _3-10 Cycloalkyl radical C _1-6 Alkyl radical, C _3-10 Cycloalkyl oxy, C _2-9 Heterocyclic group, C _2-9 Heterocyclyl radical C _1-6 Alkyl radical, C _2-9 Heterocyclyloxy, C _6-14 Aryl radical, C _6-14 Aryl radical C _1-6 Alkyl radical, C _6-14 Aryloxy radical, C _1-9 Heteroaryl group, C _1-9 Heteroaryl C _1-6 Alkyl or C _1-9 Substituted with a substituent of heteroaryloxy;

M ² is- (CR) ¹² R ¹³ ) _p -O-R ¹⁴ 、-(CR ¹² R ¹³ ) _p -NR ¹⁵ R ¹⁶ 、-(CR ¹² R ¹³ ) _p -C(＝O)R ¹⁷ 、-(CR ¹² R ¹³ ) _p -S(＝O) _n R ¹⁸ 、C _3-12 Cycloalkyl radical, C _3-12 Cycloalkyl radical C _1-6 Alkyl radical, C _2-9 Heterocyclic group, C _2-9 Heterocyclyl radical C _1-6 Alkyl radical, C _6-14 Aryl radical, C _6-14 Aryl radical C _1-6 Alkyl radical, C _1-9 Heteroaryl or C _1-9 Heteroaryl C _1-6 An alkyl group; wherein M is ² Optionally substituted with one or more groups selected from H, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, mercapto, amino, nitro, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl, sulfonyl, sulfinyl, C _3-10 Cycloalkyl radical, C _3-10 Cycloalkyl radical C _1-6 Alkyl radical, C _3-10 Cycloalkyl oxy, C _2-9 Heterocyclic group, C _2-9 Heterocyclyl radical C _1-6 Alkyl radical, C _2-9 Heterocyclyloxy, C _6-14 Aryl radical, C _6-14 Aryl radical C _1-6 Alkyl radical, C _6-14 Aryloxy radical, C _1-9 Heteroaryl, C _1-9 Heteroaryl C _1-6 Alkyl or C _1-9 Substituted with a substituent of heteroaryloxy;

provided that M is ¹ 、M ² Is not phenyl at the same time;

wherein each R is ¹² And R ¹³ Independently H, fluorine, chlorine, bromine, cyano, hydroxyl, mercapto, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radical, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-14 Aryl or C _1-9 A heteroaryl group; wherein R is ¹² And R ¹³ C as described in (1) _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radical, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-14 Aryl and C _1-9 Heteroaryl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, mercapto, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl or sulfonyl;

R ¹⁴ is halo C _1-6 Alkyl, acyl, sulfonyl, C _3-10 Cycloalkyl radical, C _3-10 Cycloalkyl radical C _1-6 Alkyl radical, C _2-9 Heterocyclic group, C _2-9 Heterocyclyl radical C _1-6 Alkyl radical, C _6-14 Aryl radical, C _6-14 Aryl radical C _1-6 Alkyl radical, C _1-9 Heteroaryl or C _1-9 Heteroaryl C _1-6 An alkyl group; wherein R is ¹⁴ The halogen of (A) to (B) _1-6 Alkyl radical, C _3-10 Cycloalkyl, C _3-10 Cycloalkyl radical C _1-6 Alkyl radical, C _2-9 Heterocyclic group, C _2-9 Heterocyclyl radical C _1-6 Alkyl radical, C _6-14 Aryl radical, C _6-14 Aryl radical C _1-6 Alkyl radical, C _1-9 Heteroaryl and C _1-9 Heteroaryl C _1-6 Alkyl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, mercapto, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl or sulfonyl;

R ¹⁵ is H, C _1-6 Alkyl, haloGeneration C _1-6 Alkyl radical, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-14 Aryl or C _1-9 A heteroaryl group; wherein R is ¹⁵ C as described in (1) _1-6 Alkyl, halo C _1-6 Alkyl radical, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-14 Aryl and C _1-9 Heteroaryl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, mercapto, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl or sulfonyl;

R ¹⁶ is C _1-6 Alkyl, halo C _1-6 Alkyl, acyl, sulfonyl, C _3-10 Cycloalkyl, C _2-9 Heterocyclic group, C _6-10 Aryl or C _1-9 A heteroaryl group; wherein R is ¹⁶ C as described in (1) _1-6 Alkyl, halo C _1-6 Alkyl, acyl, sulfonyl, C _3-10 Cycloalkyl, C _2-9 Heterocyclic group, C _6-10 Aryl and C _1-9 Heteroaryl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, mercapto, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl, sulfonyl, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-10 Aryl or C _1-9 Heteroaryl, or a substituted heteroaryl;

each R ¹⁷ And R ¹⁸ Independently of each other H, -O-R ¹⁹ Hydroxy, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-14 Aryl or C _1-9 A heteroaryl group; wherein R is ¹⁷ And R ¹⁸ C as described in (1) _1-6 Alkyl, halo C _1-6 Alkyl radical, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-14 Aryl and C _1-9 Heteroaryl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, mercapto, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl, sulfonyl, C _3-10 Cycloalkyl, C _2-9 Heterocyclic group, C _6-10 Aryl or C _1-9 Heteroaryl, or a substituted heteroaryl;

wherein each R is ¹⁹ Independently H, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _3-12 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-14 Aryl or C _1-9 A heteroaryl group; wherein R is ¹⁹ C as described in (1) _1-6 Alkyl, halo C _1-6 Alkyl radical, C _3-12 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-14 Aryl and C _1-9 Heteroaryl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, mercapto, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl, sulfonyl, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-10 Aryl or C _1-9 Heteroaryl group is substituted.

In some embodiments, each R is ¹⁰ And R ¹¹ Independently H, fluorine, chlorine, bromine, cyano, hydroxyl, mercapto, amino, C _1-4 Alkyl, halo C _1-4 Alkyl or C _1-4 An alkoxy group; wherein R is ¹⁰ And R ¹¹ C as described in (1) _1-4 Alkyl, halo C _1-4 Alkyl and C _1-4 Alkoxy is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, -NH ₂ Methylamino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, carboxyl, sulfonic acid, or methylsulfonyl.

In some embodiments, M ¹ Is C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-10 Aryl or C _1-9 A heteroaryl group; wherein M is ¹ Optionally substituted with one or more groups selected from H, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, mercapto, amino, nitro, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl, sulfonyl, sulfinyl, C _3-10 Cycloalkyl radical, C _3-10 Cycloalkyl radical C _1-6 Alkyl radical, C _3-10 Cycloalkyl oxy, C _2-9 Heterocyclic group, C _2-9 Heterocyclyl radical C _1-6 Alkyl radical, C _2-9 Heterocyclyloxy, C _6-10 Aryl radical, C _6-10 Aryl radical C _1-6 Alkyl radical, C _6-10 Aryloxy radical, C _1-9 Heteroaryl group, C _1-9 Heteroaryl C _1-6 Alkyl or C _1-9 Substituted with a substituent of heteroaryloxy;

M ² is-O-R ¹⁴ 、-NR ¹⁵ R ¹⁶ 、-C(＝O)R ¹⁷ 、-S(＝O) _n R ¹⁸ 、C _3-10 Cycloalkyl, C _3-10 Cycloalkyl radical C _1-6 Alkyl radical, C _2-9 Heterocyclic group, C _2-9 Heterocyclyl radical C _1-6 Alkyl radical, C _6-10 Aryl radical, C _6-10 Aryl radical C _1-6 Alkyl radical, C _1-9 Heteroaryl or C _1-9 Heteroaryl C _1-6 An alkyl group; wherein, M ² Optionally substituted with one or more groups selected from H, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, mercapto, amino, nitro, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl, sulfonyl, sulfinyl, C _3-10 Cycloalkyl, C _3-10 Cycloalkyl radical C _1-6 Alkyl radical, C _3-10 Cycloalkyloxy radical, C _2-9 Heterocyclic group, C _2-9 Heterocyclyl radical C _1-6 Alkyl radical, C _2-9 Heterocyclyloxy, C _6-10 Aryl radical, C _6-10 Aryl radical C _1-6 Alkyl radical, C _6-10 Aryloxy radical, C _1-9 Heteroaryl group, C _1-9 Heteroaryl C _1-6 Alkyl or C _1-9 Substituted with a substituent of heteroaryloxy;

with the proviso that M ¹ 、M ² Is not phenyl at the same time;

wherein R is ¹⁴ Is halo C _1-4 Alkyl, acyl, sulfonyl, C _3-8 Cycloalkyl radical, C _3-8 Cycloalkyl radical C _1-4 Alkyl radical, C _2-7 Heterocyclic group, C _2-7 Heterocyclyl radical C _1-4 Alkyl radical, C _6-10 Aryl radical, C _6-10 Aryl radical C _1-4 Alkyl radical, C _1-9 Heteroaryl or C _1-9 Heteroaryl C _1-4 An alkyl group; wherein R is ¹⁴ C as described in (1) _3-8 Cycloalkyl radical, C _3-8 Cycloalkyl radical C _1-4 Alkyl radical, C _2-7 Heterocyclic group, C _2-7 Heterocyclyl radical C _1-4 Alkyl radical, C _6-10 Aryl radical, C _6-10 Aryl radical C _1-4 Alkyl radical, C _1-9 Heteroaryl and C _1-9 Heteroaryl C _1-4 Alkyl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, -NH ₂ Methylamino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, carboxyl, sulfonic acid, or methylsulfonyl;

R ¹⁵ is H or C _1-4 An alkyl group; wherein R is ¹⁵ C as described in (1) _1-4 Alkyl is optionally substituted by one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, -NH ₂ Methylamino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, carboxyl, sulfonic acid, or methylsulfonyl;

R ¹⁶ is C _1-4 Alkyl, acyl, sulfonyl, C _3-8 Cycloalkyl, C _2-7 Heterocyclic group, C _6-10 Aryl or C _1-9 A heteroaryl group; wherein R is ¹⁶ C as described in (1) _1-4 Alkyl radical, C _3-8 Cycloalkyl radical, C _2-7 Heterocyclic group, C _6-10 Aryl and C _1-9 Heteroaryl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, -NH ₂ Methylamino, dimethylamino, methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, carboxyl, methylsulfonyl, sulfonic acid, cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, or pyrimidinyl;

each R ¹⁷ And R ¹⁸ Independently H, hydroxy, amino, C _1-4 Alkyl radical, C _3-8 Cycloalkyl radical, C _2-7 Heterocyclic group, C _6-10 Aryl or C _1-9 A heteroaryl group; wherein R is ¹⁷ And R ¹⁸ C as described in (1) _1-4 Alkyl radical, C _3-8 Cycloalkyl radical, C _2-7 Heterocyclic group, C _6-10 Aryl and C _1-9 Heteroaryl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, -NH ₂ Methylamino, dimethylamino, methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, carboxyl, methylsulfonyl, sulfonic acid, cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, or pyrimidinyl.

In other embodiments, M ¹ Is C _3-8 Cycloalkyl, C _2-7 Heterocyclic group, C _6-10 Aryl or C _1-7 A heteroaryl group; wherein, M ¹ Optionally substituted with one or more groups selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, nitro, cyano, -NH ₂ 、C _1-4 Alkyl, halo C _1-4 Alkyl radical, C _1-4 Alkoxy, halo C _1-4 Alkoxy, acyl, sulfonyl, C _3-6 Cycloalkyl radical, C _3-6 Cycloalkyl radical C _1-4 Alkyl radical, C _2-5 Heterocyclic group, C _2-5 Heterocyclyl radical C _1-4 Alkyl radical, C _6-10 Aryl radical, C _6-10 Aryl radical C _1-4 Alkyl radical, C _1-5 Heteroaryl or C _1-5 Heteroaryl C _1-4 Alkyl is substituted by a substituent;

M ² is C _3-8 Cycloalkyl radical, C _3-8 Cycloalkyl radical C _1-4 Alkyl radical, C _2-7 Heterocyclic group, C _2-7 Heterocyclyl radical C _1-4 Alkyl radical, C _6-10 Aryl radical, C _6-10 Aryl radical C _1-4 Alkyl radical, C _1-9 Heteroaryl or C _1-9 Heteroaryl C _1-4 An alkyl group; wherein M is ² Optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, nitro, cyano, -NH ₂ 、C _1-4 Alkyl, halo C _1-4 Alkyl radical, C _1-4 Alkoxy, halo C _1-4 Alkoxy, acyl, sulfonyl, C _3-6 Cycloalkyl radical, C _3-6 Cycloalkyl radical C _1-4 Alkyl radical, C _2-5 Heterocyclic group, C _2-5 Heterocyclyl radical C _1-4 Alkyl radical, C _6-10 Aryl radical, C _6-10 Aryl radical C _1-4 Alkyl radical, C _1-5 Heteroaryl or C _1-5 Heteroaryl C _1-4 Alkyl is substituted by a substituent;

with the proviso that M ¹ 、M ² Not phenyl at the same time.

In still other embodiments, M ¹ Is C _3-6 Cycloalkyl radical, C _2-5 Heterocyclic group, C _6-10 Aryl or C _1-5 A heteroaryl group; wherein M is ¹ Optionally substituted with one or more groups selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, nitro, cyano, mercapto, -NH ₂ Methylamino, dimethylamino, methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, 1, 2-difluoroethyl, 1-difluoroethyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, 1, 2-difluoroethoxy, 1-difluoroethoxy, cyclopropyl, cyclopentyl, cyclohexyl, glycidyloxy, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl, pyrrolyl, pyridinyl, pyrimidinyl, acetyl, carboxyl, methylsulfonyl, or sulfonic;

M ² is C _3-6 Cycloalkyl radical, C _3-6 Cycloalkyl radical C _1-4 Alkyl radical, C _2-5 Heterocyclic group, C _2-5 Heterocyclyl radical C _1-4 Alkyl radical, C _6-10 Aryl radical, C _6-10 Aryl radical C _1-4 Alkyl radical, C _1-5 Heteroaryl or C _1-5 Heteroaryl C _1-4 An alkyl group; wherein M is ² Optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, nitro, cyano, -NH ₂ Methylamino, dimethylamino, methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, 1, 2-difluoroethyl, 1-difluoroethyl, methoxy, ethoxy, propoxySubstituted with a substituent selected from the group consisting of phenyl, trifluoromethyl, difluoromethoxy, 1, 2-difluoroethoxy, 1-difluoroethoxy, acetyl, carboxyl, methylsulfonyl, sulfonic acid, methylsulfinyl, cyclopropyl, cyclopentyl, cyclopropylethyl, cyclohexylmethyl, cyclopropyloxy, pyrrolidinyl, piperidinyl, morpholinylmethyl, piperidinyloxy, phenyl, naphthyl, benzyl, phenoxy, pyrrolyl, pyridinyl, pyrimidinyl, pyridylmethyl, and pyrimidinyloxy;

with the proviso that M ¹ 、M ² Not phenyl at the same time.

In some embodiments, each R is ² 、R ³ 、R ⁴ And R ⁵ Independently of each other H, -O-R ²⁰ Halogen, nitro, cyano, C _1-6 Alkyl, halo C _1-6 Alkyl, amino, acyl, sulfonyl, C _3-12 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-10 Aryl or C _1-9 A heteroaryl group; wherein R is ² 、R ³ 、R ⁴ And R ⁵ C as described in (1) _1-6 Alkyl, halo C _1-6 Alkyl radical, C _3-12 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-10 Aryl and C _1-9 Heteroaryl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl, sulfonyl, sulfinyl, C _3-10 Cycloalkyl, C _3-10 Cycloalkyl radical C _1-6 Alkyl radical, C _3-10 Cycloalkyl oxy, C _2-9 Heterocyclic group, C _2-9 Heterocyclyl radical C _1-6 Alkyl radical, C _2-9 Heterocyclyloxy, C _6-14 Aryl radical, C _6-14 Aryl radical C _1-6 Alkyl radical, C _6-14 Aryloxy radical, C _1-9 Heteroaryl, C _1-9 Heteroaryl C _1-6 Alkyl or C _1-9 Substituted with a substituent of heteroaryloxy;

each R ²⁰ Independently H, C _1-6 Alkyl, halo C _1-6 Alkyl, acyl, sulfonyl, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic radical、C _6-10 Aryl or C _1-9 A heteroaryl group; wherein R is ²⁰ C as described in (1) _1-6 Alkyl, halo C _1-6 Alkyl radical, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-10 Aryl and C _1-9 Heteroaryl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl, sulfonyl, sulfinyl, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-14 Aryl radical, C _6-14 Aryl or C _1-9 Heteroaryl group is substituted.

In other embodiments, each R ² 、R ³ 、R ⁴ And R ⁵ Independently is H, -O-R ²⁰ Fluorine, chlorine, bromine, nitro, cyano, C _1-4 Alkyl, halo C _1-4 Alkyl, amino, acyl, sulfonyl, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-10 Aryl or C _1-9 A heteroaryl group; wherein R is ² 、R ³ 、R ⁴ And R ⁵ C as described in (1) _1-4 Alkyl radical, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-10 Aryl and C _1-9 Heteroaryl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl, sulfonyl, sulfinyl, C _3-10 Cycloalkyl radical, C _3-10 Cycloalkyl radical C _1-6 Alkyl radical, C _3-10 Cycloalkyloxy radical, C _2-9 Heterocyclic group, C _2-9 Heterocyclyl radical C _1-6 Alkyl radical, C _2-9 Heterocyclyloxy, C _6-14 Aryl radical, C _6-14 Aryl radical C _1-6 Alkyl radical, C _6-14 Aryloxy radical, C _1-9 Heteroaryl group, C _1-9 Heteroaryl C _1-6 Alkyl or C _1-9 Substituted with a substituent of heteroaryloxy;

each R ²⁰ Independently H, C _1-4 Alkyl radicalHalogen substituted C _1-4 Alkyl, acyl, sulfonyl, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-10 Aryl or C _1-9 A heteroaryl group; r ²⁰ C as described in (1) _1-4 Alkyl radical, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-10 Aryl and C _1-9 Heteroaryl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, amino, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy, acyl, sulfonyl, sulfinyl, C _3-10 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-14 Aryl radical, C _6-14 Aryl or C _1-9 A substituent of the heteroaryl group.

In other embodiments, each R is ² 、R ³ 、R ⁴ And R ⁵ Independently is H, -O-R ²⁰ Fluorine, chlorine, bromine, nitro, cyano, C _1-4 Alkyl, amino, acyl, or sulfonyl; wherein R is ² 、R ³ 、R ⁴ And R ⁵ C as described in (1) _1-4 Alkyl is optionally substituted with one or more groups selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, -NH ₂ Methylamino, dimethylamino, methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, carboxyl, methylsulfonyl, sulfonic acid, cyclopropyl, cyclopentyl, cyclopropylethyl, cyclohexylmethyl, pyrrolidinyl, piperidinyl, morpholinylmethyl, phenyl, naphthyl, benzyl, pyrrolyl, pyridinyl, or pyridylmethyl;

each R ²⁰ Independently H, C _1-4 Alkyl radical, C _3-6 Cycloalkyl radical, C _2-5 Heterocyclic group, C _6-10 Aryl or C _1-5 A heteroaryl group; wherein R is ²⁰ C as described in (1) _1-4 Alkyl radical, C _3-6 Cycloalkyl radical, C _2-5 Heterocyclic group, C _6-10 Aryl and C _1-5 Heteroaryl is independently optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, -NH ₂ Methyl, ethyl, trifluoromethyl, methoxy, trisFluoromethoxy, acetyl, carboxyl, methylsulfonyl or sulfonic acid.

In some embodiments, R ⁶ Is H or hydroxy;

R ⁷ is hydrogen or C _1-4 Alkyl radical, said C _1-4 Alkyl is optionally substituted by one or more groups selected from fluoro, chloro, bromo, -NH ₂ Hydroxy, methoxy, cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl, or pyridinyl;

each R ⁸ And R ⁹ Independently is H or C _1-4 Alkyl, said C _1-4 Alkyl is optionally substituted by one or more groups selected from fluoro, chloro, bromo, -NH ₂ Hydroxyl, methoxy, cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl, or pyridinyl.

In other embodiments, each R is ¹⁰ And R ¹¹ Independently H, methyl, ethyl, propyl or butyl; wherein R is ¹⁰ And R ¹¹ Wherein said methyl, ethyl, propyl and butyl groups are independently optionally substituted with one or more substituents selected from the group consisting of H, oxo (═ O), fluoro, chloro, bromo, hydroxy, -mercapto, -NH ₂ Methyl, trifluoromethyl, methoxy or trifluoromethoxy.

In some embodiments, M ¹ Is cyclopropyl, cyclopentyl, cyclohexyl, epoxyethyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, oxazolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, tetrahydropyrimidinyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl or imidazolyl; wherein, M ¹ Optionally substituted with one or more groups selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, nitro, cyano, -NH ₂ Methylamino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, carboxyl, methylsulfonyl, or sulfonic acid;

M ² is cyclopropyl, cyclopentyl, cyclohexyl or cyclopropylmethylA group selected from the group consisting of a phenyl group, a pyridyl group, a pyrimidyl group, a pyrrolidinylmethyl group, a piperidyl group, a pyridyl group, a pyrimidyl group, a pyrrolidinyl group, a pyridyl group, a piperidyl group, a pyrrolidinyl group, a piperidyl group, a morpholinyl group, a pyridyl group, a naphthyl group, a phenylmethyl group, a phenylethyl group, a pyridyl group, a pyrimidyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a pyridylmethyl group, a pyridylethyl group, a pyrrolylmethyl group, a pyrimidylmethyl group, and a pyrimidylethyl group; wherein M is ² Optionally substituted with one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, hydroxy, mercapto, nitro, cyano, -NH ₂ Methylamino, dimethylamino, methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, carboxy, methylsulfonyl, sulfonic acid, or methylsulfinyl;

provided that M is ¹ 、M ² Not phenyl at the same time.

In another aspect, the compounds of the present invention comprise the structure of one of:

or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, metabolic precursor, pharmaceutically acceptable salt or prodrug thereof.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention.

In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.

In one aspect, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition of the present invention for the manufacture of a medicament for protecting, treating or ameliorating HIF-associated and/or EPO-associated conditions in a subject.

In another aspect, the invention features the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention, treatment, or amelioration of a disease mediated at least in part by HIF prolyl hydroxylase. In some embodiments, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition of the present invention in the manufacture of a medicament for protecting, treating, or ameliorating a HIF prolyl hydroxylase mediated disease in a patient.

In one aspect, the invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the preparation of a medicament for the prevention, treatment or alleviation of anemia, ischemia, vascular disease, angina pectoris, myocardial ischemia, myocardial infarction, metabolic disorders or wound healing disorders in a patient.

In some embodiments, the use of the invention, wherein the disease is anemia; the anemia includes acute or chronic kidney disease, infection, inflammation, cancer, radiation, toxin, diabetes or anemia caused by operation.

The invention encompasses the use of a compound of the invention, and pharmaceutically acceptable salts thereof, for the manufacture of a pharmaceutical product for treating HIF-related and/or EPO-related disorders, including those described herein, in a patient. The present invention encompasses pharmaceutical compositions comprising therapeutically effective amounts of a compound represented by formula (I) or formula (II) in combination with at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle.

The invention also encompasses methods of treating or ameliorating a HIF-associated and/or EPO-associated condition, or a condition responsive thereto, in a subject, comprising treating the subject with a therapeutically effective amount of a compound represented by formula (I) or formula (II).

Unless otherwise indicated, all hydrates, solvates and pharmaceutically acceptable salts of the compounds of the invention are within the scope of the invention.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions which must be compatible with chemical or toxicological considerations, in connection with the other ingredients comprising the formulation and the mammal being treated.

Salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of, intermediates used in the preparation or purification of the compounds of formula (I) or formula (II) or isolated enantiomers of the compounds of formula (I) or formula (II).

Salts of the compounds of the present invention may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, and the like. Or using organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranonic acids, such as glucuronic and galacturonic acids; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and the like.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with CAS version of the periodic Table of the elements, and with handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is open-ended, i.e. including what is specified in the invention, but not excluding other aspects.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.andWilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, e.g., the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energybarrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (value tautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those of the above general formula, or as specified in the examples, subclasses, and groups encompassed by the present invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent may be, but is not limited to, oxo (═ O), hydrogen, deuterium, cyano, nitro, halogen, hydroxy, mercapto, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, acyl, acyloxy, sulfonyl, sulfinyl, carboxy, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, -Y-R, etc.; wherein Y is O or S, and R is H, alkyl, haloalkyl, acyl, sulfonyl, sulfinyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C ₁ -C ₆ Alkyl "means in particular independently disclosed methyl, ethyl, C ₃ Alkyl radical, C ₄ Alkyl radical, C ₅ Alkyl and C ₆ An alkyl group.

In each of the parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for this variable recites "alkyl" or "aryl," it is to be understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms; in still other embodiments, the alkyl group contains 1 to 3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl), hexyl (including n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl and 3, 3-dimethyl-2-butyl), and the like.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy and the like.

The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

The term "amino" denotes the group-NR ^a R ^b Wherein R is ^a 、R ^b Each independently H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, or sulfonyl, and the like. Wherein said amino group may be optionally substituted with one or more substituents as described herein. Examples include, but are not limited to, amino (-NH) ₂ ) Methyl amino (-NHCH) ₃ ) Dimethylamino group (-N (CH) ₃ ) ₂ ) Ethyl amino (-NHCH) ₂ CH ₃ ) Phenylamino (-NHPh), pyridylamino, acetylamino, methylsulfonylamino and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Wherein said cycloalkyl group may be optionally substituted with one or more substituents as described herein. In some embodiments, cycloalkyl groups contain 3 to 12 carbon atoms; in other embodiments, cycloalkyl groups contain 3 to 8 carbon atoms; in still other embodiments, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term "cycloalkylalkyl" denotes a cycloalkyl group linked to the rest of the molecule through an alkyl group, wherein cycloalkyl and alkyl have the meaning described herein. The cycloalkylalkyl group may be optionally substituted with one or more substituents described herein. Examples include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl and the like.

The term "cycloalkyloxy" denotes a cycloalkyl group attached to the rest of the molecule through an oxygen atom, wherein cycloalkyl has the meaning described herein. The cycloalkyloxy group may be optionally substituted with one or more substituents described herein. Examples include, but are not limited to, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

The term "heterocyclyl" refers to a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Wherein said heterocyclyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, a heterocyclic group may be carbon-or nitrogen-based, and-CH ₂ -the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to the N-oxide. In some embodiments, heterocyclyl is C _2-10 Heterocyclyl, meaning that heterocyclyl contains 2 to 10 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heterocyclyl is C _2-9 Heterocyclyl, meaning that heterocyclyl contains 2 to 9 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heterocyclyl is C _2-7 Heterocyclyl, meaning that heterocyclyl contains 2 to 7 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heterocyclyl is C _2-5 Heterocyclyl, meaning that heterocyclyl contains 2 to 5 carbon atoms and at least one heteroatom selected from O, S and N. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, thietanyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dihydrothienyl, dihydropyranyl, piperidinyl, morpholinyl, tetrahydropyrimidinyl, oxazinidinyl, thiomorpholinyl, piperazinyl, and the like. In heterocyclic radicals of-CH ₂ Examples of the substituent represented by — C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, 2-piperidonyl, 3-morpholinonyl, 3-thiomorpholinonyl, oxotetrahydropyrimidinyl and the like.

The term "heterocyclylalkyl" means that the heterocyclyl group is attached to the rest of the molecule through an alkyl group, where heterocyclyl and alkyl have the meaning described herein. The heterocyclylalkyl group may be optionally substituted with one or more substituents described herein. Examples include, but are not limited to, pyrrolidinylmethyl, piperidinyl methyl, piperidinylethyl, morpholinylmethyl, morpholinylethyl, and the like.

The term "heterocyclyloxy" means that the heterocyclyl group is attached to the rest of the molecule through an oxygen atom, wherein heterocyclyl has the meaning described herein. The heterocyclyloxy may be optionally substituted with one or more substituents described herein. Examples include, but are not limited to, pyrrolidinyloxy, morpholinyloxy, piperidinyloxy, and the like.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, 2, 3-dihydro-1H-indenyl, naphthyl and anthryl. The aryl group may be optionally substituted with one or more substituents described herein.

The term "arylalkyl" means that the aryl group is attached to the rest of the molecule through an alkyl group, where aryl and alkyl have the meaning described herein. The arylalkyl group can be optionally substituted with one or more substituents described herein. Examples include, but are not limited to, benzyl, phenylethyl, naphthylmethyl, and the like.

The term "aryloxy" means an aryl group attached to the rest of the molecule through an oxygen atom, wherein aryl has the meaning described herein. The aryloxy group may be optionally substituted with one or more substituents described herein. Examples include, but are not limited to, cyclic phenoxy, naphthyloxy, and the like.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is C _1-9 Heteroaryl, meaning that heteroaryl contains 1 to 9 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heteroaryl is C _1-7 Heteroaryl, meaning that heteroaryl contains 1 to 7 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heteroaryl is C _1-6 Heteroaryl, meaning that heteroaryl contains 1 to 6 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heteroaryl is C _1-5 Heteroaryl, meaning that heteroaryl contains 1 to 5 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heteroaryl is C _1-4 Heteroaryl, meaning that heteroaryl contains 1 to 4 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, heteroaryl is C _1-3 Heteroaryl, meaning heteroaryl containingHaving 1 to 3 carbon atoms and at least one heteroatom selected from O, S and N. Examples include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, and the like; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl, oxoindolyl, indolinyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl and the like. The heteroaryl group may be optionally substituted with one or more substituents described herein.

The term "heteroarylalkyl" means that the heteroaryl group is attached to the rest of the molecule through an alkyl group, wherein heteroaryl and alkyl have the meaning described herein. The heteroarylalkyl group may be optionally substituted with one or more substituents described herein. Examples include, but are not limited to, pyridylmethyl, pyrrolylethyl, quinolylmethyl and the like.

The term "heteroaryloxy" means that the heteroaryl group is attached to the rest of the molecule through an oxygen atom, where heteroaryl has the meaning described herein. The heteroaryloxy group may be optionally substituted with one or more substituents described herein. Examples include, but are not limited to, pyridyloxy, pyrimidyloxy, and the like.

The term "acyl" denotes — C (═ O) -R, where the substituent R is attached to the rest of the molecule through a carbonyl group (-C (═ O) -), where R is a substituent described herein, including alkyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like. Wherein alkyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl have the meaning as indicated in the present invention, and such examples include, but are not limited to, acetyl (-C (═ O) CH ₃ ) Carboxy (-C (═ O) OH), methoxyacyl (-C (═ O) OCH) ₃ ) Carbamoyl (-O-CO) NH ₂ ) Phenylformyl, and the like.

The term "sulfonyl" denotes-S (═ O) ₂ -R, wherein the substituent R is substituted by a sulfonyl group (-S (═ O) ₂ -) is attached to the rest of the molecule, wherein R is a substituent described herein, including alkyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like. Wherein alkyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl have the meaning as indicated in the present invention, and such examples include, but are not limited to, sulfonic acid groups (-S (═ O) ₂ OH), methylsulfonyl (-S (═ O) ₂ CH ₃ ) Methoxysulfonyl (-S (═ O) ₂ OCH ₃ ) Aminosulfonyl (-S (═ O) ₂ NH ₂ ) Phenylsulfonyl, and the like.

The term "sulfinyl" denotes-S (═ O) -R where the substituent R is attached to the rest of the molecule through a sulfonyl group (═ S) -, where R is a substituent described herein, including alkyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like. Wherein alkyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl have the meaning as indicated in the present invention, and such examples include, but are not limited to, sulfinyl (-S (═ O) OH), methylsulfinyl (-S (═ O) CH ₃ ) Phenylsulfinyl, and the like.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I) or formula (II). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and can be phenyl ester, aliphatic (C) _1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, which can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: t.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S..Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assays as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate; organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate; or by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophospho-phosphatesAcid salts, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by reaction with a suitable base include alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 Alkyl radical) ₄ A salt. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

By "Erythropoietin (EPO) -associated disorder" is meant any condition associated with subnormal, abnormal or inappropriate regulation of endogenous erythropoietin. EPO-related disorders include any disorder in which increased EPO levels will provide therapeutic benefit. EPO is a naturally occurring hormone produced by HIF α that stimulates the production of red blood cells (erythrocytes) that carry oxygen throughout the body. EPO-related diseases include, but are not limited to, anemia, including anemia associated with diabetes, ulcers, renal failure, cancer, infection, dialysis, surgery, and chemotherapy; conditions of ischemia and hypoxia, for example, arterial occlusive disease, angina pectoris, intestinal infarction, pulmonary infarction, cerebral ischemia and myocardial infarction.

"HIF-associated disease" refers to any condition associated with subnormal, abnormal, or inappropriate regulation of HIF. HIF-associated disorders include any disorder in which elevated HIF levels would provide a beneficial therapeutic effect. HIF-associated conditions include, but are not limited to, heart disease, stroke, peripheral vascular disease, ulcers, burns, chronic wounds, chronic ischemia, pulmonary embolism, ischemia-reperfusion injury, inflammation, anemia, and the like.

HIF-related and/or EPO-related disorders include, but are not limited to, anemia, ischemia, vascular disease, angina, myocardial ischemia, myocardial infarction, metabolic disorders, wound healing, and the like.

"A disease mediated at least in part by HIF prolyl hydroxylase (HIF-PHD)" may be used interchangeably with "HIF prolyl hydroxylase-related disease" and refers to any condition caused by an abnormality in HIF-PHD, including HIF-related diseases caused by an abnormality in HIF-PHD. HIF-PHD associated conditions include, but are not limited to, anemia and ischemia.

"anemia" refers to any abnormality or deficiency in hemoglobin or red blood cells that results in a reduction in the oxygen content of the blood. Anemia may be associated with abnormal production, processing or performance of red blood cells and/or hemoglobin. The term anemia refers to any reduction in the number of red blood cells and/or the hemoglobin content of the blood relative to normal blood content. Anemia can result from a variety of conditions, such as acute or chronic kidney disease, infection, inflammation, cancer, radiation, toxins, diabetes, and surgery. The infection may be caused by, for example, viruses, bacteria, and/or parasites. Inflammation may be caused by infection or autoimmune disorders such as rheumatoid arthritis and the like. Anemia may also be associated with blood loss caused by, for example, gastric ulcers, duodenal ulcers, hemorrhoids, gastric or large bowel cancers, trauma, injury, surgical procedures, and the like. Anemia may also develop in association with radiation therapy, chemotherapy and renal dialysis. Anemia is also associated with HIV-infected patients who are treated with zidovudine or other reverse transcriptase inhibitors, and can develop in cancer patients who are receiving chemotherapy (e.g., chemotherapy with cyclic cisplatin or without cisplatin). Aplastic anemia and myelodysplastic syndrome are diseases associated with bone marrow failure that result in a reduction in red blood cell production. Additionally, anemia may be caused by hemoglobin or red blood cell defects or abnormalities, including, for example, disorders such as microcytic anemia, hypopigmented anemia, and the like. Anemia can be caused by disorders in iron transport, processing and utilization, such as sideroblastic anemia (sideroblastic anemia), and the like.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H， ³ H， ¹¹ C， ¹³ C， ¹⁴ C， ¹⁵ N， ¹⁷ O， ¹⁸ O， ¹⁸ F， ³¹ P， ³² P， ³⁵ S， ³⁶ Cl and ¹²⁵ I。

in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present ³ H， ¹⁴ C and ¹⁸ those of F, or in which a nonradioactive isotope is presentElements, e.g. ² H and ¹³ C. the isotopically enriched compounds can be used for metabolic studies (use) ¹⁴ C) Reaction kinetics study (using, for example ² H or ³ H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient. ¹⁸ F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.

In addition, heavier isotopes are particularly preferred for deuterium (i.e., ² substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is to be considered as a substituent of the compound of formula (I) or formula (II). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D ₂ O, acetone-d ₆ 、DMSO-d ₆ Those solvates of (a).

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.

Pharmaceutical compositions, formulations, administration and uses of the compounds of the invention

According to another aspect, the pharmaceutical compositions of the invention are characterized by comprising a quinolinone compound of formula (I) or formula (II), a compound listed in the present invention, or a compound of examples 1-6, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the compositions of the invention is effective to treat or ameliorate HIF-related and/or EPO-related conditions in a subject.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents: in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, NewYork, taken together with The disclosure of this document, indicates that different carriers can be used In The preparation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated by the present invention.

Substances which may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol, phosphate buffered solutions, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants.

The pharmaceutical compositions of the present invention may be administered directly or in the form of pharmaceutical compositions or medicaments, together with suitable carriers or excipients, as is well known in the art. The methods of treatment of the present invention may comprise administering to a subject in need thereof an effective compound of the present invention; for example, individuals suffering from or at risk for anemia arising from chronic renal failure, diabetes, cancer, aids, radiation therapy, chemotherapy, renal dialysis or surgery; or an individual suffering from or at risk of ischemia resulting from myocardial infarction, congestive heart failure, cardiogenic liver cirrhosis, pulmonary insufficiency, atherosclerosis, or peripheral vascular disease, and the like. In some embodiments, the subject is a mammalian subject, and in some preferred embodiments, the subject is a human subject.

Effective amounts of the compounds, pharmaceutical compositions or medicaments of the present invention can be readily determined by routine experimentation, as can the most effective and convenient route of administration and the most appropriate formulation.

Suitable routes of administration may include oral, rectal, transmucosal, nasal or enteral administration, and parenteral delivery, further including intramuscular, subcutaneous, intramedullary injections, as well as intrathoracic, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. The agents or compositions thereof may be administered locally rather than systemically. For example, a suitable agent may be delivered via injection or in a targeted drug delivery system comprising a long acting or sustained release formulation.

Pharmaceutical dosage forms of the compounds of the invention may be provided in the form of immediate release, controlled release, sustained release or targeted drug release systems. For example, common dosage forms include solutions and suspensions, (micro) emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols and freeze-dried preparations. Depending on the route of administration used, Special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators or Special bottles (Special flash). Pharmaceutical dosage forms often consist of a drug, excipients, and a container/closure system. One or more excipients (also known as inactive ingredients) may be added to the compounds of the present invention to improve or facilitate the manufacture, stability, administration, and safety of the drug, and may provide a means to obtain the desired drug release profile. Thus, the type of excipient added to a drug may depend on various factors, such as the physical and chemical properties of the drug, the route of administration, and the preparation steps. Pharmaceutical excipients exist in the art and include those listed in various pharmacopoeias. (see U.S. Pharmacopoeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP) and British Pharmacopoeia (BP), the United states food and Drug administration (www.fda.gov) Drug Evaluation and Research Center (Center for Drug Evaluation and Research, CEDR) publications, such as "Guide for Inactive ingredients" (Inactive Ingredient Guide,1996), Handbook of Pharmaceutical Additives (Handbook of Pharmaceutical Additives,2002, Union Information Resources, Inc., Endocumentary, C.) (the U.S. Pharmacopoeia, JP), European Pharmacopoeia (EP) and British Pharmacopoeia (BP)).

Pharmaceutical dosage forms of the compounds of the invention may be manufactured by any method well known in the art, for example, by means of conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, grinding, emulsifying, (nano/micro) encapsulating, entrapping or lyophilizing processes. As noted above, the compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into a formulation for pharmaceutical use.

Appropriate formulations will depend on the desired route of administration. For example, for intravenous injection, the compositions may be formulated in aqueous solution, with physiologically compatible buffers, if necessary, including, for example, phosphate, histidine or citrate for adjusting the pH of the formulation, and tonicity agents such as sodium chloride or dextrose. For transmucosal or nasal administration, a semi-solid, liquid formulation or patch, possibly containing a penetration enhancer, may be preferred; such penetrants are generally known in the art. For oral administration, the compounds may be formulated in liquid or solid dosage forms and as immediate release or controlled/sustained release formulations. Suitable dosage forms for oral ingestion by a subject include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions and emulsions. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

Solid oral dosage forms can be obtained using excipients which include fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, anti-adherents, cationic exchange resins, wetting agents, antioxidants, preservatives, coloring and flavoring agents. These excipients may be of synthetic or natural origin. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silica, sodium benzoate, sorbitol, starch, stearic acid or salts thereof, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage (tragacanth mucilage), vegetable oils (hydrogenated), and waxes. Ethanol and water may be used as granulation aids. In some cases, it is desirable to coat the tablets with, for example, a taste-masking film, a gastric acid-resistant film, or a delayed-release film. Natural and synthetic polymers are often used to coat tablets in combination with colorants, sugars, and organic solvents or water to produce sugar coated pills. Where capsules are preferred over tablets, the pharmaceutical powders, suspensions or solutions may be delivered in the form of compatible hard or soft shell capsules.

In some embodiments, the compounds of the present invention may be administered topically, e.g. by means of a skin patch, a semi-solid or liquid formulation, such as a gel, (micro) emulsion, ointment, solution, (nano/micro) suspension or foam. Skin and underlying tissue penetration of the drug may be regulated by: for example, the use of penetration enhancers; using appropriate selection and combination of lipophilic, hydrophilic and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, emulsifiers; by adjusting the pH value; and the use of complexing agents. Other techniques, such as iontophoresis (ionophoresi), may also be used to modulate skin permeation of the compounds of the present invention. Transdermal or topical administration will be preferred, for example, in situations where topical administration with minimal systemic exposure is desired.

For administration by inhalation or nasal administration, the compounds for use according to the invention are conveniently administered from pressurized packs or nebulizers in the form of solutions, suspensions, emulsions or semi-solid aerosols, usually with the aid of propellants, such as halocarbons derived from methane and ethane, carbon dioxide or any other suitable gas. For topical aerosols, hydrocarbons such as butane, isobutene and pentane are suitable. In the case of a pressurized aerosol, the appropriate dosage unit may be determined by providing a valve to deliver a metered dose. Capsules and cartridges of, for example, gelatin may be formulated for use in an inhaler or insufflator. These generally comprise a powder mix of the compound with a suitable powder base such as lactose or starch.

Compositions formulated for parenteral administration by injection are generally sterile and may be presented in unit dosage form, for example, in ampoules, syringes, injection pens, or multi-dose containers, the latter typically containing a preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as buffers, tonicity agents, viscosity enhancing agents, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives. Depending on the injection site, the carrier may contain water, synthetic or vegetable oils and/or organic co-solvents. In some cases, e.g., for lyophilized products or concentrates, the parenteral formulation will be reconstituted or diluted prior to administration. Depot formulations (depot formulations) that provide controlled or sustained release of the compounds of the invention may include injectable suspensions of nano/micron sized particles or nano/micron sized or non-micronized crystals. Other well known matrices in the art, polymers such as poly (lactic acid), poly (glycolic acid) or copolymers thereof, may be used as the controlled/sustained release matrix. Other depot (depot) delivery systems may be provided in the form of implants and pumps requiring incisions.

Suitable carriers for the compounds of the invention for intravenous injection are well known in the art and include aqueous based solutions containing a base (e.g., sodium hydroxide) for forming the ionic compound; sucrose or sodium chloride as tonicity agent; such as buffers containing phosphate or histidine. A co-solvent such as polyethylene glycol may be added. These water-based systems are effective in dissolving the compounds of the present invention and produce low toxicity after systemic administration. The proportions of the components of the solution system can be varied considerably without destroying the solubility and toxicity characteristics. In addition, the nature of the components may be varied. For example, low toxicity surfactants such as polysorbates or poloxamers (poloxamers) may be used, polyethylene glycols or other co-solvents may be used, biocompatible polymers such as polyethylene-pyrrolidone may be added, and other sugars and polyols may be used in place of dextrose.

The therapeutically effective dose can first be estimated using various methods well known in the art. The initial dose for animal studies can be based on the effective concentration established in cell culture assays. Dosage ranges suitable for human individuals can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention may be prepared as medicaments for oral administration. An exemplary dose of the compounds of the invention in a medicament for oral administration is from about 0.1 to about 10mg/kg (where kg denotes the body weight of the subject). In some embodiments, the agent comprises from about 0.5 to about 10mg/kg (where kg represents the weight of the subject), or optionally from about 0.7 to about 5.0mg/kg (where kg represents the weight of the subject), or optionally from about 1.0 to about 2.5mg/kg (where kg represents the weight of the subject). The dosing regimen for a medicament typically for oral administration is three times a week, twice a week, once a week, three times a day, twice a day, or once a day.

An effective or therapeutically effective amount or dose of an agent (e.g., a compound of the invention) refers to the amount of the agent or compound that causes improvement in the symptoms or prolongation of survival of the individual. Toxicity and therapeutic efficacy of the molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining LD ₅₀ (dose lethal to 50% of population) and ED ₅₀ (a dose therapeutically effective for 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as LD ₅₀ /ED ₅₀ . Agents that exhibit high therapeutic indices are preferred.

An effective or therapeutically effective amount is that amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The dosage is preferably chosen to include an ED with minimal or no toxicity ₅₀ In the circulating concentration range of (2). The dosage may vary within this range depending upon the dosage form employed and/or the route of administration utilized. The correct formulation, route of administration, dosage and time between administrations should be selected according to methods known in the art, taking into account the specificity of the individual condition.

The dose and interval may be adjusted individually to provide plasma levels of the active moiety sufficient to achieve the desired effect; i.e. the Minimum Effective Concentration (MEC). The MEC for each compound will vary, but can be estimated, for example, from in vitro (in vitro) data and animal experiments. The dosage necessary to obtain MEC will depend on the individual characteristics and route of administration. In the case of topical administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

The amount of the agent or composition administered can depend on a variety of factors, including the sex, age and weight of the subject being treated, the severity of the affliction, the mode of administration and the judgment of the prescribing physician.

The compositions of the present invention may be provided in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient, as desired. For example, the package or device may comprise a metal or plastic foil (e.g., a blister pack) or glass and a rubber stopper, such as in a vial. The packaging or dispensing device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of a specified condition.

The compounds of the invention may be used alone or, if desired, in combination with other active compounds. The invention also provides a medicament comprising at least one compound according to the invention and one or more further active substances, in particular for the treatment and/or prophylaxis of the diseases described herein. Suitable active substances in the combinations which may be mentioned include: ACE inhibitors, angiotensin II receptor antagonists, beta-receptor blockers, calcium antagonists, PDE inhibitors, mineralocorticoid receptor antagonists, diuretics, aspirin, iron supplements, vitamin B12 and folic acid supplements, statins, digitoxin derivatives, tumor chemotherapeutics and antibiotics.

The compounds of the present invention may be used to inhibit HIF hydroxylase activity, thereby modulating the stability and/or activity of HIF and activating expression of HIF regulatory genes. The compounds are useful in methods of treating, pretreating, or delaying the onset or progression of HIF-associated conditions, including, but not limited to, anemia and ischemia, as well as conditions of hypoxia.

In various embodiments, the compounds of the present invention are administered beginning after diagnosis of a condition associated with ischemia, such as myocardial infarction, pulmonary embolism, intestinal infarction, ischemic stroke, renal ischemia-reperfusion injury, cardiogenic cirrhosis, macular degeneration, pulmonary embolism, chronic kidney disease, transient cerebral ischemia, peripheral vascular disease, acute respiratory failure, neonatal respiratory distress syndrome, and congestive heart failure. In other embodiments, the compound is administered immediately after the trauma or injury. In other embodiments, the compounds may be administered directly to a patient based on a triggering disorder, such as hypertension, diabetes, occlusive arterial disease, chronic venous insufficiency, raynaud's disease, chronic skin ulcers, liver cirrhosis, congestive heart failure, and systemic sclerosis. In other embodiments, the compounds may be administered to pre-treat a patient to reduce or prevent the development of tissue damage associated with ischemia or hypoxia.

In particular embodiments, the compounds of the invention are useful for increasing endogenous Erythropoietin (EPO). The compounds may be administered for the prevention, prophylaxis or treatment of EPO-associated conditions, including, for example, anemia and neurological disorders. Conditions associated with anemia include, but are not limited to: acute or chronic kidney disease, diabetes, cancer, ulcers, viral (e.g., HIV), bacterial or parasitic infection; inflammation, and the like. Anemia disorders can further be associated with procedures or treatments including, for example, radiation therapy, chemotherapy, dialysis, and surgery. Additionally, anemia is associated with hemoglobin and/or red blood cell abnormalities, such as seen in disorders such as microcytic anemia, hypopigmentary anemia, aplastic anemia, and the like.

The compounds of the invention are useful for increasing endogenous EPO in individuals undergoing prophylactic or concurrent specific therapy or surgery, e.g., anemic HIV-infected patients undergoing treatment with zidovudine or other reverse transcription inhibitors, anemic cancer patients receiving cisplatin-or cisplatin-free chemotherapy, or anemic or non-anemic patients scheduled for surgery. In addition, the compounds can be used to increase endogenous EPO levels in anemic or non-anemic patients scheduled for surgery to reduce the need for allogenic transfusions or to promote preoperative blood stores.

General synthetic procedure

In this specification, a structure is dominant if there is any difference between the chemical name and the chemical structure.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare other compounds of the invention, and other methods for preparing compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

In the examples described below, all temperatures are given in degrees celsius unless otherwise indicated. Unless otherwise indicated, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and dAlfa Chemical Company and used without further purification; general reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. Glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. NMR spectral data were measured by Bruker Avance 400 NMR spectrometer or Bruker Avance III HD 600 NMR spectrometer, CDC1 ₃ ,d ₆ -DMSO,CD ₃ OD or d ₆ Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.25ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet ), t (triplet, triplet), m (multiplet ), br (broadded, broad), dd (doublet of doublets, quartet), dt (doublet of triplets), ddd (doublet of doublets, doublet), ddt (doublet of doublets ), dddd (doublet of doublets). Coupling constants, expressed in hertz (Hz).

Low resolution Mass Spectral (MS) data were determined by Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316ATCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was used for LC-MS spectrometer.

Low resolution Mass Spectrometry (MS) data were determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316ATCC (column temperature maintained at 30 ℃), with the G1329A autosampler and G1315D DAD detector applied for analysis, and the ESI source applied to the LC-MS spectrometer.

Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:

TABLE 1 gradient elution conditions for low resolution mass spectrometry mobile phase

Time (min)	A(CH ₃ CN，0.1％HCOOH)	B(H2O，0.1％HCOOH)
			0-3	5-100	95-0
3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

The following acronyms are used throughout the invention:

CDC1 ₃ deuterated chloroform d ₆ -Acetone deuterated Acetone

K ₂ CO ₃ Potassium carbonate

d ₆ -DMF deuterated N, N-dimethylformamide EA, EtOAc ethyl acetate

CuI cuprous iodide

d ₆ -DMSO deuterodimethylSulfoxide base DMF N, N-dimethyl formamide

Na ₂ SO ₄ Sodium sulfate

MgSO ₄ Magnesium sulfate mg

mL of

NaHCO ₃ Mol mole of sodium bicarbonate

Microliter of μ L

NaOH sodium hydroxide mmol

EPO erythropoietin

HCl hydrochloric acid for h

ATCC American culture Collection

g min

The following reaction scheme describes the steps for preparing the compounds disclosed herein.

Reaction scheme 1

Compound 7 can be prepared by the methods described in scheme 1, wherein R ^a Is Cl, Br, I or OH, R ^b Is methyl or ethyl, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ Have the meaning as described in the present invention. The compound 1 is reacted with triphosgene or the like in a solvent (e.g., tetrahydrofuran or the like) to obtain a compound 2. The compound 2 and the compound 3 are subjected to substitution reaction under appropriate conditions (such as under the action of alkali such as sodium hydroxide or potassium carbonate, or under the action of reagents such as triphenylphosphine and diisopropyl azodicarboxylate) to generate a compound 4. The compound 4 reacts with the compound 5 under basic conditions (such as sodium tert-butoxide and the like) to obtain a compound 6. And reacting the compound 6 with sodium glycinate under the heating condition to obtain a compound 7.

Reaction scheme 2

Compound 6 can be prepared by the method described in scheme 2, wherein Hal is Cl or Br, R ^b Is methyl or ethyl, R ^c Is OH, Cl or Br, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ Have the meaning as described in the present invention. Compound 8 and R ¹ NH ₂ Under the alkaline condition (such as potassium carbonate, cesium carbonate and the like), under the action of a catalyst (such as a palladium catalyst (such as bis (dibenzylacetyl) palladium and the like) and a ligand (such as 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl and the like), a coupling reaction is carried out to generate a compound 9. The compound 9 and the compound 10 are subjected to condensation reaction under the action of a base (such as pyridine, triethylamine and the like) or a condensation reagent (such as HATU and the like) and a base (such as N, N-diisopropylethylamine and the like) to obtain a compound 11. The compound 11 undergoes intramolecular cyclization under the action of alkali (such as sodium ethoxide, sodium methoxide and the like) to obtain a compound 6.

Reaction scheme 3

Compound 7 can be prepared by the methods described in scheme 3, wherein R ^b Is methyl or ethyl, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ Have the meaning as described in the present invention. Compound 6 is reacted with tert-butyl glycinate under basic conditions (such as triethylamine, etc.) to produce compound 12. The compound 12 is hydrolyzed under the action of a reagent such as trifluoroacetic acid and the like to obtain a compound 7.

The following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention.

Examples

Example 12- (4-hydroxy-2-oxo-1- (4- (3-oxomorpholinyl) benzyl) -1, 2-dihydroquinoline-3-carboxamido) acetic acid

Step 14- (4- (hydroxymethyl) phenyl) morpholin-3-one

Under nitrogen protection, (4-bromophenyl) methanol (1.00g,5.35mmol), morpholin-3-one (0.648g,6.41mmol), N were added sequentially to a three-necked flask ¹ ,N ² Dimethylethane-1, 2-diamine (0.220mL,2.04mmol), CuI (0.203g,1.07mmol), K ₂ CO ₃ (1.85g,13.4mmol) and toluene (20mL) were heated to 110 ℃ and reacted overnight. Cooled to room temperature, filtered, the filtrate concentrated under reduced pressure and the crude product purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give a white solid (0.975g, 88.0%).

MS(ESI,pos.ion)m/z:208.1(M+1).

Step 21- (4- (3-oxomorpholinyl) benzyl) -1H-benzo [ d ] [1,3] oxazine-2, 4-dione

Under the protection of nitrogen, 4- (4- (hydroxymethyl) phenyl) morpholin-3-one (0.975g,4.70mmol), 1H-benzo [ d ] [1,3] oxazine-2, 4-dione (0.845g,5.18mmol) and triphenylphosphine (1.85g,7.05mmol) were dissolved in tetrahydrofuran (20mL), cooled to 0 ℃, diisopropyl azodicarboxylate (1.36mL,6.92mmol) was added dropwise to the reaction solution, and the reaction was raised to 25 ℃ for 4 hours. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give a white solid (1.61g, 97.1%).

MS(ESI,pos.ion)m/z:353.2(M+1).

Step 34-hydroxy-2-oxo-1- (4- (3-oxomorpholinyl) benzyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester

A suspension of sodium tert-butoxide (0.350g,3.64mmol) and dimethyl malonate (0.600g,4.54mmol) in N, N-dimethylformamide (5mL) was added dropwise to 1- (4- (3-oxomorpholine)Linyl) benzyl) -1H-benzo [ d][1,3]A solution of oxazine-2, 4-dione (0.800g,2.27mmol) in N, N-dimethylformamide (40mL) was heated to 95 ℃ for 1 hour. After cooling to 25 ℃, 2M HCl (10mL) was added to the reaction mixture, extraction was performed with ethyl acetate (30mL × 3), and the organic layers were combined, washed with water (10mL) and saturated brine (10mL), and washed with anhydrous Na ₂ SO ₄ And (5) drying. Filtration, evaporation of the solvent under reduced pressure and purification of the crude product by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) gave a white solid (0.523g, 56.4%).

MS(ESI,pos.ion)m/z:409.3(M+1)；

¹ H NMR(600MHz,CDCl ₃ )δ:14.25(s,1H),8.24(d,J＝8.0Hz,1H),7.60(t,J＝7.9Hz,1H),7.30(t,J＝5.4Hz,4H),7.26(dd,J＝14.3,6.9Hz,2H),5.51(s,2H),4.34(s,2H),4.07(s,3H),4.05–3.99(m,2H),3.76–3.67(m,2H).

Step 42- (4-hydroxy-2-oxo-1- (4- (3-oxomorpholinyl) benzyl) -1, 2-dihydroquinoline-3-carboxamido) acetic acid

To a three-necked flask were added methyl 4-hydroxy-2-oxo-1- (4- (3-oxomorpholinyl) benzyl) -1, 2-dihydroquinoline-3-carboxylate (0.523g,1.28mmol), sodium glycinate (0.200g,2.06mmol) and ethylene glycol monomethyl ether (30mL) in this order, and the mixture was heated to 115 ℃ for reaction for 2 hours. Cooled to room temperature, the solvent was removed under reduced pressure, water (40mL) was added, the aqueous layer was washed with ethyl acetate (20mL × 3), the pH was adjusted to 3 with 1M hydrochloric acid, filtered, and the filter cake was dried to obtain a white solid (0.270g, 46.7%).

MS(ESI,pos.ion)m/z:452.3(M+1)；

¹ H NMR(600MHz,d ₆ -DMSO)δ:12.96(s,1H),10.52(t,J＝5.5Hz,1H),8.19–8.09(m,1H),7.73(dd,J＝11.4,4.3Hz,1H),7.52(d,J＝8.6Hz,1H),7.40–7.31(m,3H),7.26(d,J＝8.5Hz,2H),5.56(s,2H),4.18(s,2H),4.15(d,J＝5.5Hz,2H),3.98–3.91(m,2H),3.73–3.64(m,2H).

Example 22- (1- ((1- (2-chlorophenyl) piperidin-4-yl) methyl) -4-hydroxy-2-oxo-1, 2-dihydroquinoline-3-carboxamido) acetic acid

Step 11- (2-chlorophenyl) piperidine-4-carboxylic acid methyl ester

Under the protection of nitrogen, 1-bromo-2-chlorobenzene (3.00g,15.7mmol), piperidine-4-carboxylic acid methyl ester (2.47g,17.3mmol), L-proline (0.542g,4.71mmol), CuI (0.596g,3.13mmol), K ₂ CO ₃ (4.33g,31.3mmol) and dimethyl sulfoxide (30mL) were heated to 85 ℃ and reacted for 18 hours. Cool to room temperature, pour the reaction into water (50mL), extract the mixture with ethyl acetate (50 mL. times.3), combine the organic phases, wash with saturated brine (20mL), anhydrous Na ₂ SO ₄ And (5) drying. Filtration and evaporation of the solvent under reduced pressure gave a crude product which was purified by column chromatography (petroleum ether/dichloromethane (v/v) ═ 4/1) to give a colorless oily liquid (1.23g, 30.9%).

MS(ESI,pos.ion)m/z:254.2(M+1).

Step 2(1- (2-chlorophenyl) piperidin-4-yl) methanol

To a solution of methyl 1- (2-chlorophenyl) piperidine-4-carboxylate (1.23g,4.85mmol) in ethanol (20mL) at 0 deg.C was added sodium borohydride (0.458g,12.1mmol) in portions, and after stirring for 0.5 hour, the mixture was raised to 25 deg.C, stirred for 3 hours, and then raised to 70 deg.C to continue the reaction for 4 hours. Cooling to room temperature, removing solvent under reduced pressure, adding into water (20mL), extracting the mixture with ethyl acetate (50mL × 3), combining the organic phases, washing with saturated brine (20mL), and removing anhydrous Na ₂ SO ₄ And (5) drying. Filtration and evaporation of the solvent under reduced pressure followed by column chromatography of the crude product (petroleum ether/ethyl acetate (v/v) ═ 10/1) gave a colorless oily liquid (0.240g, 21.9%).

MS(ESI,pos.ion)m/z:226.1(M+1).

Step 31- ((1- (2-chlorophenyl) piperidin-4-yl) methyl) -1H-benzo [ d ] [1,3] oxazine-2, 4-dione

Under the protection of nitrogen, (1- (2-chlorophenyl) piperidin-4-yl) methanol (0.240g,1.06mmol), 1H-benzo [ d ] [1,3] oxazine-2, 4-dione (0.190g,1.16mmol) and triphenylphosphine (0.418g,1.59mmol) were dissolved in tetrahydrofuran (60mL), cooled to 0 ℃, diisopropyl azodicarboxylate (0.305mL,1.55mmol) was added dropwise to the reaction solution, and the reaction was raised to 25 ℃ for 4 hours. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give a white solid (0.165g, 41.8%).

MS(ESI,pos.ion)m/z:370.9(M+1).

Step 41- ((1- (2-chlorophenyl) piperidin-4-yl) methyl) -4-hydroxy-2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester

A suspension of sodium tert-butoxide (0.69g,7.20mmol) and dimethyl malonate (0.118g,0.893mmol) in N, N-dimethylformamide (5mL) was added dropwise to 1- ((1- (2-chlorophenyl) piperidin-4-yl) methyl) -1H-benzo [ d][1,3]A solution of oxazine-2, 4-dione (0.165g,0.445mmol) in N, N-dimethylformamide (20mL) was heated to 95 ℃ and reacted for 1 hour. After cooling to 25 ℃, 2M HCl (5mL) was added to the reaction mixture, extraction was performed with ethyl acetate (20 mL. times.3), and the organic layer was washed with water (10mL) and saturated brine (10mL) in that order, and washed with anhydrous Na ₂ SO ₄ After drying, the solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give a white solid (0.125g, 65.8%). MS (ESI, pos. ion) M/z 427.2(M +1).

Step 52- (1- ((1- (2-chlorophenyl) piperidin-4-yl) methyl) -4-hydroxy-2-oxo-1, 2-dihydroquinoline-3-carboxamido) acetic acid

To a three-necked flask were added methyl 1- ((1- (2-chlorophenyl) piperidin-4-yl) methyl) -4-hydroxy-2-oxo-1, 2-dihydroquinoline-3-carboxylate (0.125g,0.293mmol), sodium glycinate (0.045g,0.46mmol) and ethylene glycol monomethyl ether (20mL) in this order, and the mixture was heated to 115 ℃ for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure, water (20mL) was added, the aqueous layer was washed with ethyl acetate (20mL × 3), the pH was adjusted to 3 with 1M hydrochloric acid, and the filter cake was dried to obtain a white solid (0.068g, 49%).

MS(ESI,pos.ion)m/z:470.2(M+1)；

¹ H NMR(600MHz,d ₆ -DMSO)δ10.59(t,J＝5.4Hz,1H),8.13(d,J＝6.9Hz,1H),7.83(t,J＝7.2Hz,1H),7.77(d,J＝8.7Hz,1H),7.39(dd,J＝11.1,4.4Hz,2H),7.30–7.22(m,1H),7.11(dd,J＝8.1,1.3Hz,1H),7.06–6.97(m,1H),4.33(d,J＝7.2Hz,2H),4.14(d,J＝5.5Hz,2H),3.26(d,J＝11.6Hz,2H),2.55(d,J＝11.7Hz,2H),2.08–1.92(m,J＝13.2,7.2Hz,1H),1.76–1.65(m,2H),1.63–1.50(m,J＝11.7,8.6Hz,2H).

Example 32- (4-hydroxy-2-oxo-1- ((5-oxo-1-phenylpyrrolidin-3-yl) methyl) -1, 2-dihydroquinoline-3-carboxamido) acetic acid

Step 15-oxo-1-phenylpyrrolidine-3-carboxylic acid

A solution of aniline (10.0g,107mmol) and itaconic acid (16.8g,129mmol) in water (30mL) was added to the sealed tube and heated to 110 deg.C for 20 hours. Cooled to 25 ℃, filtered, and the filter cake washed with water and dried to give a white solid (22.0g, 100%).

MS(ESI,pos.ion)m/z:206.1(M+1).

Step 24- (hydroxymethyl) -1-phenylpyrrolidin-2-one

5-oxo-1-phenylpyrrolidine-3-carboxylic acid (8.00g,39.0mmol) was dissolved in tetrahydrofuran (200mL) under nitrogen, cooled to 0 deg.C, and 1.0M borane in tetrahydrofuran (50mL,50.0mmol) was added slowly dropwise, and the temperature was raised to 25 deg.C after the addition was complete, and reacted overnight. The reaction was quenched by addition of methanol (50mL), the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give a colorless oily liquid (6.00g, 80.5%).

Step 3 (5-oxo-1-phenylpyrrolidin-3-yl) methyl methanesulfonate

To a solution of 4- (hydroxymethyl) -1-phenylpyrrolidin-2-one (2.50g,13.0mmol) in dichloromethane (50mL) under nitrogen was added triethylamine (3.5mL,26.0mmol), cooled to 0 deg.C, and methanesulfonyl chloride (1.52mL,19.6mmol) was added dropwise, after which the reaction was raised to 25 deg.C for 2.5 hours. The solvent was evaporated under reduced pressure, the remaining liquid was dissolved in methylene chloride (100mL), and the organic layer was successively saturated with water (20mL)And sodium bicarbonate solution (20mL), over anhydrous Na ₂ SO ₄ After drying, the solvent was evaporated under reduced pressure to give a gray oily liquid (3.25g, 92.0%).

MS(ESI,pos.ion)m/z:270.0(M+1).

Step 44- (azidomethyl) -1-phenylpyrrolidin-2-one

(5-oxo-1-phenylpyrrolidin-3-yl) methyl methanesulfonate (3.25g,12.1mmol) and sodium azide (1.57g,24.2mmol) were dissolved in N, N-dimethylformamide (50mL) and heated to 90 ℃ for 2 hours. After the reaction, the mixture was cooled to room temperature, water (20mL) was added, the mixture was poured into a mixed solution of dichloromethane (100mL) and saturated sodium bicarbonate (30mL), extracted with dichloromethane (30 mL. times.3), the organic layers were combined, and the mixture was dried over anhydrous Na ₂ SO ₄ After drying, the solvent was evaporated under reduced pressure to give a gray oily liquid (2.50g, 96.0%).

MS(ESI,pos.ion)m/z:217.1(M+1).

Step 54- (aminomethyl) -1-phenylpyrrolidin-2-one

Add water (5mL) and triphenylphosphine (6.55g,25.0mmol) to a solution of 4- (azidomethyl) -1-phenylpyrrolidin-2-one (2.70g,12.0mmol) in tetrahydrofuran (50mL) and react at 25 ℃ overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/dichloromethane (v/v) ═ 1/10) to give a yellow oily liquid (1.87g, 79.0%).

MS(ESI,pos.ion)m/z:191.2(M+1).

Step 62- (((5-oxo-1-phenylpyrrolidin-3-yl) methyl) amino) benzoic acid methyl ester

4- (aminomethyl) -1-phenylpyrrolidin-2-one (445mg,2.34mmol), bis (dibenzylacetyl) palladium (110mg,0.120mmol), cesium carbonate (1.89g,5.80mmol), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (216mg,0.373mmol), methyl 2-bromobenzoate (0.330mL,2.40mmol) and toluene (30mL) were added in this order to a three-necked flask under nitrogen, and heated to 110 ℃ for reaction overnight. After the reaction is finished, cooling toAt room temperature, filtration was carried out, and the residue was washed with ethyl acetate (30 mL). The combined organic phases were washed successively with water (10mL), saturated brine (10mL) and anhydrous Na ₂ SO ₄ After drying, the solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give a gray oily liquid (700mg, 92.0%).

MS(ESI,pos.ion)m/z:325.0(M+1).

Step 72 methyl- (3-ethoxy-3-oxo-N- ((5-oxo-1-phenylpyrrolidin-3-yl) methyl) propionylamino) benzoate

To a solution of methyl 2- (((5-oxo-1-phenylpyrrolidin-3-yl) methyl) amino) benzoate (700mg,2.16mmol) and pyridine (0.25mL,3.10mmol) in dichloromethane (20mL) was added ethyl chloroformylacetate (0.35mL,2.80mmol) in an ice bath, and the mixture was heated to 25 ℃ for reaction for 2 hours. The reaction was diluted with dichloromethane (10mL) and the organic phase was successively diluted with saturated NaHCO ₃ (10mL) and brine (10mL), over anhydrous MgSO ₄ After drying, the solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give a yellow oily liquid (830mg, 87.7%).

MS(ESI,pos.ion)m/z:439.3(M+1).

Step 84-hydroxy-2-oxo-1- ((5-oxo-1-phenylpyrrolidin-3-yl) methyl) -1, 2-dihydroquinoline-3-carboxylic acid ethyl ester

To a solution of methyl 2- (3-ethoxy-3-oxo-N- ((5-oxo-1-phenylpyrrolidin-3-yl) methyl) propionylamino) benzoate (400mg,0.912mmol) in ethanol (20mL) was added sodium ethoxide (130mg,1.83mmol), and the reaction was carried out at 25 ℃ for 4 hours. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give a white solid (260mg, 70.1%).

MS(ESI,pos.ion)m/z:407.3(M+1).

Step 92- (4-hydroxy-2-oxo-1- ((5-oxo-1-phenylpyrrolidin-3-yl) methyl) -1, 2-dihydroquinoline-3-carboxamido) acetic acid

Ethyl 4-hydroxy-2-oxo-1- ((5-oxo-1-phenylpyrrolidin-3-yl) methyl) -1, 2-dihydroquinoline-3-carboxylate (300mg,0.738mmol), sodium glycinate (170mg,1.75mmol) and ethylene glycol monomethyl ether (30mL) were added to a three-necked flask in this order and heated to 115 ℃ for 2.5 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, water (20mL) was added, the aqueous layer was washed with ethyl acetate (20mL × 3), the pH was adjusted to 3 with 1M hydrochloric acid, and the filter cake was dried to obtain a white solid (200mg, 61.8%).

MS(ESI,pos.ion)m/z:436.3(M+1)；

¹ H NMR(400MHz,d ₆ -DMSO)δ:10.49(d,J＝5.2Hz,1H),8.14(d,J＝7.5Hz,1H),7.84–7.74(m,2H),7.62(s,2H),7.39(dt,J＝15.9,8.0Hz,3H),7.14(t,J＝7.4Hz,1H),4.56–4.44(m,2H),4.13(d,J＝5.5Hz,2H),3.99–3.89(m,2H),3.75(dd,J＝9.8,5.5Hz,2H),3.03–2.93(m,1H).

Example 42- (4-hydroxy-2-oxo-1- ((1-phenylpiperidin-4-yl) methyl) -1, 2-dihydroquinoline-3-carboxamido) acetic acid

Step 11-Phenylpiperidine-4-carboxylic acid methyl ester

To a reaction flask were added methyl piperidine-4-carboxylate (3.00g,21.1mmol), CuI (800mg,4.20mmol), potassium carbonate (5.79g,41.9mmol), L-proline (965mg,8.38mmol), bromobenzene (2.41mL,23.0mmol) and dimethyl sulfoxide (50mL) in that order under nitrogen, and heated to 90 ℃ for reaction overnight. After the reaction, the reaction mixture was cooled to room temperature, water (40mL) was added to the reaction mixture, ethyl acetate (80 mL. times.3) was extracted, and the organic layers were combined and washed with anhydrous Na ₂ SO ₄ After drying, the solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20/1) to give a white solid (1.38g, 30.0%).

MS(ESI,pos.ion)m/z:220.3(M+1).

Step 2 (1-phenylpiperidin-4-yl) methanol

To a solution of methyl 1-phenylpiperidine-4-carboxylate (1.39g,1.00mmol) in ethanol (50mL) at 0 deg.C was added sodium borohydride (600mg,15.7mmol) in portions, stirred for 30 minutes, then warmed to 25 deg.C, stirred for 2 hours, then warmed to 90 deg.C and reacted overnight. Cooling to 25 deg.C, removing solvent under reduced pressure, adding the residue into water (20mL), extracting with ethyl acetate (50 mL. times.3), combining organic layers, and purifying with anhydrous Na ₂ SO ₄ After drying, the solvent was evaporated under reduced pressure to give a white solid (850mg, 70.1%).

MS(ESI,pos.ion)m/z:192.2(M+1).

Step 31- ((1-phenylpiperidin-4-yl) methyl) -1H-benzo [ d ] [1,3] oxazine-2, 4-dione

(1-phenylpiperidin-4-yl) methanol (850mg,4.44mmol), 1H-benzo [ d ] [1,3] oxazine-2, 4-dione (800mg,4.90mmol) and triphenylphosphine (1.75g,6.67mmol) were dissolved in tetrahydrofuran (25mL) under nitrogen, cooled to 0 deg.C, diisopropyl azodicarboxylate (1.32mL,6.66mmol) was added dropwise to the reaction mixture, and the mixture was raised to 25 deg.C and reacted for 4 hours. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give a white solid (500mg, 33.4%).

MS(ESI,pos.ion)m/z:337.1(M+1).

Step 44-hydroxy-2-oxo-1- ((1-phenylpiperidin-4-yl) methyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester

A suspension of sodium tert-butoxide (200mg,2.02mmol) and dimethyl malonate (0.25mL,2.20mmol) in N, N-dimethylformamide (5mL) was added dropwise to 1- ((1-phenylpiperidin-4-yl) methyl) -1H-benzo [ d][1,3]A solution of oxazine-2, 4-dione (350mg,1.04mmol) in N, N-dimethylformamide (50mL) was heated to 95 ℃ and reacted for 1 hour. Cooling to 25 deg.C, adding into the reaction solution2M HCl (4mL) was added, extraction was performed with ethyl acetate (30 mL. times.3), and the organic layers were combined, washed with water (10mL) and saturated brine (10mL) in this order, and washed with anhydrous Na ₂ SO ₄ After drying, the solvent was evaporated under reduced pressure to give a white solid (410mg, 100.0%).

MS(ESI,pos.ion)m/z:393.3(M+1).

Step 52- (4-hydroxy-2-oxo-1- ((1-phenylpiperidin-4-yl) methyl) -1, 2-dihydroquinoline-3-carboxamido) acetic acid

To a three-necked flask were added methyl 4-hydroxy-2-oxo-1- ((1-phenylpiperidin-4-yl) methyl) -1, 2-dihydroquinoline-3-carboxylate (330mg,0.841mmol), sodium glycinate (150mg,1.55mmol) and ethylene glycol monomethyl ether (25mL) in this order, and the mixture was heated to 115 ℃ to react for 2 hours. Cooled to room temperature, the solvent was removed under reduced pressure, water (20mL) was added, and the aqueous layer was washed with diethyl ether (20mL × 3) and adjusted to pH 3 with 1M hydrochloric acid. The mixture was extracted with ethyl acetate (40 mL. times.3), and the organic layers were combined, washed successively with water (10mL) and saturated brine (10mL), and dried over anhydrous Na ₂ SO ₄ After drying, the solvent was evaporated under reduced pressure to give a yellow solid (100mg, 26.4%).

MS(ESI,pos.ion)m/z:436.1(M+1)；

¹ H NMR(400MHz,d ₆ -DMSO)δ:12.92(s,1H),10.57(t,J＝5.5Hz,1H),8.13(dd,J＝8.0,1.4Hz,1H),7.90–7.69(m,2H),7.38(dd,J＝14.7,7.4Hz,1H),7.18(dd,J＝8.6,7.3Hz,2H),6.91(d,J＝8.0Hz,2H),6.73(t,J＝7.2Hz,1H),4.27(s,2H),4.14(d,J＝5.5Hz,2H),3.69(d,J＝12.4Hz,1H),2.56(m,2H),2.08–1.94(m,1H),1.67(d,J＝12.2Hz,2H),1.47(qd,J＝12.6,3.6Hz,2H).

Example 5(S) -2- (4-hydroxy-2-oxo-1- ((2-oxo-3-phenyloxazolidin-5-yl) methyl) -1, 2-dihydroquinoline-3-carboxamido) acetic acid

Step 1(S) -2- ((2-oxo-3-phenyloxazolidin-5-yl) methyl) isoindoline-1, 3-dione

Under the protection of nitrogen, adding (R) -2- ((2-oxo-oxazolidin-5-yl) methyl into a three-neck bottle in sequence) Isoindoline-1, 3-dione (5.00g,20.3mmol), cesium carbonate (17.0g,52.2mmol), tris (dibenzylideneacetone) dipalladium (1.00g,1.07mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (1.80g,3.08mmol), bromobenzene (2.5mL,23.7mmol) and 1, 4-dioxane (100mL) were heated to 120 ℃ and reacted overnight. After the reaction, the reaction mixture was cooled to 25 ℃ and filtered, and the filtrate was washed with water (10mL) and saturated brine (10mL) in this order, and dried over anhydrous Na ₂ SO ₄ And (5) drying. Filtration, evaporation of the solvent under reduced pressure and purification of the crude product by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave a white solid (2.55g, 39.0%).

MS(ESI,pos.ion)m/z:323.0(M+1).

Step 25- (aminomethyl) -3-phenyloxazolidin-2-one

Add 40% aqueous methylamine (4.0mL,40.4mmol) to a solution of (S) -2- ((2-oxo-3-phenyloxazolidin-5-yl) methyl) isoindoline-1, 3-dione (2.55g,7.91mmol) in EtOH (50mL) and heat to 90 ℃ for 2 h. After completion of the reaction, it was cooled to 25 ℃, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give a white solid (4.00g, 45.0%).

MS(ESI,pos.ion)m/z:193.1(M+1).

Step 3(S) -methyl 2- (((2-oxo-3-phenyloxazolidin-5-yl) methyl) amino) benzoate

To a solution of 5- (aminomethyl) -3-phenyloxazolidin-2-one (1.50g,7.80mmol) in toluene (50mL) under nitrogen, cesium carbonate (6.36g,19.5mmol), tris (dibenzylideneacetone) dipalladium (350mg,0.382mmol), 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene (722mg,1.25mmol) and methyl o-bromobenzoate (1.1mL,7.80mmol) were added in that order and heated to 110 deg.C for reaction overnight. After the reaction was completed, it was cooled to 25 ℃ and filtered, and the residue was washed with ethyl acetate (30 mL). The combined organic phases were washed successively with water (10mL) and saturated brine (10mL) anhydrous Na ₂ SO ₄ And (5) drying. Filtering, evaporating the solvent under reduced pressure, and purifying the crude product by column chromatography (petroleum ether/ethyl acetate)Ester (v/v) ═ 3/1) to give a grey solid (926mg, 36.0%).

MS(ESI,pos.ion)m/z:327.1(M+1).

Step 4(S) -methyl 2- (3-ethoxy-3-oxo-N- ((2-oxo-3-phenyloxazolidin-5-yl) methyl) propionylamino) benzoate

Methyl (S) -2- (((2-oxo-3-phenyloxazolidin-5-yl) methyl) amino) benzoate (926mg,2.84mmol) and pyridine (0.35mL,4.30mmol) were dissolved in dichloromethane (20mL) under nitrogen, cooled to 0 ℃, and ethyl chloroformylacetate (0.50mL,4.00mmol) was added dropwise. After the completion of the dropwise addition, the reaction system was reacted at 25 ℃ for hours. The reaction was diluted with dichloromethane (30mL) and successively with saturated NaHCO ₃ The solution (20mL) was washed with saturated brine (20mL) and dried over anhydrous Na ₂ SO ₄ And (5) drying. Filtration, evaporation of the solvent under reduced pressure and column chromatography of the crude product (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave a yellow oily liquid (1.10g, 88.0%).

MS(ESI,pos.ion)m/z:441.3(M+1).

Step 5(S) -4-hydroxy-2-oxo-1- ((2-oxo-3-phenyloxazolidin-5-yl) methyl) -1, 2-dihydroquinoline-3-carboxylic acid ethyl ester

Sodium ethoxide (210mg,2.96mmol) was added to a solution of methyl (S) -2- (3-ethoxy-3-oxo-N- ((2-oxo-3-phenyloxazolidin-5-yl) methyl) propionylamino) benzoate (650mg,1.47mmol) in ethanol (20mL) and reacted at 25 ℃ for 2 hours. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give a white solid (500mg, 83.0%).

MS(ESI,pos.ion)m/z:409.0(M+1).

Step 6 tert-butyl (S) -2- (4-hydroxy-2-oxo-1- ((2-oxo-3-phenyloxazolidin-5-yl) methyl) -1, 2-dihydroquinoline-3-carboxamido) acetate

To a solution of ethyl (S) -4-hydroxy-2-oxo-1- ((2-oxo-3-phenyloxazolidin-5-yl) methyl) -1, 2-dihydroquinoline-3-carboxylate (50.0mg,0.120mmol) in 1, 4-dioxane (10mL) was added tert-butyl glycinate hydrochloride (24.0mg,0.140mmol) and triethylamine (0.04mL,0.290mmol) and the mixture was heated to 110 ℃ for 24 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride (50mL), washed with saturated brine (20mL), anhydrous Na ₂ SO ₄ And (5) drying. Filtration, evaporation of the solvent under reduced pressure and purification of the crude product by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) gave a white solid (4.00g, 45.0%).

MS(ESI,neg.ion)m/z:492.0(M-1).

Step 7(S) -2- (4-hydroxy-2-oxo-1- ((2-oxo-3-phenyloxazolidin-5-yl) methyl) -1, 2-dihydroquinoline-3-carboxamido) acetic acid

To a solution of tert-butyl (S) -2- (4-hydroxy-2-oxo-1- ((2-oxo-3-phenyloxazolidin-5-yl) methyl) -1, 2-dihydroquinoline-3-carboxamido) acetate (150mg,0.300mmol) in dichloromethane (10mL) was added trifluoroacetic acid (5mL) and the reaction was reacted at 25 ℃ for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, water (20mL) was added, the mixture was extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, washed with saturated brine (20mL), and dried over Na ₂ SO ₄ And (5) drying. Filtration and evaporation of the solvent under reduced pressure gave a white solid (100mg, 74.4%).

MS(ESI,pos.ion)m/z:437.8(M+1)；

¹ H NMR(400MHz,d ₆ -DMSO)δ:10.46(t,J＝5.5Hz,1H),8.14(d,J＝7.9Hz,1H),7.89(d,J＝8.7Hz,1H),7.83(t,J＝7.7Hz,1H),7.58(d,J＝7.9Hz,2H),7.41(t,J＝7.8Hz,3H),7.15(t,J＝7.3Hz,1H),5.06(dd,J＝12.2,5.7Hz,1H),4.86(dd,J＝15.0,8.6Hz,1H),4.60(dd,J＝15.0,3.4Hz,1H),4.27(t,J＝8.9Hz,1H),4.15(d,J＝5.5Hz,2H),4.01(dd,J＝8.9,6.7Hz,1H).

Example 62- (4-hydroxy-2-oxo-1- ((2-oxo-1-phenylpyrrolidin-3-yl) methyl) -1, 2-dihydroquinoline-3-carboxamido) acetic acid

Step 12-oxo-1-phenylpyrrolidine-3-carboxylic acid

A solution of 6, 6-dimethyl-5, 7-dioxaspiro [2.5] octane-4, 8-dione (500mg,2.97mmol) and aniline (0.9mL,10.0mmol) in ethanol (3.5mL) was placed in a microwave reactor and reacted at 100 ℃ for 5 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, water (30mL) was added, the pH was adjusted to 8 with a 1N naoh solution, the mixture was washed with ethyl acetate (10mL × 3), and the aqueous phase was adjusted to pH 5 with 1N HCl. Filtration, washing of the filter cake with water and drying gave a white solid (480mg, 78.7%).

MS(ESI,pos.ion)m/z:206.1(M+1).

Step 22-oxo-1-phenylpyrrolidine-3-carboxylic acid methyl ester

To a mixed solution of 2-oxo-1-phenylpyrrolidine-3-carboxylic acid (2.06g,10.0mmol) in methanol (20mL) and dichloromethane (60mL) was added dropwise trimethylsilyldiazomethane (7.5mL,15.0mmol) and the reaction was allowed to react overnight at 25 ℃. The solvent was removed under reduced pressure to give a white solid (2.20g, 100%).

MS(ESI,pos.ion)m/z:220.1(M+1).

Step 33- (hydroxymethyl) -1-phenylpyrrolidin-2-one

To a solution of methyl 2-oxo-1-phenylpyrrolidine-3-carboxylate (2.71g,12.4mmol) in ethanol (100mL) in ice bath was added sodium borohydride (2.43g,62.9mmol) in portions, stirred for 0.5 h, then warmed to 25 ℃ for reaction overnight. After completion of the reaction, the solvent was removed under reduced pressure, water (30mL) was added, the mixture was extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, washed with saturated brine (20mL), and dried over anhydrous Na ₂ SO ₄ And (5) drying. Filtration, evaporation of the solvent under reduced pressure and purification of the crude product by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) gave a white solid (1.70g, 72.0%). MS (ESI, pos.ion) M/z 192.1(M +1).

Step 4 (2-oxo-1-phenylpyrrolidin-3-yl) methyl methanesulfonate

To a solution of 3- (hydroxymethyl) -1-phenylpyrrolidin-2-one (1.92g,10.0mmol) in dichloromethane (50mL) under nitrogen was added triethylamine (2.70mL,20.0mmol), cooled to 0 deg.C, and methanesulfonyl chloride (1.20mL,15.5mmol) was added dropwise, after which time the reaction was allowed to warm to 25 deg.C for 2 hours. After the reaction was complete, the reaction mixture was washed with 0.1M hydrochloric acid (20mL), the aqueous layer was extracted with dichloromethane (50 mL. times.3), the organic phases were combined, washed successively with water (20mL) and saturated sodium bicarbonate solution (30mL), anhydrous Na ₂ SO ₄ And (5) drying. Filtration and evaporation of the solvent under reduced pressure gave a white solid (2.58g, 95.4%).

MS(ESI,pos.ion)m/z:270.2(M+1).

Step 53- (azidomethyl) -1-phenylpyrrolidin-2-one

(2-oxo-1-phenylpyrrolidin-3-yl) methyl methanesulfonate (2.58g,9.58mmol) and sodium azide (1.26g,19.4mmol) were dissolved in N, N-dimethylformamide (50mL) and heated to 90 ℃ for reaction for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, water (20mL) was added, the mixture was poured into a mixed solution of dichloromethane (100mL) and saturated sodium bicarbonate solution (30mL), extraction was performed with dichloromethane (30 mL. times.3), organic layers were combined, and the mixture was purified over anhydrous Na ₂ SO ₄ After drying, the solvent was evaporated under reduced pressure to give a white solid (1.80g, 87.0%).

MS(ESI,pos.ion)m/z:217.1(M+1).

Step 63- (aminomethyl) -1-phenylpyrrolidin-2-one

Add water (2.5mL) and triphenylphosphine (4.35g,16.6mmol) to a solution of 3- (azidomethyl) -1-phenylpyrrolidin-2-one (1.90g,8.80mmol) in tetrahydrofuran (25mL) and react at 25 ℃ overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/methanol (v/v) ═ 10/1) to give a yellow oily liquid (1.40g, 84.0%).

MS(ESI,pos.ion)m/z:191.1(M+1).

Step 72- (((2-oxo-1-phenylpyrrolidin-3-yl) methyl) amino) benzoic acid methyl ester

3- (aminomethyl) -1-phenylpyrrolidin-2-one (1.00g,5.25mmol), bis (dibenzylacetyl) palladium (240mg,0.262mmol), cesium carbonate (4.30g,13.0mmol), 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (450mg,0.77mmol), methyl 2-bromobenzoate (0.75mL,5.30mmol) and toluene (30mL) were added in this order to a three-necked flask under nitrogen, and the mixture was heated to 110 ℃ for reaction overnight. After the reaction was completed, it was cooled to room temperature, filtered, and the residue was washed with ethyl acetate (30 mL). The combined organic phases were washed successively with water (20mL), brine (20mL) and anhydrous Na ₂ SO ₄ After drying, the solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give a gray oily liquid (1.70g, 100%).

MS(ESI,pos.ion)m/z:325.3(M+1).

Step 82- (3-ethoxy-3-oxo-N- ((2-oxo-1-phenylpyrrolidin-3-yl) methyl) propionylamino) benzoic acid methyl ester

Ethyl chloroformylacetate (0.80mL,6.40mmol) was added to a solution of methyl 2- (((2-oxo-1-phenylpyrrolidin-3-yl) methyl) benzoate (1.70g,5.20mmol) and pyridine (0.60mL,7.50mmol) in dichloromethane (50mL) in an ice bath and the mixture was allowed to warm to 25 ℃ for 4 hours. The reaction solution was diluted with dichloromethane (10mL) and then sequentially saturated NaHCO ₃ The solution (50mL) was washed with saturated brine (50mL) and dried over anhydrous MgSO ₄ After drying, the solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give a yellow oily liquid (2.00g, 87.0%).

MS(ESI,pos.ion)m/z:439.4(M+1).

Step 94-hydroxy-2-oxo-1- ((2-oxo-1-phenylpyrrolidin-3-yl) methyl) -1, 2-dihydroquinoline-3-carboxylic acid ethyl ester

To a solution of methyl 2- (3-methoxy-3-oxo-N- ((2-oxo-1-phenylpyrrolidin-3-yl) methyl) propionylamino) benzoate (2.00g,4.56mmol) in ethanol (50mL) was added sodium ethoxide (650mg,9.17mmol), and the reaction was carried out at 25 ℃ for 2 hours. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give a white solid (1.50g, 81.0%).

MS(ESI,pos.ion)m/z:407.3(M+1).

Step 102- (4-hydroxy-2-oxo-1- ((2-oxo-1-phenylpyrrolidin-3-yl) methyl) -1, 2-dihydroquinoline-3-carboxamido) acetic acid

Ethyl 4-hydroxy-2-oxo-1- ((2-oxo-1-phenylpyrrolidin-3-yl) methyl) -1, 2-dihydroquinoline-3-carboxylate (500mg,1.23mmol), sodium glycinate (300mg,3.09mmol) and ethylene glycol monomethyl ether (30mL) were added to a three-necked flask in this order, and the mixture was heated to 110 ℃ for reaction for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, water (20mL) was added, the mixture was washed with diethyl ether (30mL × 3), the aqueous layer was adjusted to pH 3 with 1M hydrochloric acid, and the filtrate was dried to obtain a white solid (300mg, 55.6%).

MS(ESI,pos.ion)m/z:436.0(M+1)；

¹ H NMR(400MHz,d ₆ -DMSO)δ:10.52(s,1H),8.14(d,J＝7.8Hz,1H),7.86–7.76(m,2H),7.66(d,J＝7.9Hz,2H),7.43–7.34(m,3H),7.15(t,J＝7.4Hz,1H),4.71(dd,J＝14.4,8.9Hz,1H),4.55(dd,J＝14.4,5.1Hz,1H),4.14(d,J＝5.6Hz,2H),3.87–3.73(m,2H),3.17(dd,J＝8.7,5.4Hz,1H),2.24–2.12(m,1H),2.10–1.97(m,1H).

EXAMPLE 7 in vitro Erythropoietin (EPO) -inducing Activity assay of the Compounds of the invention

The in vitro Erythropoietin (EPO) -inducing activity of the compounds of the present invention was evaluated using the cell line Hep3B (ATCC, Manassas, VA) derived from human liver cancer. Hep3B cells were cultured overnight (96-well plate, 2.5X 10) in DMEM Medium (Dulbecco's modified eagle's Medium) at 37 ℃ in the presence of 10% Fetal Bovine Serum (FBS) ⁴ Cells/well). The culture supernatant was discarded on the second day, and fresh DMEM (containing 0.5% dimethyl sulfoxide and 0.5% fetal calf serum) or solvent control containing the compounds of the present invention (0.31-160.00 μ M) at serial concentrations or solvent control was added(DMEM containing 0.5% dimethyl sulfoxide, 0.5% fetal bovine serum), and the cells were cultured at 37 ℃ for 24 hours. After recovering the culture supernatant, EPO concentration in the culture supernatant was quantified using a human EPO ELISA kit (Abcam). EPO-inducible Activity of each Compound is expressed as half maximal Effector Concentration (EC) ₅₀ ). The results of the experiment are shown in table 2.

TABLE 2 in vitro Erythropoietin (EPO) -inducing Activity of the Compounds of the invention

Numbering	EC ₅₀ (μM)
		Example 2	3.34
Example 4	6.45

Conclusion of the experiment

As can be seen from the data in Table 2, the compounds of the present invention have high EPO-inducing activity.

Claims

1. A compound which is a compound represented by formula (II) or a pharmaceutically acceptable salt of a compound represented by formula (II),

wherein R is ¹ Is- (CR) ¹⁰ R ¹¹ ) _m -M ¹ -M ² ；

Wherein each R is ¹⁰ And R ¹¹ Independently is H, or C _1-4 An alkyl group;

M ¹ is a piperidinyl group;

M ² is phenyl; wherein, M ² Optionally substituted with one or more substituents selected from fluoro, chloro or bromo;

each R ² 、R ³ 、R ⁴ And R ⁵ Independently is H, -O-R ²⁰ Fluorine, chlorine, bromine, nitro, cyano, C _1-4 Alkyl or halo C _1-4 An alkyl group;

each R ²⁰ Independently H, C _1-4 Alkyl or halo C _1-4 An alkyl group;

each m is independently 1,2 or 3.

2. The compound of claim 1, wherein,

each R ¹⁰ And R ¹¹ Independently H, methyl, ethyl, propyl or butyl;

each R ² 、R ³ 、R ⁴ And R ⁵ Independently of each other H, -O-R ²⁰ Fluorine, chlorine, bromine, nitro, cyano or C _1-4 An alkyl group;

each R ²⁰ Independently is H or C _1-4 An alkyl group.

3. The compound of claim 1, selected from the structures of one of:

or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a compound of any one of claims 1-3; which further comprises pharmaceutically acceptable adjuvants.

5. The pharmaceutical composition of claim 4, wherein the adjuvant is selected from at least one of a carrier, a diluent, and a vehicle.

6. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the prevention, treatment or alleviation of an EPO-associated disorder in a patient.

7. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the treatment of anemia or ischemia.

8. Use according to claim 7, wherein the ischemia is myocardial ischemia.