WO2019096089A1

WO2019096089A1 - Indolizine derivative and application thereof in medicine

Info

Publication number: WO2019096089A1
Application number: PCT/CN2018/115013
Authority: WO
Inventors: 刘栋; 陈冬冬; 邓彪; 涂相云; 方子楠; 吴浩浩; 顾丹燕; 刘静
Original assignee: 杭州安道药业有限公司
Priority date: 2017-11-14
Filing date: 2018-11-12
Publication date: 2019-05-23
Also published as: CN107739378A

Abstract

The present invention relates to an indolizine derivative and an application thereof in medicine. In particular, disclosed in the present invention are a novel substituted indolizine derivative represented by formula I, or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. The present invention further relates to an application of these compounds in medicine.

Description

Pyridazine derivatives and their application in medicine

The present application claims the priority of the Japanese Patent Application No. JP-A--------

Technical field

The invention belongs to the field of medicine and relates to a pyridazine derivative, its preparation and its application in medicine. In particular, the invention relates to the treatment of diseases associated with proline hydroxylase, such as anemia, and the like.

Background technique

Anemia is a disease caused by a decrease in the number of red blood cells or a decrease in red blood cell hemoglobin content in the body's blood. Because the main function of hemoglobin is to carry oxygen to various organs for use, low levels of hemoglobin directly lead to insufficient oxygen supply in various organs of the body. Since the normal physiological activities of the body depend on the full utilization of oxygen, various degrees of anemia can cause various clinical symptoms. Common anemia secondary diseases include cardiovascular diseases (heart failure, atrial fibrillation, angina pectoris, etc.), urinary system diseases (renal failure, proteinuria), nervous system diseases (dizziness, headache, tinnitus, vertigo, lack of energy, fatigue and lethargy, Irritability, concentration is not easy to concentrate. Severe anemia can occur fainting), digestive diseases (loss of appetite, constipation), reproductive system diseases (sexual desire to decline, irregular menstruation) and so on. Anemia can not only seriously affect the patient's health and quality of life, but can even threaten the patient's life if the anemia is not corrected in time.

There are many causes of anemia, usually caused by decreased production of erythropoietin (EPO). Chronic kidney disease (CKD, Chronic Kidney Disease) causes a decrease in erythropoietin synthesis, so most patients with chronic kidney disease have anemia. In addition, after receiving radiotherapy and chemotherapy, cancer patients with bone marrow hematopoietic stem cells are inhibited, which can also cause anemia. Some antiviral drugs (such as drugs for treating hepatitis C and HIV) and inflammation can also cause anemia.

Stabilizing hypoxia-inducible factor (HIF) can increase erythropoietin production by inhibiting proline hydroxylase (Cell, 2001, 107, 43-54). Hypoxia-inducible factor is a transcriptional regulator that plays a crucial role in regulating oxygen balance in the body's hypoxia response (Molecular Cellular Biology 1992, 12, 5447-5454). Hypoxia-inducible factor-1 is a heterodimer that upregulates the expression of many genes when it is linked to the promoter region of the hypoxia-responsive element (HRE) (Nature Reviews Cancer 2003, 3, 721-732). Proteins encoded by genes regulated by hypoxia-inducible factor-1 can cause many biological effects, including erythropoiesis, angiogenesis, vasodilation, glycolysis, immune regulation, neuroprotection, ischemic protection of the heart, cerebral ischemia Protection and so on. In the case of normal oxygen levels, the hypoxia-inducible factor-1 alpha subunit is hydroxylated at the proline residue by proline hydroxylase. The hydroxylated hypoxia inducible factor-1 alpha is linked to the von Hippel Lindau protein and then degraded by the proteosome by ubiquitination. In the absence of oxygen, the inhibitory activity of proline hydroxylase is inhibited, so the hypoxia-inducible factor-1α subunit is stabilized, and the amount of hypoxia-inducible factor-1α subunit is increased, and the genes regulated by it include Elevated levels of erythropoietin (Science 2001, 292, 464-468).

Collagen proline hydroxylase inhibitors have been disclosed in the literature, for example, J. Med. Chem. 1992, 35, 800-804; J. Med. Chem. 1992, 35, 2652-2658; J. Med. Chem. 36,3853-3858; Patent document EP 661 269 also discloses a collagen proline hydroxylase inhibitor. In the field of proline hydroxylases associated with hypoxia-inducible factors, inhibitors in this regard have also been disclosed, such as WO2004108681, WO2007070359, WO2007150011, WO2008076425, WO2011007856, WO201206472, WO2013043621, WO2014102818, and the like. Most of the proline hydroxylase inhibitors associated with hypoxia inducible factors in these patents are mimics of 2-oxoglutaric acid.

However, to date, no proline hydroxylase inhibitor drugs associated with hypoxia-inducible factors have been approved for market entry. Therefore, it is still necessary to find a novel proline hydroxylase inhibitor, so that patients with diseases related to hypoxia-inducing factors may have various options in the future.

Summary of the invention

1. A compound of the invention

It is an object of the present invention to provide a novel proline hydroxylase inhibitor. Another object of the present invention is to provide a novel compound for treating or preventing a disease associated with hypoxia-inducible factors such as anemia.

Accordingly, one aspect of the invention provides a compound of Formula I, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or A pharmaceutically acceptable salt, or a prodrug thereof, wherein Formula I is as follows:

among them:

R ¹ and R ^{2 are} independently selected from cyano, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, amino, R ⁹ O-, R ⁹ S-, R ⁹ ( O=)S-, R ⁹ (O=) ₂ S-, wherein R ⁹ is alkyl, heterocyclic, alkenyl, alkynyl, aryl or heteroaryl; wherein the above alkyl, hetero A cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, amino group is optionally substituted by one or more substituents, wherein the substituents are independently selected from halo, cyano, hydroxy, amino, Carboxyl, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, =O, =S, -SH, R ¹⁰ O-, R ¹⁰ S-, R ¹⁰ (O=)S And R ¹⁰ (O=) ₂ S-, wherein R ¹⁰ is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; or R ¹ and R ^{2 taken} together to form a ring;

R ³ , R ⁴ and R ^{5 are} independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, R ¹¹ O-, R ¹¹ S-, R ¹¹ (O=)S-, R ¹¹ (O=) ₂ S-, wherein R ¹¹ is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl And wherein the above alkyl group, heterocyclic group, alkenyl group, alkynyl group, aryl group, heteroaryl group, acyl group, amino group are optionally substituted by one or more substituents, wherein the substituents are independently selected from In halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, =0, =S, -SH, R ¹² O-, R ¹² S-, R ¹² (O=)S-, R ¹² (O=) ₂ S-, wherein R ¹² is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl;

R ⁶ and R ^{6' are} independently selected from hydrogen and optionally substituted alkyl;

R ^{7 is} selected from the group consisting of hydrogen, alkyl and acyl; wherein the alkyl and acyl groups are optionally substituted by the following groups: halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkyne Base, aryl, heteroaryl, =O, =S, -SH, R ¹³ O-, R ¹³ S-, R ¹³ (O=)S-, R ¹³ (O=) ₂ S-, wherein R ¹³ is an alkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an aryl group, or a heteroaryl group;

R ^{8 is} selected from the group consisting of hydrogen, alkyl and -OC(O)R ¹⁴ , wherein R ¹⁴ is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; wherein alkyl, heterocycle The base, alkenyl, alkynyl, aryl or heteroaryl group is optionally substituted by the following groups: halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl , aryl, heteroaryl, =O, =S, -SH, R ¹⁵ O-, R ¹⁵ S-, R ¹⁵ (O=)S-, R ¹⁵ (O=) ₂ S-; wherein R ¹⁵ Is an alkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an aryl group, or a heteroaryl group;

X is an oxygen atom or a sulfur atom or NH.

Another aspect of the invention provides a compound of formula I, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or A pharmaceutically acceptable salt, or a prodrug thereof, wherein Formula I is as follows:

among them:

R ¹ and R ^{2 are} independently selected from cyano, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 Cycloalkenyl, heterocycloalkyl having 3 to 8 ring atoms, heterocycloalkenyl group having 3 to 8 ring atoms, heteroaryl group having 5 to 14 ring atoms, C1-C12 chain alkyl-C (=O)-, C2-C12 alkenyl-C(=O)-, amino, R ⁹ O-, R ⁹ S-, R ⁹ (O=)S-, R ⁹ (O=) ₂ S- Wherein R ⁹ is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, containing 3 to a heterocyclic alkyl group having 8 ring atoms, a heterocycloalkenyl group having 3 to 8 ring atoms; wherein the above C1-C12 chain alkyl group, C2-C12 alkenyl group, C2-C12 alkynyl group, C6- C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring atoms, heterocycloalkenyl having 3 to 8 ring atoms, containing 5 to 14 rings a heteroaryl group of an atom, a C1-C12 chain alkyl-C(=O)-, a C2-C12 alkenyl-C(=O)-, an amino group, optionally substituted with from 1 to 3 substituents, wherein The substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 alkyl, C3-C8 ring a C2-C6 alkenyl-, C2-C6 alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl group having 5 to 14 ring atoms, C1-C6-chain alkyl-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyl-O-, C2-C6 alkynyl-O-, C3-C8 cycloalkenyl-O-, C6-C14 aryl-O-, heteroaryl-O-, C1-C6-chain alkyl-S-, C3-C8 cycloalkyl-S-, C2-C6 alkenyl group having 5 to 14 ring atoms -S-, C2-C6 alkynyl-S-, C3-C8 cycloalkenyl-S-, C6-C14 aryl-S-, heteroaryl-S- having 5 to 14 ring atoms, containing 3 Heterocycloalkyl group to 8 ring atoms, heterocycloalkenyl group having 3 to 8 ring atoms, =O, =S, -SH, -CF ₃ , -CO ₂ C ₁ -C ₆ chain alkyl group, C1 -C6 alkyl-S-, C1-C6 alkyl (O=)S- and C1-C6 alkyl (O=) ₂ S-;

R ¹ and R ^{2 taken} together to form an optionally substituted cycloalkane ring, a cycloolefin ring, a heterocycloalkane ring, a heterocycloalkene ring having 3 to 8 ring atoms;

R ³ , R ⁴ and R ^{5 are} independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C14 aryl , C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring atoms, heterocycloalkenyl having 3 to 8 ring atoms, heterocyclic ring having 5 to 14 ring atoms Aryl, C1-C12-chain alkyl-C(=O)-, C2-C12 alkenyl-C(=O)-, amino, R ¹¹ O-, R ¹¹ S-, R ¹¹ (O=)S -, R ¹¹ (O=) ₂ S-, wherein R ¹¹ is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl a C3-C8 cycloalkenyl group, a heterocycloalkyl group having 3 to 8 ring atoms, a heterocycloalkenyl group having 3 to 8 ring atoms; wherein the above C1-C12 chain alkyl group, C2-C12 alkene , C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring atoms, containing from 3 to 8 ring atoms Heterocyclenyl, heteroaryl having 5 to 14 ring atoms, C1-C12 alkyl-C(=O)-, C2-C12 alkenyl-C(=O)-, amino optionally Substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of a hydroxyl group, a halogen, and a cyano group Amino, carboxy, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl-, C2-C6 alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6- C14 aryl, heteroaryl group having 5 to 14 ring atoms, C1-C6 chain alkyl-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyl-O-, C2-C6 chain alkynyl-O-, C3-C8 cycloalkenyl-O-, C6-C14 aryl-O-, heteroaryl-O-, C1-C6-chain alkyl-S-, having 5 to 14 ring atoms, C3-C8 cycloalkyl-S-, C2-C6 alkenyl-S-, C2-C6 alkynyl-S-, C3-C8 cycloalkenyl-S-, C6-C14 aryl-S-, Heteroaryl-S- of 5 to 14 ring atoms, heterocycloalkyl group having 3 to 8 ring atoms, heterocycloalkenyl group having 3 to 8 ring atoms, =O, =S, -SH, - CF ₃ , -CO ₂ C ₁ -C ₆ alkyl, C1-C6 alkyl-S-, C1-C6 alkyl (O=)S- and C1-C6 alkyl (O=) ₂ S -;

R ⁶ and R ^{6' are} independently selected from the group consisting of hydrogen, C1-C6 alkyl and C3-C8 cycloalkyl; the above C1-C6 alkyl and C3-C8 cycloalkyl are optionally 1 to 3 substituents Substituted, wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl-, C2-C6 alkyne Base-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl containing 5 to 14 ring atoms, C1-C6-chain alkyl-O-, C3-C8 naphthenic -O-, C2-C6 alkenyl-O-, C2-C6 alkynyl-O-, C3-C8 cycloalkenyl-O-, C6-C14 aryl-O-, and 5 to 14 a heteroaryl-O- ring atom;

R ^{7 is} selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl-C(=O)-, and C2-C6 alkenyl-C(=O)-; C1-C6-chain alkyl, C3-C8 cycloalkyl, C1-C6-chain alkyl-C(=O)-, C2-C6 alkenyl-C(=O)- are optionally substituted by 1 to 3 Substituted, wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl-, C2-C6 chain Alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl containing 5 to 14 ring atoms, C1-C6-chain alkyl-O-, C3-C8 ring Alkyl-O-, C2-C6 alkenyl-O-, C2-C6 alkynyl-O-, C3-C8 cycloalkenyl-O-, C6-C14 aryl-O-, and 5 to 14 a hetero atom of the ring atom -O-;

R ^{8 is} selected from the group consisting of hydrogen, C1-C12 alkyl, C3-C8 cycloalkyl and -OC(O)-C1-C12 alkyl; wherein C1-C12 alkyl, C3-C8 cycloalkyl and The OC(O)-C1-C12 alkyl group is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of a hydroxyl group, a halogen, a cyano group, an amino group, a carboxyl group, and a C1-C6 alkyl group. , C3-C8 cycloalkyl, C2-C6 alkenyl-, C2-C6 alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, containing 5 to 14 rings Atomic heteroaryl, C1-C6-chain alkyl-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyl-O-, C2-C6 alkynyl-O-, C3-C8 ring Alkenyl-O-, C6-C14 aryl-O-, and heteroaryl-O- having 5 to 14 ring atoms;

X is an oxygen atom or a sulfur atom or NH.

In some preferred embodiments of the invention, in Formula I, R ¹ and R ^{2 are} independently selected from cyano, amino, unsubstituted C1-C6 alkyl; or R ¹ and R ² are taken together An optionally substituted cycloalkane or heterocycloalkane ring containing from 3 to 8 ring atoms.

In some preferred embodiments of the invention, in Formula I, R ¹ and R ^{2 are} independently selected from methyl, ethyl; or R ¹ and R ^{2 taken} together to form a cyclopropane ring, a cyclobutane ring. , a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a tetrahydrofuran ring or a tetrahydropyran ring, or a ring substituted with a methyl group.

In some preferred embodiments of the invention, in Formula I, R ³ , R ⁴ and R ^{5 are} independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, C1-C6 alkyl, C6. a C14 aryl group, a C3-C8 cycloalkyl group, a C1-C6 alkyl group-O-, a heteroaryl group having 5 to 14 ring atoms; wherein the above C1-C6 alkyl group, C6-C14 aryl group a C3-C8 cycloalkyl group, a C1-C6 alkyl-O- group, an amino group, optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of a hydroxyl group, a halogen, a cyano group, an amino group, Carboxyl, C6-C14 aryl and C1-C6 alkyl.

In some preferred embodiments of the invention, in Formula I, R ³ , R ⁴ and R ^{5 are} independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, methyl, ethyl, propyl. , butyl, phenyl, benzyl, tolyl, methoxyphenyl, chlorophenyl, fluorophenyl, bromophenyl, dimethoxyphenyl, dichlorophenyl, difluorophenyl, dibromophenyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and pyridyl.

In some preferred embodiments of the invention, in Formula I, R ⁶ and R ^{6' are} independently selected from hydrogen, unsubstituted C1-C6 alkyl, unsubstituted C3-C8 cycloalkyl, and 1- 3 halogen-substituted C1-C6-chain alkyl groups.

In some preferred embodiments of the invention, in Formula I, R ⁶ and R ^{6' are} independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, cyclopropyl, and cyclobutyl.

In some preferred embodiments of the invention, in Formula I, R ^{7 is} selected from the group consisting of hydrogen, unsubstituted C1-C6 alkyl, unsubstituted C1-C6 alkyl-C(=O)-, and Unsubstituted C2-C6 alkenyl-C(=O)-.

In some preferred embodiments of the present invention, in formula I, R ⁷ is selected from hydrogen, methyl, ethyl, formyl and acetyl.

In some preferred embodiments of the invention, in Formula I, R ^{8 is} selected from the group consisting of hydrogen, C1-C6 alkyl, and -OC(O)-C1-C12 alkyl; wherein C1-C6 alkane And the -OC(O)-C1-C12 alkyl group are optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1- C6 alkyl and C1-C6 alkyl-O-.

In some preferred embodiments of the invention, in Formula I, R ^{8 is} selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, formyloxy, acetoxy, propionyloxy Base, butyryloxy and valeryloxy.

In some preferred embodiments of the invention, in Formula I, R ¹ and R ^{2 are} independently selected from methyl, ethyl, or R ¹ and R ^{2 taken} together to form a cyclopropane ring, a cyclobutane ring. a cyclopentane ring, a cyclohexane ring, or a methyl substituted ring; R ³ , R ⁴ and R ^{5 are} independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, propyl, butyl, and ring. hexyl group, a phenyl group, and said groups substituted by halogen or methyl or methoxy group; R ⁶ and R ^{6 'are} independently selected from hydrogen, methyl, ethyl, propyl, butyl; R ⁷ is selected from From hydrogen, methyl, ethyl; R ^{8 is} selected from hydrogen, methyl, ethyl, propyl, butyl; X is an oxygen atom.

In the various preferred embodiments above, the preferred options for each substituent may be combined with one another, and various combinations thereof are within the scope of the invention.

In a most preferred embodiment of the invention, the compound of formula I is each specific compound shown in Examples 1 to 17 herein.

As used herein, "a compound of formula I" or "a compound of formula I" or "a compound of the invention" also encompasses any optical isomer, geometric isomer, tautomer of a compound of formula I. Or a mixture of isomers.

The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center may have an R configuration or an S configuration, and the various isomers thus constituted are optically different. Structure. Optical isomers include all diastereomers, enantiomers, meso forms, racemates or mixtures thereof. For example, optical isomers can be separated by chiral chromatography or by chiral synthesis.

The term "geometric isomer" means that when a double bond is present in a compound, the compound may exist as a cis isomer, a trans isomer, an E isomer, and a Z isomer. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers, or mixtures thereof.

The term "tautomer" refers to an isomer that is produced by the rapid movement of an atom in a molecule at two positions. Those skilled in the art will appreciate that tautomers can transition to each other and coexist in an equilibrium state in a certain state. As used herein, "a compound of formula I" also encompasses any tautomer of a compound of formula I. In particular, the inventors have discovered that the compounds of formula I may have the following tautomers:

Thus, unless otherwise indicated, reference to "a compound of formula I" or "a compound of formula I" or "a compound of the invention" is also encompassed by the above formula Ia, Ib, Ic, or Id. compound of. Likewise, a particular compound represented by a particular structural formula in any of the embodiments herein also includes tautomers thereof in the form of I-a, I-b, I-c, or I-d.

Unless otherwise indicated, reference herein to "a compound of formula I" or "a compound of formula I" or "a compound of the invention" also encompasses isotopes obtained by substituting any of the atoms of the compound with their isotopic atoms. Label the compound.

The invention includes all pharmaceutically acceptable isotopically-labeled compounds of the formula I wherein one or more atoms are held by atoms having the same atomic number but different atomic mass or mass number than those normally found in nature. replace.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as ² H(D) and ³ H(T), isotopes of carbon such as ¹¹ C, ¹³ C and ¹⁴ C, isotopes of chlorine, such as ³⁶ Cl, an isotopes of fluorine, such as ¹⁸ F, isotopes of iodine, such as ¹²³ I and ¹²⁵ I, isotopes of nitrogen, such as ¹³ N and ¹⁵ N, isotopes of oxygen, such as ¹⁵ O, ¹⁷ O and ¹⁸ O, and sulfur Isotope, such as ³⁵ S.

Certain isotopically-labeled compounds of Formula I (such as those containing radioisotopes) are useful in drug and/or substrate tissue distribution studies. The radioisotope ruthenium (i.e., ² H) and carbon-14 (i.e., ¹⁴ C) are particularly useful for this purpose in view of ease of introduction and convenience of detection means.

Substitution with heavier isotopes such as deuterium (i.e., ² H) may provide certain therapeutic benefits and may therefore be preferred in certain circumstances, the therapeutic benefit being enhanced by greater metabolic stability ( For example, increased in vivo half-life or reduced dose requirements).

Substitution with positron-emitting radioisotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N can be used in Positron Emission Topography (PET) studies to detect substrate receptor occupancy.

Isotopically labeled compounds of Formula I can generally be substituted for previously described non-labeled reagents by conventional techniques known to those skilled in the art or by the use of suitable isotopically labeled reagents, similar to the methods described in the Examples and Preparations Attached herein. , to prepare.

Certain compounds of the invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, the compounds of formula I, whether present in solvated form or in unsolvated form, are included within the scope of the invention.

Certain compounds of the invention may exist in different crystalline or amorphous forms, and in any form, the compounds of Formula I are included within the scope of the invention.

To avoid ambiguity, the definitions of the terms used herein are given below. Unless otherwise stated, the meanings of the terms used herein are as follows.

The term "hydroxy" refers to -OH.

The term "halogen" or "halo" means -F, -Cl, -Br, or -I.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "carboxy" refers to -C(=O)OH.

The term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in the group are independently replaced by a corresponding number of substituents.

The term "independently" means that when the number of substituents exceeds one, these substituents may be the same or different.

The term "optional" or "optionally" means that the event described therein may or may not occur. For example, a group "optionally substituted" means that the group may be unsubstituted or substituted.

The term "heteroatom" as used herein denotes oxygen (O), nitrogen (N), or S(O) _m (wherein m may be 0, 1 or 2, ie a sulfur atom S, or a sulfoxide group SO, or a sulfonyl group S (O) ₂ ).

The term "alkyl" refers to a group formed by a saturated hydrocarbon consisting solely of two elements, C and H, after losing a hydrogen atom at any carbon atom. The "alkyl group" described herein includes an alkyl group such as a linear alkyl group and a branched alkyl group; and a cycloalkyl group such as a monocyclic alkyl group, a spirocycloalkyl group, a fused cycloalkyl group, and a bridged cycloalkyl group. The alkyl group may be unsubstituted or substituted.

"Alkyl" as used herein includes an optionally substituted alkenyl group which preferably has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms, and most preferably from 1 to 6 carbon atoms; for example, Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, chloromethyl, fluoroethyl, trifluoromethyl or 1,1,1-trifluoroethyl and the like.

"Alkyl" as used herein also includes optionally substituted cycloalkyl (eg, C3-C20 cycloalkyl or C3-C12 cycloalkyl or C3-C8 cycloalkyl), for example, cyclopropyl, cyclobutene , cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalinyl, norbornyl, adamantyl, fluorocyclopropyl, 2-iodocyclobutyl, 2,3-dimethyl Cyclopentyl, 2,2-dimethoxycyclohexyl and 3-phenylcyclopentyl and the like.

"C1-C6-chain alkyl", also known as "lower-chain alkyl", refers to a subset of alkyl groups which refers to straight-chain alkyl groups and branched-chain alkyl groups having from 1 to 6 carbon atoms, including, for example, Base, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.

The "alkyl" group described herein is optionally substituted by one or more substituents, wherein the substituents are independently selected from halo, cyano, nitro (-NO ₂ ), hydroxy, amino, carboxy, acyl. , alkyl, heterocyclic, alkenyl, alkynyl, aryl, heteroaryl, =O, =S, -SH, R ¹⁶ O-, R ¹⁶ S-, R ¹⁶ (O=)S-, R ¹⁶ (O=) ₂ S-, wherein R ¹⁶ is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl.

Preferably, the "alkyl" group described herein is optionally substituted with from 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, halo, nitro, cyano, amino, carboxy, C1-C6. Alkenyl, C3-C8 cycloalkyl, C2-C6 alkenyl-, C2-C6 alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, containing 5 to 14 ring atom heteroaryl, C1-C6 chain alkyl-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyl-O-, C2-C6 alkynyl-O-, C3 -C8 cycloalkenyl-O-, C6-C14 aryl-O-, heteroaryl-O-, C1-C6-chain alkyl-S-, C3-C8 cycloalkyl-containing 5 to 14 ring atoms S-, C2-C6 alkenyl-S-, C2-C6 alkynyl-S-, C3-C8 cycloalkenyl-S-, C6-C14 aryl-S-, having 5 to 14 ring atoms Heteroaryl-S-, heterocycloalkyl group having 3 to 8 ring atoms, heterocycloalkenyl group having 3 to 8 ring atoms, =O, =S, -SH, -CF ₃ , -CO ₂ C _1- C ₆ alkyl, C1-C6 alkyl-S-, C1-C6 alkyl (O=)S- and C1-C6 alkyl (O=) ₂ S-.

The term "alkenyl" refers to any hydrocarbon which consists of only two elements, C and H, and which contains one or more carbon-carbon double bonds but no carbon-carbon triple bonds or aromatic bonds, loses one hydrogen at any carbon atom. A group formed after an atom. The "alkenyl group" as used herein includes alkenyl groups such as linear alkenyl groups and branched alkenyl groups; and includes cyclic alkenes such as monocycloalkenyl groups, spirocycloalkenyl groups, fused cycloalkenyl groups and bridged cycloalkenyl groups. The alkenyl group may be unsubstituted or substituted.

"Alkenyl" as used herein includes an alkenyl group which is optionally substituted, preferably having from 2 to 20 carbon atoms, more preferably from 2 to 12 carbon atoms, most preferably from 2 to 6 carbon atoms; for example, ethylene Base, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, isohexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octene Base, 4-octenyl, 1-decenyl, 1-decenyl, 1-undecylalkenyl, 1-dodecylalkenyl, and the like.

The term "alkenyl" as used herein also includes optionally substituted cycloalkenyl (eg, C3-C20 cycloalkenyl or C3-C12 cycloalkenyl or C3-C8 cycloalkenyl), eg, cyclobutenyl, Cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cycloheptatriene, and the like.

The "alkenyl" groups described herein are optionally substituted by one or more (e.g., 1-3) substituents, wherein the substituents are selected and preferred in the same range as the substituents of the "alkyl" group.

The term "alkynyl" refers to a group formed by a hydrocarbon composed of only two elements, C and H, and having one or more carbon-carbon triple bonds but no aromatic bonds, which is formed after any hydrogen atom loses one hydrogen atom. group. "Alkynyl" as used herein includes alkynyl groups such as straight-chain alkynyl, branched alkynyl, and the like, and includes cycloalkynyl groups such as monocycloalkynyl, spirocycloalkynyl, fused cycloalkynyl, and bridged alkynyl. An alkynyl group can optionally contain one or more carbon-carbon double bonds. The alkynyl group may be unsubstituted or substituted.

As used herein, "alkynyl" includes an alkynyl group which is optionally substituted, preferably having from 2 to 20 carbon atoms, more preferably from 2 to 12 carbon atoms, most preferably from 2 to 6 carbon atoms; for example, acetylene , propynyl, 1-butynyl, 2-butynyl, isobutynyl, 1-pentynyl, 2-pentynyl, isopenynyl, 3-methyl-3-butynyl , 1-hexynyl, 2-hexynyl, 3-hexynyl, 3-heptynyl, 1-octynyl, 1-decynyl, 1-decynyl, 1-undecynyl , 1-dodecylalkynyl and the like.

The term "alkynyl" as used herein also includes optionally substituted cycloalkynyl (eg, C8-C18 cycloalkynyl), eg, cyclooctynyl, and the like.

The "alkynyl" groups described herein are optionally substituted by one or more (e.g., 1-3) substituents, wherein the substituents are selected and preferred in the same range as the substituents of the "alkyl" group.

The term "heterocyclyl" refers to a monocyclic or polycyclic compound substituent which is saturated or contains a carbon-carbon double bond or a carbon-carbon triple bond; it contains 3 to 20 ring atoms (preferably 3 to 12 ring atoms, more preferably 3 to 8 ring atoms), wherein one or more ring atoms are selected from heteroatoms, and the remaining ring atoms are carbon; any one of the rings has no aromaticity. "Heterocyclyl" as used herein also includes spiroheterocyclyl, fused heterocyclyl and bridged heterocyclyl. The heterocyclic group may be unsubstituted or substituted. The heterocyclic group may be a heterocycloalkyl group, a heterocycloalkenyl group or a heterocyclic alkynyl group. Examples of suitable monocyclic heterocycles include, but are not limited to, piperidinyl, pyrrolidinyl, piperazinyl, azetidinyl, azacyclopropyl, morpholinyl, thietanyl, oxa Cyclopentyl (tetrahydrofuranyl), oxacyclohexyl (tetrahydropyranyl) and the like.

It will be understood that the "heterocyclyl" described herein is optionally substituted by one or more (e.g., one to three) substituents, wherein the substituents are selected and preferred in the same range as the "alkyl" substituents.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic group having a conjugated pi-electron system. The aryl ring may be a heteroaromatic ring, a heterocyclic ring, a cycloalkane, a spirocycloalkane, a condensed naphthenic ring, a bridged cycloalkane, a cycloalkenylene, a spirocycloalkene, a fused ringene, a bridged cycloalkene, a cycloalkyne, a spirocycloalkyne, a thick The cycloalkyne or bridged cycloalkyne is fused. The aryl group may be unsubstituted or substituted. Examples include, but are not limited to, phenyl, naphthyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, methoxyphenyl (eg 2-methoxyphenyl, 3 -methoxyphenyl, 4-methoxyphenyl), chlorophenyl (such as 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl), fluorophenyl (such as 2-fluorophenyl) , 3-fluorophenyl, 4-fluorophenyl), bromophenyl (such as 2-bromophenyl, 3-bromophenyl, 4-bromophenyl), 2-chloro-3-methylphenyl, 2 -Chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 3-chloro-2-methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-2-methyl Phenylphenyl, 4-chloro-3-methylphenyl, 5-chloro-2-methylphenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichloro Phenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, and the like.

The "aryl" groups described herein are optionally substituted with from 1 to 4 or from 1 to 3 substituents, wherein the substituents are selected and preferred in the same range as the substituents of the "alkyl" group.

The term "heteroaryl" refers to an aromatic system containing from 5 to 18 ring atoms, preferably from 5 to 14 ring atoms, and wherein one to four ring atoms are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. Heteroaryl can be combined with an aromatic ring, a heterocyclic ring, a cycloalkane, a spirocycloalkane, a condensed cycloalkane, a bridged cycloalkane, a cycloalkenene, a spirocycloalkene, a condensed cycloalkene, a bridged alkene, a cycloalkyne, a spirocyclic alkyne, or a thick The cycloalkyne or bridged cycloalkyne is fused. It may be unsubstituted or substituted. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, pyrazinyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, Benzooxazolyl, benzimidazolyl, indenyl, quinolyl, isoquinolyl and quinazolinyl, and the like.

The "heteroaryl" groups described herein are optionally substituted with from 1 to 4 or from 1 to 3 substituents, wherein the substituents are selected and preferred in the same range as the substituents of the "alkyl" group.

The term "acyl" as used herein refers to RC(=O)-, wherein R is C1-C18 (preferably C1-C12, more preferably C1-C6)alkyl. Examples of "acyl" include, but are not limited to, formyl, acetyl, benzoyl, nicotinyl, propionyl, isobutyryl, oxalyl, and the like.

The acyl group RC(=O)- is optionally substituted by one or more (e.g., 1-3) substituents, wherein the substituents are selected and preferred in the same range as the substituent of the "alkyl group".

The term "ringing" as used herein means a cyclic structure such as a cycloalkane ring, a cycloalkene ring, a cycloalkyne ring, an aromatic ring, a heterocycloalkane ring, a heterocyclic alkene ring, a heterocyclic alkyne ring, a heteroaryl ring or the like. The cyclic structure may be a monocyclic, bicyclic or polycyclic structure including its fused ring, bridged ring, and spiro ring structure. Particularly, the ring formed by the substituents R ¹ and R ² herein is preferably a 3- to 12-membered ring, particularly preferably a 3- to 12-membered cycloalkane ring, a cycloolefin ring, a heterocycloalkane ring, a heterocyclic olefin ring, and most preferably 3 Up to 8 membered cycloalkane ring, cycloolefin ring, heterocycloalkane ring, heterocyclic olefin ring, such as cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, tetrahydrofuran ring, four Hydropyran ring and the like. The ring structure is optionally substituted with one or more (e.g., 1-3) substituents, wherein the substituents are selected and preferred in the same range as the "alkyl" substituents.

Herein, the range of numbers relating to the number of substituents, the number of carbon atoms, and the number of ring atoms represents an enumeration of all integers in the range, and the range is only a simplified representation. E.g:

"1-4 substituents" means 1, 2, 3 or 4 substituents;

"1-3 substituents" means a 1, 2 or 3 substituent;

"3 to 12-membered ring" means a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-membered ring;

"3 to 8 membered ring" means a 3, 4, 5, 6, 7, or 8 membered ring;

"1-12 carbon atoms" or "C1-C12" means 1 (C1), 2 (C2), 3 (C3), 4 (C4), 5 (C5), 6 (C6) , 7 (C7), 8 (C8), 9 (C9), 10 (C10), 11 (C11) or 12 carbon atoms (C12);

"1-6 carbon atoms" or "C1-C6" means 1 (C1), 2 (C2), 3 (C3), 4 (C4), 5 (C5) or 6 carbon atoms ( C6);

"2-6 carbon atoms" or "C2-C6" means 2 (C2), 3 (C3), 4 (C4), 5 (C5) or 6 carbon atoms (C6);

"C3-C8" means 3 (C3), 4 (C4), 5 (C5), 6 (C6), 7 (C7) or 8 carbon atoms (C8);

"3 to 8 ring atoms" means 3, 4, 5, 6, 7, or 8 ring atoms.

Thus, the range of numbers associated with the number of substituents, the number of carbon atoms, and the number of ring atoms also encompasses any one of its subranges, and each subrange is also considered to be disclosed herein.

2. Application of the compounds of the invention

Applicants have found through experimentation that the compound according to the invention is a specific inhibitor of the hypoxia-inducible factor proline hydroxylase. The compounds of the present invention provide a hypoxic synergistic response to the body, which increases erythropoietin and increases hemoglobin levels by inhibiting proline hydroxylase. It has been found that the compounds according to the invention are useful for the treatment and/or prevention of diseases associated with hypoxia-inducible factor HIF, such as anemia, cardiovascular disease, diabetes, neurological diseases, etc., in particular cardiac insufficiency, coronary heart disease, angina pectoris, Myocardial infarction, stroke, arteriosclerosis, spontaneous hypertension, pulmonary hypertension, malignant hypertension, and peripheral arterial obstructive disease.

In particular, diseases of the formula I according to the invention which are suitable for the treatment and/or prevention include:

Blood-forming diseases such as idiopathic anemia, renal anemia and anemia associated with neoplastic diseases (especially chemotherapy-induced anemia), infectious diseases (especially HIV-infected diseases) or additional inflammatory diseases such as rheumatoid arthritis;

Due to blood loss anemia, iron deficiency anemia, vitamin deficiency anemia (eg due to insufficient vitamin B12 or due to lack of folic acid), cell aplastic and aplastic anemia or hemolytic anemia, or due to iron utilization disease (iron-deficient anemia) Anemia or anemia due to other endocrine diseases such as hypothyroidosis;

Surgery-related ischemia and its continuous symptoms after surgery, especially regarding cardiac intervention using cardiopulmonary machines (eg, bypass surgery, heart valve transplantation), carotid intervention, aortic intervention, and instrumentation with skull capacity Open or penetrated intervention;

Continuous symptoms of acute and prolonged cerebral ischemic conditions (eg stroke, fetal suffocation);

Damage to cancer and health conditions that occur during cancer treatment, especially in the health conditions that occur after treatment with cytostatics, antibiotics, and radiation;

Types of rheumatism and other forms of disease that are considered to be autoimmune diseases, particularly treatment and/or prevention of damage to health conditions that occur during the course of drug treatment of the disease;

Eye diseases (eg glaucoma), central nervous system diseases (eg dementia, chronic pain), chronic kidney disease, renal insufficiency and acute renal failure;

Sexual dysfunction (such as loss of libido);

Diabetes and its continuous symptoms such as diabetic macroangiopathy and microangiopathy, diabetic nephropathy and neuropathy;

Fibrotic diseases such as fibrosis of heart, lung and liver;

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, etc.;

Ischemic diseases, such as ischemic cerebrovascular disease, ischemicrenaldisease (IRD), ischemic cardiomyopathy (ICM), and the like.

Furthermore, the compounds according to the invention are also suitable for the general treatment and/or prevention of surgery, with the aim of promoting wound healing and reducing recovery time.

The compounds according to the invention are also suitable for increasing the in vitro use of hematocrit in order to obtain blood for pre-operative blood autodonation.

Accordingly, another aspect of the invention relates to a compound of formula I (or a preferred compound of formula I) or a isotope-labeled compound thereof, or a isotope-labeled compound thereof, as a medicament for the treatment and/or prevention of a disease associated with a hypoxia-inducible factor, or An optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Another aspect of the invention relates to a compound of formula I (or a preferred compound of formula I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, Or the use thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, for treating and/or preventing a disease associated with hypoxia-inducible factors.

Another aspect of the invention relates to a compound of formula I (or a preferred compound of formula I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, Or a pharmaceutically acceptable salt thereof, or a prodrug thereof, for use in the preparation of a proline hydroxylase inhibitor.

Another aspect of the invention relates to a compound of formula I (or a preferred compound of formula I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, Use of a pharmaceutically acceptable salt thereof, or a prodrug thereof, for the manufacture of a medicament for the treatment and/or prevention of a disease associated with hypoxia-inducible factors.

Another aspect of the invention relates to a method of treating and/or preventing a disease associated with hypoxia-inducible factor HIF, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I (or preferred formula I) a compound) or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Another aspect of the invention relates to a method of treating and/or preventing a disease associated with hypoxia-inducible factor HIF, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising a formula a compound of I (or a preferred compound of formula I) or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or Its prodrug, and one or more pharmaceutically acceptable carriers, diluents or excipients.

Another aspect of the invention relates to a compound of formula I (or a preferred compound of formula I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, Or the use thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, for use in wound healing and/or shortening recovery time in surgery.

Another aspect of the invention relates to a compound of formula I (or a preferred compound of formula I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, Or the use thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, for the manufacture of a medicament for use in surgery to accelerate wound healing and/or reduce recovery time.

Another aspect of the invention relates to a compound of formula I (or a preferred compound of formula I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, Or a pharmaceutically acceptable salt thereof, or a prodrug thereof, for use in increasing hematocrit, which may be used for therapeutic purposes, for diagnostic purposes, or for non-therapeutic non-diagnostic purposes (eg, experimental studies only) And increase hematocrit).

Another aspect of the invention relates to a method of obtaining self-donated blood prior to surgery, the method comprising adding to a blood sample a compound of formula I (or a preferred compound of formula I) or an isotopically labeled compound thereof, or an optically different thereof A conformation, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

As used herein, the term "patient" means all mammals, and includes humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, rats, pigs, and rabbits.

As used herein, the term "disease associated with hypoxia-inducible factors" includes, but is not limited to, anemia (eg, idiopathic anemia, renal anemia, anemia associated with neoplastic disease (especially chemotherapy-induced anemia), caused by blood loss Anemia, iron deficiency anemia, vitamin deficiency anemia, cell ablation and aplastic anemia, hemolytic anemia, iron-deficient anemia, anemia caused by hypothyroidism, etc.), cardiovascular disease (eg, cardiac insufficiency, Coronary heart disease, angina pectoris, myocardial infarction, stroke, arteriosclerosis, spontaneous hypertension, pulmonary hypertension, malignant hypertension, and peripheral arterial obstructive disease), neurological disease, HIV infection, rheumatoid arthritis, local surgery-related defects Blood, fetal suffocation, cancer and cancer-related symptoms (such as damage to health conditions after treatment with cytostatics, antibiotics, and radiation), eye diseases (such as glaucoma), central nervous system diseases (such as dementia, chronic pain) , chronic kidney disease, renal insufficiency and acute renal failure, sexual dysfunction (such as loss of libido), diabetes and complications (eg Such as diabetic macroangiopathy and microvascular disease, diabetic nephropathy), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, etc.), ischemic diseases (such as ischemic cerebrovascular disease, ischemic nephropathy) , ischemic cardiomyopathy, etc.) and fibrotic diseases (such as fibrosis of heart, lung and liver).

Preferably, "a disease associated with hypoxia-inducible factor" refers to anemia, including but not limited to, idiopathic anemia, renal anemia, anemia associated with neoplastic disease (especially chemotherapy-induced anemia), anemia caused by blood loss, Iron deficiency anemia, vitamin deficiency anemia, cytomegaloosis and aplastic anemia, hemolytic anemia, iron loss of anemia, anemia caused by hypothyroidism, etc.; neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, etc.; ischemic diseases (eg, ischemic cerebrovascular disease, ischemic nephropathy, ischemic cardiomyopathy, etc.) and fibrotic diseases (eg, fibrosis of heart, lung, and liver).

A "pharmaceutically acceptable salt" of a compound of formula I as described herein refers to a mineral acid and an organic acid addition salt or an organic base of the compound suitable for use in mammals (ie, safe and effective when applied). Inorganic base addition salt. These salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the free form of the pure compound with a suitable organic or inorganic acid or base and separating the formed salt. Typical salts include hydrobromides, hydrochlorides, sulfates, hydrogen sulfates, nitrates, acetates, oxalates, valerates, oleates, palmitates, stearates, laurates , borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, glucoheptonate, lactose Acid salt, lauryl sulfonate, and the like. These salts may include cations based on alkali metals and alkaline earth metals (eg, sodium, lithium, potassium, calcium, magnesium, etc.), as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, A salt of tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, or the like.

A "prodrug" of a compound of formula I as described herein refers to a derivative of the compound suitable for use in mammals (ie, safe and effective when applied), which releases Formula I in vivo after use. a compound or a pharmaceutically acceptable salt thereof. Examples of prodrugs include amino acid addition salts, esters, amides and the like.

3. Pharmaceutical compositions and pharmaceutical dosage forms containing the compounds of the invention

For therapeutic use, the compounds of formula I are typically administered to a patient in the form of a pharmaceutical composition comprising at least one of the above compounds as an active ingredient, optionally including pharmaceutically acceptable adjuvants and/or excipients And a pharmaceutically acceptable solid or liquid carrier.

Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula I (or a preferred compound of formula I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer thereof, tautomer thereof A mixture or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

The present invention also relates to a process for the preparation of the above pharmaceutical composition comprising the compound of formula I (or a preferred compound of formula I) or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer The construct or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, is admixed with a pharmaceutically acceptable carrier, adjuvant or excipient.

The pharmaceutical composition of the present invention can be formulated into a dosage form suitable for oral, parenteral (including subcutaneous, intramuscular, cortical and intravenous) administration, bronchial administration or nasal administration, as needed. Thus, if a solid carrier is employed, the preparation may be tableted, placed in the form of a powder or granules in a hard gelatin capsule, or in the form of a lozenge or lozenge. The solid carrier can include conventional excipients such as binders, fillers, tableting lubricants, disintegrating agents, wetting agents, and the like. The tablet can be coated by conventional techniques if desired. If a liquid carrier is used, the preparation may be in the form of a syrup, an emulsion, a soft gel capsule, a sterile carrier for injection, an aqueous or nonaqueous liquid suspension, or may be reconstituted with water or other suitable vehicle before use. Dry goods. The liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, nonaqueous vehicles (including edible oils), preservatives, and flavoring and/or coloring agents. For parenteral administration, usually the carrier comprises at least a large part of sterile water, but a saline solution, a glucose solution or the like can also be used. Injectable suspensions may also be employed, in which case conventional suspending agents may be employed. Conventional preservatives, buffering agents and the like can also be added to parenteral dosage forms. The pharmaceutical compositions are prepared by conventional techniques which are suitable for the preparation of the preparation containing the active ingredient (i.e., a compound of formula I of the invention).

Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for use in sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous vehicles, diluents, solvents include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (eg, olive oil), and injectables Organic ester (for example, ethyl oleate).

These compositions may also contain various excipients such as preservatives, wetting agents, emulsifying agents and dispersing agents. Inhibition of the action of microorganisms can be ensured by various antibacterial and antifungal agents (for example, parabens, chlorobutanol, phenol, sorbic acid, etc.). Isotonic agents, for example, sugars, sodium chloride, and the like, may also be included. Prolonged absorption of the injectable pharmaceutical dosage form can be brought about by the use of delayed absorption agents (for example, aluminum monostearate and gel).

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such a solid dosage form, the active compound is mixed with at least one inert excipient (or carrier) (for example, sodium citrate or dicalcium phosphate), which may also include: (a) a filler or a mixture (for example, (b) binder (eg, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic); (c) a humectant (eg, glycerol); (d) a disintegrant (eg, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) a solution a retarder (for example, paraffin); (f) an absorption enhancer (for example, a quaternary ammonium compound); (g) a wetting agent (for example, cetyl alcohol and glyceryl monostearate); (h) adsorption Agents (for example, kaolin and bentonite) and (i) lubricants (for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate) or mixtures thereof.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gel capsules using, for example, lactose and high molecular weight polyethylene glycols as excipients.

Solid dosage forms (e.g., tablets, dragees, capsules, pills, and granules) can be prepared with coatings and shells (e.g., enteric coatings and others known in the art). They may contain opacifying agents, which may also be a combination of active compounds or active compounds in a certain portion of the intestinal tract in a delayed manner. Examples of useful embedding compositions are polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents (for example, water or other solvents), solubilizers and emulsifiers commonly used in the art (for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzene) Methanol, benzyl benzoate, propylene glycol, 1,3 butanediol, dimethylformamide), oil (specifically, cottonseed oil, groundnut oil, corn oil, olive oil, castor oil, sesame oil), C Fatty acid esters of triols, tetrahydrofuranol, polyethylene glycol, and sorbitan, or mixtures of these, and the like.

In addition to these inert diluents, the compositions may also include, for example, wetting agents, emulsifying and suspending agents, flavoring agents, flavoring agents, and perfuming agents.

In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline fibers, aluminum metahydroxide, bentonite, agar-agar and Astragalus gum or a mixture of these substances, and the like.

Dosage forms for topical administration of the compounds of the invention include ointments, powders, sprays and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any required preservative, buffer or propellant. Ophthalmic formulations, eye ointments, powders and solutions are also included within the scope of the invention.

The amount of the compound of formula I in the pharmaceutical compositions and dosage forms can be suitably determined by those skilled in the art as needed, for example, a compound of formula I can be present in a pharmaceutical composition or dosage form in a therapeutically effective amount.

4. Dose of the compound of the invention

As used herein, the term "therapeutically effective amount" is an amount that, when administered to a patient, effectively delays or eliminates the symptoms of the patient or improves the health of the patient. The specific application dose can be determined by the doctor according to the specific circumstances of the patient. The precise dose to be used depends not only on the route of administration, the condition, the severity of the condition to be treated, and the various physical factors associated with the subject being treated, but can also be determined in accordance with the judgment of the health care practitioner. In vitro or in vivo tests can be used to help determine the optimal dosage range.

For example, a compound of formula I of the invention may be administered to a patient at a dose of from about 0.01 to 4000 mg (or 0.05 to 2000 mg, or 0.1 to 1000 mg, or 0.1 to 500 mg) per day. For an adult having a normal body weight of about 70 kilograms, the dosage can be, for example, from about 0.001 to about 100 mg per kilogram of body weight per day or from 0.01 to about 100 mg per kilogram of body weight or from 0.05 to about 50 mg per kilogram of body weight. However, the particular dosage used can vary. It is known to those skilled in the art how to determine the optimal dose for a particular patient.

The above daily dose may be administered continuously continuously, for example every 2 hours, every 6 hours, every 8 hours, every 12 hours, about every 24 hours, or every 2 days, every day, every week, every two weeks. Apply once every three weeks and every month. The dose and frequency corresponding to the entire course of treatment will be determined based on the judgment of the health care practitioner. In one embodiment, a compound of the invention, or a pharmaceutically acceptable salt thereof, is administered concurrently with another therapeutic agent.

In one embodiment, a composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an effective amount of another therapeutic agent in the same composition can be administered. Effective amounts of other therapeutic agents are known to those skilled in the art. Moreover, the range of determining the optimal effective amount of other therapeutic agents is within the skill of the artisan.

5. Method for preparing the compound of the present invention

The compounds of formula I of the present invention can be synthesized by a variety of methods familiar to those skilled in the art of organic synthesis. Some exemplary synthetic methods are given below which are well known in the art of synthetic chemistry. The compounds of formula I are synthesized according to the methods described below, as well as the methods commonly employed by organic synthetic chemists and combinations or variations of such methods. The synthetic route of the compounds in the present invention is not limited to the methods summarized below. Individual compounds may require adjustment of the operating conditions to meet the requirements of various functional groups. Various protecting groups known to those skilled in the art may be necessary. Purification can be accomplished, if desired, by silica gel column elution with a suitable organic solvent system or by recrystallization. In addition, various specific examples herein also illustrate methods of synthesizing the compounds of the invention.

The compounds of the present invention are mainly synthesized by the following technical scheme.

The alkylation reaction of the R ³ group-substituted acetoacetate starting material (I-0) under basic conditions gives the intermediate I-1. Intermediate I-1 is then disubstituted under basic conditions (in some embodiments the disubstituted group can be cyclized) to give intermediate I-2. Intermediate I-2 is reacted with ammonium acetate under acidic medium to form pyrrole intermediate I-3; the preferred acidic medium is acetic acid; the reaction temperature is from room temperature to reflux of the acidic medium; the preferred reaction temperature is from 80 ° C to the reflux temperature of acetic acid. The pyrrole intermediate I-3 is hydrolyzed by a three-step reaction strong base (such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.) to obtain a carboxylic acid, and the obtained carboxylic acid is further reacted with HOBT and DCC to obtain an HOBT activated ester, and finally an activated ester. The tricarbonyl intermediate I-4 is obtained with sodium malonate (prepared by reaction of malonic acid ester with NaH). The tricarbonyl intermediate I-4 is treated with a base to give the ring closure product I-5; the preferred base is sodium methoxide. I-5 is finally heated with an amino acid under basic conditions to give Example Compound IX; the preferred base is sodium methoxide, preferably at a methanol reflux temperature.

(above, base represents alkali, malonate represents malonate)

The above shows a typical synthesis method of the IX compound as a representative example of the compound of the formula I, and those skilled in the art understand that the substitution with the IX compound can be obtained by appropriately selecting different reactants, using the same or similar synthetic methods. Other compounds of formula I are different.

In addition, the specific reaction conditions of the respective steps in the above respective synthesis schemes can be appropriately determined by those skilled in the art in accordance with the principles and requirements of conventional chemical reactions. And the reaction conditions given in the following examples of the invention can be referred to.

Specific embodiment

The invention is further illustrated by the following examples; however, these examples do not limit the scope of the invention.

The structure of the compound is determined by liquid chromatography-mass spectrometry (LCMS) or nuclear magnetic resonance (NMR). The NMR chemical shift (δ) is expressed in units of 10 ^-6 (ppm). The nuclear magnetic force was measured by a Bruker-500 nuclear magnetic resonance apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl ₃ ), etc., and the internal standard was tetramethylsilane (TMS). LCMS was determined using Shimadzu LCMS-2020.

Thin-layer chromatography silica gel plates were used in Yantai Yellow Sea HSGF254 in Shandong Province or Qingdao GF254 silica gel plate in Shandong Province. Column chromatography generally uses 200 to 300 mesh silica gel of Yantai Huanghai silica gel in Shandong Province as a carrier.

All of the starting materials used in the present invention are purchased from chemical suppliers or can be synthesized by literature methods.

The abbreviations used in the description of this article are as follows:

DMSO-d6: dimethyl sulfoxide in which six hydrogen atoms are replaced by deuterium

CDCl ₃ : Deuterated chloroform

CAS: Chemical Abstracts Accession Number

NMR: Nuclear Magnetic Resonance

LCMS: liquid chromatography-mass spectrometry

ESI: Electrospray ionization

Ppm: one in a million

δ: nuclear magnetic resonance chemical shift

TMS: tetramethylsilane

s: nuclear magnetic single peak

d: nuclear magnetic double peak

t: nuclear magnetic triplet

Br: nuclear magnetic broad peak

CDI: carbonyl diimidazole

DCC: N,N'-dicyclohexylcarbodiimide

HOBT: 1H-benzo[d][1,2,3]triazol-1-ol

NBS: N-bromocyclosuccinimide

Example 1

(7'-Hydroxy-5'-oxo-1'-phenyl-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl)glycine ( 1 )

first step

Ethyl 5-(1,3-dioxolan-2-yl)-3-oxo-4-phenylpentanoate ( 1b )

Ethyl 3-oxo-4-phenylbutanoate (1.03 g, prepared according to the procedure described in the literature [European Journal of Medicinal Chemistry, 2014, vol 84, 312-334]) was dissolved in anhydrous tetrahydrofuran (20 ml). The mixture was cooled in an ice water bath, and 60% pure mineral oil and sodium hydride mixed solid (200 mg) were slowly added in small portions under a nitrogen stream, and stirred for 0.5 hour; then hexamethylphosphoramide (2.7 g) and 1.6 were sequentially added. M-n-butyllithium hexane solution (3.13 ml); then 2-bromomethyl-1,3-dioxolane (840 mg) was added. The reaction was stirred at room temperature overnight. The reaction mixture was carefully poured into a saturated aqueous solution of ammonium chloride, and then extracted with ethyl acetate; the ethyl acetate layer was separated, and then washed twice with dilute aqueous sodium chloride; the desiccant was removed by filtration, filtrate was rotary evaporation on a rotary evaporator; the residue was purified by column chromatography to obtain the product 1b (870 mg). LCMS ESI (+): 293 ( M + 1) +.

Second step

Ethyl 1-(3-(1,3-dioxolan-2-yl)-2-phenylpropanoyl)cyclopentane-1-carboxylate ( 1c )

The product of the previous step, ethyl 5-(1,3-dioxolan-2-yl)-3-oxo-4-phenylpentanoate ( 1b ) (580 mg), 1,4-diiodo Butane (620 mg), anhydrous potassium carbonate (830 mg) and tetra-n-butylammonium iodide (74 mg) were combined in dimethylformamide (10 ml) and stirred at room temperature overnight. The reaction solution was diluted with water, and acidified to a pH of about 4 with 2M diluted aqueous hydrochloric acid; then extracted with ethyl acetate; ethyl acetate layer was separated, and then washed twice with dilute aqueous sodium chloride; The ethyl ester phase; the desiccant was removed by filtration, and the filtrate was evaporated to dryness on a rotary evaporator. The residue was purified by column chromatography to afford product 1c (415 mg). LCMS ESI (+): 347 ( M + 1) +.

third step

Ethyl 1-(3-phenyl-1H-pyrrol-2-yl)cyclopentane-1-carboxylate ( 1d )

The product of the previous step is 1-(3-(1,3-dioxolan-2-yl)-2-phenylpropanoyl)cyclopentane-1-carboxylic acid ethyl ester ( 1c ) (1 equivalent) and acetic acid Ammonium (6 equivalents) was mixed with acetic acid (3 vol) and stirred at reflux overnight. After cooling, the reaction solution was spin-dried as much as possible on a rotary evaporator, then diluted with water, and extracted with ethyl acetate; the ethyl acetate layer was separated, then washed twice with a dilute aqueous solution of sodium chloride; the ethyl acetate phase; drying agent was removed by filtration, filtrate was rotary evaporation on a rotary evaporator; the residue obtained was purified by column chromatography the product 1d. LCMS ESI (+): 284 ( M + 1) +.

the fourth step

Dimethyl 2-(1-(3-phenyl-1H-pyrrol-2-yl)cyclopentane-1-carbonyl)malonate ( 1e )

The product of the previous step, ethyl 1-(3-phenyl-1H-pyrrol-2-yl)cyclopentane-1-carboxylate ( 1d ) (1 equivalent) was suspended in 1/1 by volume of ethanol and water (total 10 volumes), lithium hydroxide monohydrate solid (4 equivalents) was added; the reaction was carried out at 50 ° C for 5 hours. After the reaction, it was cooled, diluted with water, and then acidified to a pH of about 4 with 2M diluted aqueous hydrochloric acid; then extracted with ethyl acetate; ethyl acetate layer was separated, then washed twice with dilute aqueous sodium chloride; The ethyl acetate phase was dried; the desiccant was removed by filtration, and the filtrate was dried on a rotary evaporator to yield residue.

The residue obtained above, 1H-benzo[d][1,2,3]triazole-1-ol (1.2 eq.) and DCC (1.2 eq.) were mixed in tetrahydrofuran (4 vol) and stirred at room temperature for 1 hour. . The solid was removed by filtration, the solid was washed with a small portion of anhydrous tetrahydrofuran, and filtrate and washings were combined.

In another reaction flask, dimethyl malonate (1.2 equivalents) was dissolved in anhydrous tetrahydrofuran (4 volumes), cooled in an ice water bath, and 60% pure mineral oil and sodium hydride mixed solid (1.2 equivalents) were carefully added under a nitrogen stream. Stir for 1 hour. The above filtrate and washings were then added to the second reaction flask; the reaction was stirred for 1 hour. Dilute with water, carefully add 2M dilute aqueous hydrochloric acid to acidify to pH 4; then extract with ethyl acetate; separate the ethyl acetate layer, then wash twice with dilute aqueous sodium chloride; The desiccant was removed by filtration and the filtrate was spun on a rotary evaporator. The residue was purified by column chromatography to afford product 1e . LCMS ESI (+): 370 ( M + 1) +.

the fifth step

7'-Hydroxy-5'-oxo-1'-phenyl-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carboxylic acid methyl ester ( 1f )

The product of the previous step is 2-(1-(3-phenyl-1H-pyrrol-2-yl)cyclopentane-1-carbonyl)malonic acid dimethyl ester ( 1e ) (1 equivalent) and 0.5M methanol Mix with sodium methanol solution (1 eq.); stir at room temperature for 5 minutes. The reaction solution was diluted with water, and acidified to a pH of about 4 with 2M diluted aqueous hydrochloric acid; then extracted with ethyl acetate; ethyl acetate layer was separated, and then washed twice with dilute aqueous sodium chloride; The ethyl ester phase; the desiccant was removed by filtration, and the filtrate was spun on a rotary evaporator; the residue was purified by column chromatography to afford product 1f . LCMS ESI (+): 338 ( M + 1) +.

Step 6

The product of the previous step, 7'-hydroxy-5'-oxo-1'-phenyl-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-formic acid methyl ester ( 1f ) (1 eq.), glycine (6 eq.) and 0.5 M sodium methoxide in methanol (5 eq.) were mixed; sifted dry; then n-propanol (5 vol) was added and refluxed for 2 hr. Cooling, the reaction was diluted with water, acidified with careful addition of 2M aqueous hydrochloric acid to about pH 4 with dilute; solid was precipitated; the solid was collected by filtration, the solid washed with water; and then dried to give the product 1. LCMS ESI (+): 381 ( M + 1) +.

Example 2

(1'-(4-Fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl) Glycine ( 2 )

first step

Ethyl 5-(1,3-dioxolan-2-yl)-4-(4-fluorophenyl)-3-oxopentanoate ( 2b )

Compound 2b was prepared according to the synthesis method of the first step 1b of Example 1, wherein the starting material 2a : ethyl 4-(4-fluorophenyl)-3-oxobutanoate according to the literature [European Journal of Medicinal Chemistry, 2014, vol 84, 312-334] prepared by the method. LCMS ESI (+): 311 ( M + 1) +.

Second step

Ethyl 1-(3-(1,3-dioxolan-2-yl)-2-(4-fluorophenyl)propanoyl)cyclopentane-1-carboxylate ( 2c )

Compound 2c was prepared from compound 2b according to the synthetic procedure of the second step 1c of Example 1. LCMS ESI (+): 365 ( M + 1) +.

third step

Ethyl 1-(3-(4-fluorophenyl)-1H-pyrrole0-2-yl)cyclopentane-1-carboxylate ( 2d )

Compound 2d was prepared from Compound 2c according to the synthesis method of the third step 1d of Example 1. LCMS ESI (+): 302 ( M + 1) +.

the fourth step

Dimethyl 2-(1-(3-(4-fluorophenyl)-1H-pyrrol-2-yl)cyclopentane-1-carbonyl)malonate ( 2e )

Compound 2e was prepared from Compound 2d according to the synthetic procedure of Example 4, Step 1e . LCMS ESI (+): 388 ( M + 1) +.

the fifth step

1'-(4-Fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-formic acid methyl ester ( 2f )

Compound 2f was prepared from Compound 2e according to the synthesis method of the fifth step 1f of Example 1. LCMS ESI (+): 356 ( M + 1) +.

Step 6

(7'-Hydroxy-5'-oxo-1'-phenyl-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl)glycine ( 2 )

Compound 2 was prepared from Compound 2f in accordance with the sixth synthetic method of step 1 of Example 1. LCMS ESI (+): 399 ( M + 1) +.

Example 3

(1'-(4-Fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl) Glycine ethyl ester ( 3 )

Compound 2 (1 eq.) was suspended in ethanol (5 vol), and dichloromethane (4 eq.) was carefully added dropwise; then refluxed until the reaction was completed. It was naturally cooled to room temperature and then cooled with an ice water bath, and the solid was collected by filtration and washed with cold ethanol to give Compound 3 . LCMS ESI (+): 427 ( M + 1) +.

Example 4

(1'-(4-Fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl) -L-alanine ( 4 )

Method 4 Synthesis of Compound 1 Step 1, the sixth compound was prepared from L- Alanine and 2f in accordance with embodiments. LCMS ESI (+): 413 ( M + 1) +.

Example 5

(1'-(4-Fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl) -D-alanine ( 5 )

Compound 5 was synthesized following the method of Example 1 Step 1 of the sixth embodiment and 2f compound was prepared from D- alanine. LCMS ESI (+): 413 ( M + 1) +.

Example 6

(1'-(4-Chlorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl) Glycine ( 6 )

first step

Ethyl 5-(1,3-dioxolan-2-yl)-4-(4-chlorophenyl)-3-oxopentanoate ( 6b )

Compound 6b was prepared according to the synthesis of the first step 1b of Example 1, wherein the starting material 6a : ethyl 4-(4-chlorophenyl)-3-oxobutanoate according to the literature [European Journal of Medicinal Chemistry, 2014, vol 84, 312-334] prepared by the method. LCMS ESI (+): 327 ( M + 1) +.

Second step

Ethyl 1-(3-(1,3-dioxolan-2-yl)-2-(4-chlorophenyl)propanoyl)cyclopentane-1-carboxylate ( 6c )

Compound 6c was prepared from compound 6b according to the synthetic procedure of the second step 1c of Example 1. LCMS ESI (+): 381 ( M + 1) +.

third step

Ethyl 1-(3-(4-chlorophenyl)-1H-pyrrol-2-yl)cyclopentane-1-carboxylate ( 6d )

Compound 6d was prepared from compound 6c according to the synthetic procedure of the first step 1d of Example 1. LCMS ESI (+): 318 (M+1) ⁺ .

the fourth step

Dimethyl 2-(1-(3-(4-chlorophenyl)-1H-pyrrol-2-yl)cyclopentane-1-carbonyl)malonate ( 6e )

Compound 6e was prepared from Compound 6d according to the synthetic procedure of Example 4, Step 1e . LCMS ESI (+): 404 ( M + 1) +.

the fifth step

1'-(4-Chlorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-formic acid methyl ester ( 6f )

Compound 6f was prepared from compound 6e according to the synthetic procedure of the fifth step 1f of Example 1. LCMS ESI (+): 372 ( M + 1) +.

Step 6

Compound 6 in accordance with the sixth synthetic method of Example 1 Step 1, was prepared from Compound 6f embodiment. LCMS ESI (+): 415 ( M + 1) +.

Example 7

(7'-Hydroxy-1'-(4-methoxyphenyl)-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl Glycine ( 7 )

first step

Ethyl 5-(1,3-dioxolan-2-yl)-4-(4-methoxyphenyl)-3-oxopentanoate ( 7b )

Compound 7b was prepared according to the synthesis of the first step 1b of Example 1, wherein starting material 7a : ethyl 4-(4-methoxyphenyl)-3-oxobutanoate according to the literature [European Journal of Medicinal Chemistry, 2014, Vol 84, 312-334] prepared by the method described. LCMS ESI (+): 323 ( M + 1) +.

Second step

Ethyl 1-(3-(1,3-dioxolan-2-yl)-2-(4-methoxyphenyl)propanoyl)cyclopentane-1-carboxylate ( 7c )

Compound 7c was prepared from compound 7b according to the synthetic procedure of the second step 1c of Example 1. LCMS ESI (+): 377 ( M + 1) +.

third step

Ethyl 1-(3-(4-methoxyphenyl)-1H-pyrrol-2-yl)cyclopentane-1-carboxylate ( 7d )

Compound 7d was prepared from compound 7c according to the synthesis method of the third step 1d of Example 1. LCMS ESI (+): 314 ( M + 1) +.

the fourth step

Dimethyl 2-(1-(3-(4-methoxyphenyl)-1H-pyrrol-2-yl)cyclopentane-1-carbonyl)malonate ( 7e )

Compound 7e was prepared from Compound 7d according to the synthetic procedure of Example 4, Step 1e . LCMS ESI (+): 400 ( M + 1) +.

the fifth step

7'-Hydroxy-1'-(4-methoxyphenyl)-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-formic acid A Ester ( 7f )

Compound 7f was prepared from compound 7e according to the synthetic procedure of the fifth step 1f of Example 1. LCMS ESI (+): 368 ( M + 1) +.

Step 6

Compound 7 was prepared from Compound 7f accordance with a sixth step of the synthesis method of Example 1. LCMS ESI (+): 411 ( M + 1) +.

Example 8

(1'-(3,4-Difluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6' -carbonyl)glycine ( 8 )

first step

Ethyl 4-(3,4-difluorophenyl)-5-(1,3-dioxopentan-2-yl)-3-oxopentanoate ( 8b )

Compound 8b was prepared according to the synthetic method of the first step 1b of Example 1, wherein starting material 8a : ethyl 4-(3,4-difluorophenyl)-3-oxobutanoate according to the literature [European Journal of Medicinal Chemistry, 2014, vol 84, 312-334] prepared by the method described. LCMS ESI (+): 329 ( M + 1) +.

Second step

Ethyl 1-(2-(3,4-difluorophenyl)-3-(1,3-dioxolan-2-yl)propanoyl)cyclopentane-1-carboxylate ( 8c )

Compound 8c was prepared from compound 8b according to the synthetic procedure of the second step 1c of Example 1. LCMS ESI (+): 383 ( M + 1) +.

third step

Ethyl 1-(3-(3,4-difluorophenyl)-1H-pyrrol-2-yl)cyclopentane-1-carboxylate ( 8d )

Compound 8d was prepared from compound 8c according to the synthetic procedure of the third step 1d of Example 1. LCMS ESI (+): 320 ( M + 1) +.

the fourth step

Dimethyl 2-(1-(3-(3,4-difluorophenyl)-1H-pyrrol-2-yl)cyclopentane-1-carbonyl)malonate ( 8e )

Compound 8e was prepared from Compound 8d according to the synthetic procedure of Example 4, Step 1e . LCMS ESI (+): 406 ( M + 1) +.

the fifth step

1'-(3,4-Difluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'- Methyl formate ( 8f )

Compound 8f was prepared from Compound 8e according to the synthetic procedure of Example 1 Step 5f . LCMS ESI (+): 374 ( M + 1) +.

Step 6

(7'-Hydroxy-1'-(3,4-difluorophenyl)-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6' -carbonyl)glycine ( 8 )

Compound 8 was prepared from Compound 8f was synthesized following a sixth step of the method of Example 1. LCMS ESI (+): 417 ( M + 1) +.

Example 9

(7'-Hydroxy-5'-oxo-1'-phenyl-5'H-spiro[cyclohexane-1,8'-pyridazine]-6'-carbonyl)glycine ( 9 )

first step

Ethyl 1-(3-(1,3-dioxolan-2-yl)-2-phenylpropanoyl)cyclohexane-1-carboxylate ( 9c )

Compound 9c was prepared from compound 2b and 1,5- diiodopentane according to the synthetic procedure of the second step 1c of Example 1. LCMS ESI (+): 361 ( M + 1) +.

Second step

Ethyl 1-(3-phenyl-1H-pyrrol-2-yl)cyclohexane-1-carboxylate ( 9d )

Compound 9d was prepared from compound 9c according to the synthetic procedure of the third step 1d of Example 1. LCMS ESI (+): 298 ( M + 1) +.

third step

Dimethyl 2-(1-(3-phenyl-1H-pyrrol-2-yl)cyclohexane-1-carbonyl)malonate ( 9e )

Compound 9e was prepared from compound 9d according to the synthetic procedure of the first step of step 1e of Example 1. LCMS ESI (+): 384 ( M + 1) +.

the fourth step

7'-Hydroxy-5'-oxo-1'-phenyl-5'H-spiro[methylcyclo-1,8'-pyridazine]-6'-carboxylic acid methyl ester ( 9f )

Compound 9f was prepared from compound 9e according to the synthetic procedure of the fifth step 1f of Example 1. LCMS ESI (+): 352 ( M + 1) +.

the fifth step

(7'-Hydroxy-5'-oxo-1'-phenyl-5'H-spiro[cyclohexane-1,8'-pyridazine]-6'-carbonyl)glycine

( 9 )

Method 9 Synthesis of Compound 1 Step 1 Preparation VI from Compound 9f accordance with an embodiment. LCMS ESI (+): 395 ( M + 1) +.

Example 10

(1'-(4-Fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclohexane-1,8'-pyridazine]-6'-carbonyl) Glycine ( 10 )

first step

Ethyl 1-(3-(1,3-dioxolan-2-yl)-2-(4-fluorophenyl)propanoyl)cyclohexane-1-carboxylate ( 10c )

Compound 10c was prepared from compound 2b and 1,5- diiodopentane according to the synthetic procedure of the second step 1c of Example 1. LCMS ESI (+): 378 ( M + 1) +.

Second step

Ethyl 1-(3-(4-fluorophenyl)-1H-pyrrol-2-yl)cyclohexane-1-carboxylate ( 10d )

Compound 10d was prepared from compound 10c according to the synthesis of the third step 1d of Example 1. LCMS ESI (+): 316 ( M + 1) +.

third step

Dimethyl 2-(1-(3-(4-fluorophenyl)-1H-pyrrol-2-yl)cyclohexane-1-carbonyl)malonate ( 10e )

Compound 10e was prepared from Compound 10d according to the synthetic procedure of Example 4, Step 1e . LCMS ESI (+): 402 ( M + 1) +.

the fourth step

1'-(4-Fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[methyl hexane-1,8'-pyridazine]-6'-formic acid methyl ester ( 10f )

Compound 10f was prepared from Compound 10e according to the synthetic procedure of Example 1 Step 1 1f . LCMS ESI (+): 370 ( M + 1) +.

the fifth step

Compound 10 was prepared from Compound 10f was synthesized following a sixth step of the method of Example 1. LCMS ESI (+): 413 ( M + 1) +.

Example 11

(1'-(4-Chlorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclohexane-1,8'-pyridazine]-6'-carbonyl) Glycine ( 11 )

first step

Ethyl 1-(3-(1,3-dioxolan-2-yl)-2-(4-chlorophenyl)propanoyl)cyclohexane-1-carboxylate ( 11c )

Compound 11c was prepared from compound 6b and 1,5- diiodopentane according to the synthetic procedure of the second step 1c of Example 1. LCMS ESI (+): 395 ( M + 1) +.

Second step

Ethyl 1-(3-(4-chlorophenyl)-1H-pyrrol-2-yl)cyclohexane-1-carboxylate ( 11d )

Compound 11d was prepared from compound 11c according to the synthesis of the third step 1d of Example 1. LCMS ESI (+): 332 ( M + 1) +.

third step

Dimethyl 2-(1-(3-(4-chlorophenyl)-1H-pyrrol-2-yl)cyclohexane-1-carbonyl)malonate ( 11e )

Compound 11e was prepared from compound 11d according to the synthetic method of the fourth step 1e of Example 1. LCMS ESI (+): 418 ( M + 1) +.

the fourth step

1'-(4-Chlorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[methyl hexane-1,8'-pyridazine]-6'-formic acid methyl ester ( 11f )

Compound 11f was prepared from Compound 11e according to the synthetic method of the fifth step 1f of Example 1. LCMS ESI (+): 386 ( M + 1) +.

the fifth step

Compound 11 was prepared from Compound 11f was synthesized following the method of Example 1 Step 1 of the sixth. LCMS ESI (+): 429 ( M + 1) +.

Example 12

(7'-Hydroxy-1'-(4-methoxyphenyl)-5'-oxo-5'H-spiro[cyclohexane-1,8'-pyridazine]-6'-carbonyl Glycine ( 12 )

first step

Ethyl 1-(3-(1,3-dioxolan-2-yl)-2-(4-methoxyphenyl)propanoyl)cyclohexane-1-carboxylate ( 12c )

Compound 12c was prepared from compound 7b and 1,5- diiodopentane according to the synthetic procedure of the second step 1c of Example 1. LCMS ESI (+): 391 ( M + 1) +.

Second step

Ethyl 1-(3-(4-methoxyphenyl)-1H-pyrrol-2-yl)cyclohexane-1-carboxylate ( 12d )

Compound 12d was prepared from compound 12c according to the synthetic procedure of the third step 1d of Example 1. LCMS ESI (+): 328 ( M + 1) +.

third step

Dimethyl 2-(1-(3-(4-methoxyphenyl)-1H-pyrrol-2-yl)cyclohexane-1-carbonyl)malonate ( 12e )

Compound 12e was prepared from compound 12d according to the synthetic procedure of the fourth step 1e of Example 1. LCMS ESI (+): 414 ( M + 1) +.

the fourth step

7'-Hydroxy-1'-(4-methoxyphenyl)-5'-oxo-5'H-spiro[cyclohexane-1,8'-pyridazine]-6'-formic acid A Ester ( 12f )

Compound 12f was prepared from compound 12e according to the synthetic procedure of the fifth step 1f of Example 1. LCMS ESI (+): 382 ( M + 1) +.

the fifth step

Synthesis of Compound 12 The method of Example 1 Step 1 Preparation VI from Compound 12f in accordance with the embodiment. LCMS ESI (+): 425 ( M + 1) +.

Example 13

(1'-(4-Chlorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclobutane-1,8'-pyridazine]-6'-carbonyl) Glycine ( 13 )

first step

Ethyl 1-(2-(4-chlorophenyl)-3-(1,3-dioxolan-2-yl)propanoyl)cyclobutane-1-carboxylate ( 13c )

Compound 13c was prepared from compound 6b and 1,3-dibromopropane according to the synthesis procedure of the second step 1c of Example 1. LCMS ESI (+): 367 ( M + 1) +.

Second step

Ethyl 1-(3-(4-chlorophenyl)-1H-pyrrol-2-yl)cyclobutane-1-carboxylate ( 13d )

Compound 13d was prepared from compound 13c according to the synthetic method of the third step 1d of Example 1. LCMS ESI (+): 304 ( M + 1) +.

third step

Dimethyl 2-(1-(3-(4-chlorophenyl)-1H-pyrrol-2-yl)cyclobutane-1-carbonyl)malonate ( 13e )

Compound 13e was prepared from compound 13d according to the synthetic method of the first step of step 1e of Example 1. LCMS ESI (+): 390 ( M + 1) +.

the fourth step

1'-(4-Chlorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclobutane-1,8'-pyridazine]-6'-formic acid methyl ester ( 13f )

Compound 13f was prepared from compound 13e according to the synthetic procedure of the fifth step 1f of Example 1. LCMS ESI (+): 358 ( M + 1) +.

the fifth step

Compound 13 was prepared from Compound 13f was synthesized following a sixth step of the method of Example 1. LCMS ESI (+): 401 ( M + 1) +.

Example 14

(1'-Cyclohexyl-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl)glycine ( 14 )

first step

Ethyl 4-cyclohexyl-5-(1,3-dioxopentan-2-yl)-3-oxopentanoate ( 14b )

Compound 14b was prepared according to the synthesis of the first step 1b of Example 1, wherein the starting material 14a : ethyl 4-cyclohexyl-3-oxobutanoate was according to the literature [European Journal of Medicinal Chemistry, 2014, vol 84, 312-334]. Method preparation. LCMS ESI (+): 299 ( M + 1) +.

Second step

Ethyl 1-(2-cyclohexyl-3-(1,3-dioxolan-2-yl)propanoyl)cyclopentane-1-carboxylate ( 14c )

Compound 14c was prepared from compound 14b according to the synthetic procedure of the second step 1c of Example 1. LCMS ESI (+): 353 ( M + 1) +.

third step

Ethyl 1-(3-cyclohexyl-1H-pyrrol-2-yl)cyclopentane-1-carboxylate ( 14d )

Compound 14d was prepared from compound 14c according to the synthesis of the third step 1d of Example 1. LCMS ESI (+): 290 ( M + 1) +.

the fourth step

Dimethyl 2-(1-(3-cyclohexyl-1H-pyrrol-2-yl)cyclopentane-1-carbonyl)malonate ( 14e )

Compound 14e was prepared from compound 14d according to the synthetic procedure of the fourth step 1e of Example 1. LCMS ESI (+): 376 ( M + 1) +.

the fifth step

1'-Cyclohexyl-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carboxylic acid methyl ester ( 14f )

Compound 14f was prepared from compound 14e according to the synthetic procedure of the fifth step 1f of Example 1. LCMS ESI (+): 344 ( M + 1) +.

Step 6

Compound 14 was prepared from Compound 14f was synthesized following a sixth step of the method of Example 1. LCMS ESI (+): 387 ( M + 1) +.

Example 15

(1'-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl)glycine ( 15 )

first step

Ethyl 5-(1,3-dioxolan-2-yl)-3-oxopentanoate ( 15a )

Dissolve 10 g of ethyl acetoacetate in anhydrous tetrahydrofuran, cool to 0 ° C, then carefully add sodium hydride (60% mineral oil mixture, 3.07 g) in portions; after the addition, stir at room temperature for half an hour; then add six Methylphosphoramide (13.7 g), cooled to minus 78 °C, carefully added n-butyllithium in hexane (48 mL, concentration 1.6 M), then added 2-bromomethyl-1,3-dioxolane (CAS: 4360-63-8, 12.9 g). The reaction was stirred at room temperature overnight.

After completion of the reaction, the mixture was diluted with aq. EtOAc. Purification by silica gel column chromatography gave EtOAc (EtOAc) ^{1 H NMR (500MHz, DMSO-} d6) δ (ppm): 4.93-4.91 (t, 1H), 4.21-3.83 (m, 6H), 3.46 (s, 2H), 2.69-2.66 (t, 2H), 2.02 -1.99 (m, 2H), 1.29-1.27 (t, 3H).

Second step

Ethyl 1-(3-(1,3-dioxolan-2-yl)propanoyl)cyclopentane-1-carboxylate ( 15b )

Compound 15a (6.2 g), 1,4-diiodobutane (8.89 g), potassium carbonate (11.9 g) and tetra-n-butylammonium iodide (1.06 g) were mixed in DMF (62 ml), then Stir at room temperature overnight.

Subsequently, ethyl acetate (60 ml) was added, and the solid was filtered; the filtrate was collected, the filtrate was extracted with ethyl acetate and water, and the organic phase was collected, then the organic phase was washed twice with aq. filtered and concentrated to give a brown oil residue was purified by silica gel column chromatography, 15b (5.7 g). ^{1 H NMR (500MHz, DMSO-} d6) δ (ppm): 5.08-5.06 (t, 1H), 4.14-3.84 (m, 6H), 3.50 (d, 2H), 2.11 (s, 2H), 1.18-1.16 (t, 3H).

third step

Ethyl 1-(1H-pyrrol-2-yl)cyclopentane-1-carboxylate ( 15c )

Compound 15b (5.1 g) was refluxed with ammonium acetate (8.73 g) in EtOAc (EtOAc) Then, cooling, rotating and removing most of the acetic acid, extracting with ethyl acetate and water; collecting the ethyl acetate layer, washing twice with dilute aqueous sodium chloride solution, drying over anhydrous sodium sulfate, filtering, concentrating, residue Purification by silica gel column chromatography gave EtOAc (EtOAc) ^{_{1 H NMR (500MHz, CDCl 3}} ) δ (ppm): 8.54 (s, 1H), 6.76-6.06 (m, 3H), 4.18-4.14 (d, 2H), 2.46-1.72 (m, 8H), 1.25- 1.24(t, 3H).

the fourth step

1-(1H-pyrrol-2-yl)cyclopentane-1-carboxylic acid ( 15d )

Compound 15c (1.2 g) was mixed with lithium hydroxide monohydrate (1.5 g) in 20 ml of an equal volume of ethanol water and stirred at 50 ° C for 5 hours.

Subsequently, the reaction solution was cooled, ethyl acetate and water were added, and then acidified with 2M hydrochloric acid to pH 2-3. The ethyl acetate layer was separated, the ethyl acetate layer was washed twice with dilute aqueous sodium chloride and dried over anhydrous sodium sulfate, filtered and concentrated to give product 15d (1.05 g). LCMS ESI (+): 180 ( M + 1) +.

the fifth step

5'-Hydroxy-7'-oxo-7'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carboxylic acid ethyl ester ( 15f )

Compound 15d (1.05 g), HOBT hydrate (874 mg), and DCC (1.34 g) were combined in THF (20 ml) and stirred at room temperature for 1 hour; Add diethyl malonate (1.04 g) and tetrahydrofuran to another reaction flask; cool to 0 ° C, carefully add sodium hydride (260 mg; 60%, mineral oil mixture), and stir for 1 hour; The filtrate was added and stirring was continued at room temperature for 1 hour. At this point the system was a mixture of 15e and 15f ; then a small amount of sodium ethoxide in ethanol was added and stirring was continued until there was no intermediate 15e.

The reaction was then extracted with ethyl acetate and water, acidified with dilute hydrochloric acid was added; the ethyl acetate layer was collected, then washed twice with dilute aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give product 15f . ^{_{1 H NMR (500MHz, CDCl 3}} ) δ (ppm): 15.3 (s, 1H), 7.45 (br, 1H), 6.29 (br, 1H), 6.07 (br, 1H), 4.25 (m, 2H), 2.5 -1.5 (m, 8H), 1.26 (t, 3H).

Step 6

Method 15 Synthesis of Compound 1 Step VI from Compound 15f was prepared in accordance with Example 1. ^{1 H NMR (500MHz, DMSO-} d6) δ (ppm): 18.6 (s, 1H), 13.0 (s, 1H), 9.91 (br, 1H), 7.39 (br, 1H), 6.37 (br, 1H), 6.25 (s, 1H), 4.13 (d, 2H), 4.15-4.11 (2H, d, HNCH2CO), 2.32 (m, 2H), 2.1-1.7 (m, 6H). LCMS ESI (+): 305 ( M + 1) +.

Example 16

(1'-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl)-L-alanine ( 16 )

Synthesis of Compound 16 The method of preparing a sixth step from Compound 15f and L- alanine in Example 1 in accordance with embodiments. ^{1 H NMR (500MHz, DMSO-} d 6) δ13.30 (s, 1H), 10.04 (s, 1H), 7.38 (dd, J = 3.3,1.6Hz, 1H), 6.37 (t, J = 3.3Hz, 1H), 6.25 (dd, J = 3.3, 1.6 Hz, 1H), 4.52 (p, J = 7.1 Hz, 1H), 2.31 (m, 2H), 1.99 - 1.85 (m, 6H), 1.46 (d, J) = 7.2 Hz, 3H).

Example 17

(1'-7'-hydroxy-5'-oxo-5'H-spiro[cyclohexane-1,8'-pyridazine]-6'-carbonyl)glycine ( 17 )

first step

Ethyl 1-(3-(1,3-dioxolan-2-yl)propanoyl)cyclohexane-1-carboxylate ( 17b )

Compound 17b was prepared according to the synthesis of the second step 15b of Example 15 (1,5-dibromopentane was used instead of 1,4-diiodobutane, and cesium carbonate was used instead of potassium carbonate). ^{_{1 H NMR (500MHz, CDCl 3}} ) δ (ppm): 4.87-4.85 (t, 1H), 4.19-3.80 (m, 2H) ,, 2.59-2.56 (d, 2H), 2.08-1.29 (m, 10H) , 1.26-1.23 (t, 3H).

Second step

Ethyl 1-(1H-pyrrol-2-yl)cyclohexane-1-carboxylate ( 17c )

Compound 17c was prepared according to the synthesis of the third step 15c of Example 15. LCMS ESI (+): 222 ( M + 1) +.

third step

1-(1H-pyrrol-2-yl)cyclohexane-1-carboxylic acid ( 17d )

Compound 17d was prepared according to the synthesis of the fourth step 15d of Example 15. LCMS ESI (-): 192 ( M + 1) +.

the fourth step

5'-hydroxy-7'-oxo-7'H-spiro[cyclohexane-1,8'-pyridazine]-6'-carboxylic acid ester ( 17f )

Compound 17f was prepared according to the method of the synthesis of the fifth step 15f of Example 15, wherein the sodium ethoxide ethanol solution was replaced with sodium methoxide in methanol. ^{_{1 H NMR (500MHz, CDCl 3}} ) δ (ppm): 8.31 (s, 1H), 6.71 (m, 1H), 6.12 (m, 1H), 6.04 (m, 1H), 3.68 (s, 3H), 1.8 -1.2 (m, 10H), 12H).

the fifth step

Compound 17 was prepared according to the synthesis method of the sixth step 15 of Example 15 from Compound 17f . ^{1 H NMR (500MHz, DMSO-} d6) δ (ppm): 18.9 (s, 1H), 13.1 (s, 1H), 9.95 (br, 1H), 7.45 (dd, 1H), 6.52 (dd, 1H), 6.38(t,1H),1H,s,OH), 4.12 (d, J=5.5Hz, 2H), 2.1-1.95 (m, 2H), 1.8-1.6 (m, 6H), 1.5-1.4 (m, 2H). LCMS ESI (+): 319 ( M + 1) +.

Pharmacological activity evaluation

1. The effect of compounds on the activity of proline hydroxylase-2

The determination of proline hydroxylase activity was slightly modified according to literature methods (Anal Biochem, 2004, 330: 74-80). The 96-well plates were pretreated with blocker casein and 1 mM biotin for 30 minutes, and then biotin-linked HIF-1α556-574 (biotinyl-DLDLEMLAPYIPMDDDFQL) was immobilized on a 96-well plate. The 96-well plate was then filled with an appropriate amount of HIF-PHD2-containing buffer (20 mM Tris (pH 7.5), 5 mM KCl, 1.5 mM MgCl ₂ , 20 mM 2-oxoglutarate (2-ketoglutaric acid), 10 mM FeSO ₄ , 2 mM ascorbic acid, 4% EDTA-free protease inhibitor) was incubated for 1 to 60 minutes at room temperature. The reaction mixture also contains different concentrations of proline hydroxylase inhibitors to be tested. The reaction was stopped by rinsing the 96-well plate three times with wash buffer. Hydroxylated HIF-1α556–574 and Eu-VBC protein in binding buffer were reacted in 100 μl of binding buffer (50 mM tris(hydroxymethyl)-aminomethane, pH 7.5, 120 mM NaCl) for 60 minutes at room temperature. The reaction solution was aspirated, and the unbound Eu-VBC protein was washed away by washing 3 times with an elution buffer. Subsequently, 10 μl of rabbit anti-Eu-VBC polyclonal antibody was added. After a further 30 minutes, 10 μl of anti-rabbit immunoglobulin coupled to horseradish peroxidase was added to the binding buffer. To determine the amount of bound Eu-VBC protein, it was incubated with TMB for 15 minutes. The color reaction was terminated by the addition of 100 μl of 1 M sulfuric acid. The content of bound Eu-VBC protein was determined by measuring the optical density at 450 nm. It is proportional to the amount of hydroxylated proline in the peptide substrate.

The IC ₅₀ in the table below is representative data. These values represent only the data measured by the applicant at the time of filing the application. Due to variations in reagents, measurement conditions, and mode of operation in the methods given above, the IC ₅₀ data tested may show some variation; therefore, these values should be considered relative rather than absolute.

The above IC ₅₀ data indicates that the compound of the present invention can effectively inhibit proline hydroxylase.

2. Effect of Example Compounds on Mouse Hemoglobin

Male C57Bl/6 mice (Shanghai Slack Laboratory Animals Co., Ltd.) for 8-10 weeks were orally administered with 30 mg/kg test compound (positive control rosastatin (CAS: 808118-40-3) was 60 mg/kg. The drug was administered twice a week for 2 weeks; about 30 μl of blood was taken from the mandibular vein before the first administration and 6 hours after the last administration, and the hemoglobin content was measured by a Hemocue hemoglobin meter. The hemoglobin increase is the hemoglobin value after the last administration minus the hemoglobin value before the first dose.

In addition, hemoglobin elevation was tested in the same manner using rosastatin as a positive control. Rosapstat was purchased from Selleckchem, a potent inhibitor of proline hydroxylase known in the art to increase hemoglobin production.

Listed in the table below are the elevated hemoglobin values of representative compounds.

实施例Example	血红蛋白升高值(g/dL)Hemoglobin elevation (g/dL)
11	3.53.5
66	3.03.0
77	2.22.2
99	1.11.1
1010	1.91.9
1111	2.02.0
1515	1.81.8
1616	1.71.7
1717	1.01.0
罗沙司他Rosita	1.71.7

As can be seen from the above table, the compounds of the present invention showed comparable or even better hemoglobin elevation values to rosastatin under the same measurement conditions, indicating that the compound of the present invention can be stabilized by inhibiting proline hydroxylase. Hypoxia-inducible factors, by, but not limited to, drugs that increase erythropoietin production and increase hemoglobin, and thus can be used for treating and/or preventing diseases associated with hypoxia-inducing factors such as anemia.

While the embodiments of the invention have been illustrated and described, it is not intended to Rather, the words used in the specification are merely illustrative and not restrictive, and it is understood that various changes may be made without departing from the spirit and scope of the invention.

Claims

a compound of formula I

Or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof,

among them:

R 1 and R 2 are independently selected from cyano, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, amino, R 9 O-, R 9 S-, R 9 ( O=)S-, R 9 (O=) 2 S-, wherein R 9 is alkyl, heterocyclic, alkenyl, alkynyl, aryl or heteroaryl; wherein the above alkyl, hetero A cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, amino group is optionally substituted by one or more substituents, wherein the substituents are independently selected from halo, cyano, hydroxy, amino, Carboxyl, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, =O, =S, -SH, R 10 O-, R 10 S-, R 10 (O=)S And R 10 (O=) 2 S-, wherein R 10 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; or R 1 and R 2 taken together to form a ring;

R 3 , R 4 and R 5 are independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, amino, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, R 11 O-, R 11 S-, R 11 (O=)S-, R 11 (O=) 2 S-, wherein R 11 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl And wherein the above alkyl group, heterocyclic group, alkenyl group, alkynyl group, aryl group, heteroaryl group, acyl group, amino group are optionally substituted by one or more substituents, wherein the substituents are independently selected from In halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, =0, =S, -SH, R 12 O-, R 12 S-, R 12 (O=)S-, R 12 (O=) 2 S-, wherein R 12 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl;

R 6 and R 6' are independently selected from hydrogen and optionally substituted alkyl;

R 7 is selected from the group consisting of hydrogen, alkyl and acyl; wherein the alkyl and acyl groups are optionally substituted by the following groups: halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkyne Base, aryl, heteroaryl, =O, =S, -SH, R 13 O-, R 13 S-, R 13 (O=)S-, R 13 (O=) 2 S-, wherein R 13 is an alkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an aryl group, or a heteroaryl group;

R 8 is selected from the group consisting of hydrogen, alkyl and -OC(O)R 14 , wherein R 14 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; wherein alkyl, heterocycle The base, alkenyl, alkynyl, aryl or heteroaryl group is optionally substituted by the following groups: halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl , aryl, heteroaryl, =O, =S, -SH, R 15 O-, R 15 S-, R 15 (O=)S-, R 15 (O=) 2 S-; wherein R 15 Is an alkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an aryl group, or a heteroaryl group;

X is an oxygen atom or a sulfur atom or NH.
The compound of claim 1 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof ,among them

R 1 and R 2 are independently selected from cyano, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 Cycloalkenyl, heterocycloalkyl having 3 to 8 ring atoms, heterocycloalkenyl group having 3 to 8 ring atoms, heteroaryl group having 5 to 14 ring atoms, C1-C12 chain alkyl-C (=O)-, C2-C12 alkenyl-C(=O)-, amino, R 9 O-, R 9 S-, R 9 (O=)S-, R 9 (O=) 2 S- Wherein R 9 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, containing 3 to a heterocyclic alkyl group having 8 ring atoms, a heterocycloalkenyl group having 3 to 8 ring atoms; wherein the above C1-C12 chain alkyl group, C2-C12 alkenyl group, C2-C12 alkynyl group, C6- C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring atoms, heterocycloalkenyl having 3 to 8 ring atoms, containing 5 to 14 rings a heteroaryl group of an atom, a C1-C12 chain alkyl-C(=O)-, a C2-C12 alkenyl-C(=O)-, an amino group, optionally substituted with from 1 to 3 substituents, wherein The substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 alkyl, C3-C8 ring a C2-C6 alkenyl-, C2-C6 alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl group having 5 to 14 ring atoms, C1-C6-chain alkyl-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyl-O-, C2-C6 alkynyl-O-, C3-C8 cycloalkenyl-O-, C6-C14 aryl-O-, heteroaryl-O-, C1-C6-chain alkyl-S-, C3-C8 cycloalkyl-S-, C2-C6 alkenyl group having 5 to 14 ring atoms -S-, C2-C6 alkynyl-S-, C3-C8 cycloalkenyl-S-, C6-C14 aryl-S-, heteroaryl-S- having 5 to 14 ring atoms, containing 3 Heterocycloalkyl group to 8 ring atoms, heterocycloalkenyl group having 3 to 8 ring atoms, =O, =S, -SH, -CF 3 , -CO 2 C 1 -C 6 chain alkyl group, C1 -C6 alkyl-S-, C1-C6 alkyl (O=)S- and C1-C6 alkyl (O=) 2 S-;

R 1 and R 2 taken together to form an optionally substituted cycloalkane ring, a cycloolefin ring, a heterocycloalkane ring, a heterocycloalkene ring having 3 to 8 ring atoms;

R 3 , R 4 and R 5 are independently selected from hydrogen, halogen, hydroxy, carboxy, cyano, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C14 aryl , C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring atoms, heterocycloalkenyl having 3 to 8 ring atoms, heterocyclic ring having 5 to 14 ring atoms Aryl, C1-C12-chain alkyl-C(=O)-, C2-C12 alkenyl-C(=O)-, amino, R 11 O-, R 11 S-, R 11 (O=)S -, R 11 (O=) 2 S-, wherein R 11 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl a C3-C8 cycloalkenyl group, a heterocycloalkyl group having 3 to 8 ring atoms, a heterocycloalkenyl group having 3 to 8 ring atoms; wherein the above C1-C12 chain alkyl group, C2-C12 alkene , C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring atoms, containing from 3 to 8 ring atoms Heterocyclenyl, heteroaryl having 5 to 14 ring atoms, C1-C12 alkyl-C(=O)-, C2-C12 alkenyl-C(=O)-, amino optionally Substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of a hydroxyl group, a halogen, and a cyano group Amino, carboxy, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl-, C2-C6 alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6- C14 aryl, heteroaryl group having 5 to 14 ring atoms, C1-C6 chain alkyl-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyl-O-, C2-C6 chain alkynyl-O-, C3-C8 cycloalkenyl-O-, C6-C14 aryl-O-, heteroaryl-O-, C1-C6-chain alkyl-S-, having 5 to 14 ring atoms, C3-C8 cycloalkyl-S-, C2-C6 alkenyl-S-, C2-C6 alkynyl-S-, C3-C8 cycloalkenyl-S-, C6-C14 aryl-S-, Heteroaryl-S- of 5 to 14 ring atoms, heterocycloalkyl group having 3 to 8 ring atoms, heterocycloalkenyl group having 3 to 8 ring atoms, =O, =S, -SH, - CF 3 , -CO 2 C 1 -C 6 alkyl, C1-C6 alkyl-S-, C1-C6 alkyl (O=)S- and C1-C6 alkyl (O=) 2 S -;

R 6 and R 6' are independently selected from the group consisting of hydrogen, C1-C6 alkyl and C3-C8 cycloalkyl; the above C1-C6 alkyl and C3-C8 cycloalkyl are optionally 1 to 3 substituents Substituted, wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl-, C2-C6 alkyne Base-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl containing 5 to 14 ring atoms, C1-C6-chain alkyl-O-, C3-C8 naphthenic -O-, C2-C6 alkenyl-O-, C2-C6 alkynyl-O-, C3-C8 cycloalkenyl-O-, C6-C14 aryl-O-, and 5 to 14 a heteroaryl-O- ring atom;

R 7 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl-C(=O)-, and C2-C6 alkenyl-C(=O)-; C1-C6-chain alkyl, C3-C8 cycloalkyl, C1-C6-chain alkyl-C(=O)-, C2-C6 alkenyl-C(=O)- are optionally substituted by 1 to 3 Substituted, wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl-, C2-C6 chain Alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl containing 5 to 14 ring atoms, C1-C6-chain alkyl-O-, C3-C8 ring Alkyl-O-, C2-C6 alkenyl-O-, C2-C6 alkynyl-O-, C3-C8 cycloalkenyl-O-, C6-C14 aryl-O-, and 5 to 14 a hetero atom of the ring atom -O-;

R 8 is selected from the group consisting of hydrogen, C1-C12 alkyl, C3-C8 cycloalkyl and -OC(O)-C1-C12 alkyl; wherein C1-C12 alkyl, C3-C8 cycloalkyl and The OC(O)-C1-C12 alkyl group is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of a hydroxyl group, a halogen, a cyano group, an amino group, a carboxyl group, and a C1-C6 alkyl group. , C3-C8 cycloalkyl, C2-C6 alkenyl-, C2-C6 alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, containing 5 to 14 rings Atomic heteroaryl, C1-C6-chain alkyl-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyl-O-, C2-C6 alkynyl-O-, C3-C8 ring Alkenyl-O-, C6-C14 aryl-O-, and heteroaryl-O- having 5 to 14 ring atoms;

X is an oxygen atom or a sulfur atom or NH.
The compound of claim 2 or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof ,among them

R 1 and R 2 are independently selected from cyano, amino, unsubstituted C1-C6 alkyl; or R 1 and R 2 taken together form an optionally substituted cycloalkane ring having from 3 to 8 ring atoms Or a heterocycloalkane ring.
The compound of claim 3 or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof ,among them

R 1 and R 2 are independently selected from methyl or ethyl; or R 1 and R 2 are taken together to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, These rings are substituted with a tetrahydrofuran ring or a tetrahydropyran ring or with a methyl group.
A compound according to any one of claims 1 to 4, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, Or a prodrug thereof, wherein

R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, C1-C6 alkyl, C6-C14 aryl, C3-C8 cycloalkyl, C1-C6 chain An alkyl-O-, heteroaryl group having 5 to 14 ring atoms; wherein the above C1-C6 alkyl group, C6-C14 aryl group, C3-C8 cycloalkyl group, C1-C6 chain alkyl group-O a heteroaryl group having 5 to 14 ring atoms, an amino group optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of a hydroxyl group, a halogen group, a cyano group, an amino group, a carboxyl group, and a C6- group. C14 aryl and C1-C6 alkyl.
The compound according to claim 5 or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof ,among them

R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, methyl, ethyl, propyl, butyl, phenyl, benzyl, tolyl, methoxybenzene , chlorophenyl, fluorophenyl, bromophenyl, dimethoxyphenyl, dichlorophenyl, difluorophenyl, dibromophenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and Pyridyl.
A compound according to any one of claims 1 to 6, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, Or a prodrug thereof, wherein

R 6 and R 6' are independently selected from the group consisting of hydrogen, unsubstituted C1-C6 alkyl, unsubstituted C3-C8 cycloalkyl, and 1-3 halogen-substituted C1-C6 alkyl.
The compound of claim 7 or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof ,among them

R 6 and R 6' are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, cyclopropyl and cyclobutyl.
A compound according to any one of claims 1 to 8, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, Or a prodrug thereof, wherein

R 7 is selected from hydrogen, unsubstituted C1-C6 alkyl, unsubstituted C1-C6 alkyl-C(=O)-, and unsubstituted C2-C6 alkenyl-C(=O)- .
The compound of claim 9 or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof ,among them

R 7 is selected from the group consisting of hydrogen, methyl, ethyl, formyl and acetyl.
A compound according to any one of claims 1 to 10, or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, Or a prodrug thereof, wherein

R 8 is selected from the group consisting of hydrogen, C1-C6 alkyl, and -OC(O)-C1-C12 alkyl; wherein C1-C6 alkyl, and -OC(O)-C1-C12 chain alkyl Optionally, it is substituted with from 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, halo, cyano, amino, carboxy, C1-C6 alkyl and C1-C6 alkyl-O-.
The compound of claim 11 or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof ,among them

R 8 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, formyloxy, acetoxy, propanoyloxy, butyryloxy and pentanoyloxy.
The compound of claim 1 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof Wherein: R 1 and R 2 are independently selected from methyl, ethyl, or R 1 and R 2 taken together to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, or a Methyl substituted of these rings; R 3 , R 4 and R 5 are independently selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, cyclohexyl, phenyl, and the above groups are halogen or a group substituted with a methoxy group; R 6 and R 6' are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl; R 7 is selected from hydrogen, methyl, ethyl; and R 8 is selected from In hydrogen, methyl, ethyl, propyl, butyl; X is an oxygen atom.
a compound selected from the group consisting of an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof,

(7'-hydroxy-5'-oxo-1'-phenyl-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl)glycine;

(1'-(4-Fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl) Glycine

(1'-(4-Fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl) Glycine ethyl ester;

(1'-(4-Fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl) -L-alanine;

(1'-(4-Fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl) -D-alanine;

(1'-(4-Chlorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl) Glycine

(7'-Hydroxy-1'-(4-methoxyphenyl)-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl Glycine;

(1'-(3,4-Difluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6' -carbonyl)glycine;

(7'-hydroxy-5'-oxo-1'-phenyl-5'H-spiro[cyclohexane-1,8'-pyridazine]-6'-carbonyl)glycine;

(1'-(4-Fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclohexane-1,8'-pyridazine]-6'-carbonyl) Glycine

(1'-(4-Chlorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclohexane-1,8'-pyridazine]-6'-carbonyl) Glycine

(7'-Hydroxy-1'-(4-methoxyphenyl)-5'-oxo-5'H-spiro[cyclohexane-1,8'-pyridazine]-6'-carbonyl Glycine;

(1'-(4-Chlorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclobutane-1,8'-pyridazine]-6'-carbonyl) Glycine

(1'-cyclohexyl-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl)glycine;

(1'-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl)glycine;

(1'-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-pyridazine]-6'-carbonyl)-L-alanine;

(1'-7'-Hydroxy-5'-oxo-5'H-spiro[cyclohexane-1,8'-pyridazine]-6'-carbonyl)glycine.
A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture thereof Or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.
A compound according to any one of claims 1 to 14, or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof Or the use of a prodrug thereof in the preparation of a proline hydroxylase inhibitor.
A compound according to any one of claims 1 to 14, or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof Or the use of a prodrug thereof for the manufacture of a medicament for the treatment and/or prevention of a disease associated with hypoxia-inducible factors.
The use according to claim 17, wherein the disease associated with hypoxia-inducible factor is selected from the group consisting of anemia (for example, idiopathic anemia, renal anemia, anemia associated with neoplastic disease (especially chemotherapy-induced anemia), Anemia caused by blood loss, iron deficiency anemia, vitamin deficiency anemia, cell attenuated and aplastic anemia, hemolytic anemia, iron loss of anemia, anemia caused by hypothyroidism, etc.), cardiovascular disease (for example, heart Insufficiency, coronary heart disease, angina pectoris, myocardial infarction, stroke, arteriosclerosis, spontaneous hypertension, pulmonary hypertension, malignant hypertension, and peripheral arterial obstructive disease), neurological disease, HIV infection, rheumatoid arthritis, related to surgery Ischemia, fetal choking, cancer and cancer-related symptoms (such as damage to health conditions after treatment with cytostatics, antibiotics, and radiation), eye diseases (such as glaucoma), central nervous system diseases (such as dementia, Chronic pain), chronic kidney disease, renal insufficiency and acute renal failure, sexual dysfunction (such as loss of libido), diabetes and Symptoms (such as diabetic macroangiopathy and microangiopathy, diabetic nephropathy), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, etc.), ischemic diseases (such as ischemic cerebrovascular disease, ischemia) Nephropathy, ischemic cardiomyopathy, etc.) and fibrotic diseases (eg fibrosis of heart, lung and liver).
A compound according to any one of claims 1 to 14, or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof Or the use of a prodrug thereof in the manufacture of a medicament for use in surgery to accelerate wound healing and/or reduce recovery time.
A compound according to any one of claims 1 to 14, or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof , or the use of its prodrug to increase hematocrit.