WO2020156571A1 - Pyridazine derivative, and preparation method and medicinal use thereof - Google Patents

Pyridazine derivative, and preparation method and medicinal use thereof Download PDF

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Publication number
WO2020156571A1
WO2020156571A1 PCT/CN2020/074212 CN2020074212W WO2020156571A1 WO 2020156571 A1 WO2020156571 A1 WO 2020156571A1 CN 2020074212 W CN2020074212 W CN 2020074212W WO 2020156571 A1 WO2020156571 A1 WO 2020156571A1
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alkyl
group
pyridazine derivative
general formula
substituted
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PCT/CN2020/074212
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French (fr)
Chinese (zh)
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殷建明
吕裕斌
李邦良
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杭州华东医药集团新药研究院有限公司
殷建明
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Publication of WO2020156571A1 publication Critical patent/WO2020156571A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a pyridazine derivative and its use and pharmaceutical composition in the preparation of a medicine for preventing and/or treating indications related to HIF regulation.
  • Anemia is a clinical syndrome in which peripheral red blood cell or hemoglobin volume is lower than normal due to various reasons, including weakness, dizziness, fatigue, and shortness of breath.
  • the main role of red blood cells is to carry oxygen to all tissues and organs throughout the body.
  • the number of red blood cells or the concentration of hemoglobin decreases, and this oxygen-carrying effect is affected, resulting in a series of hypoxia in tissues and organs.
  • HIF Hypoxia-inducible factor
  • HIF-PHD prolyl hydroxylase
  • hypoxic conditions may inhibit the three isoforms of HIF-PHD (PHD-1 , PHD-2, PHD-3) can stabilize HIF, thereby stimulating the production of red blood cells.
  • HIF-PHD inhibiting HIF-PHD can stabilize HIF cell levels, thereby preventing and/or treating disorders or diseases related to HIF regulation, such as anemia and ischemia.
  • disorders or diseases related to HIF regulation such as anemia and ischemia.
  • the present invention provides a pyridazine derivative, which is an ideal high-efficiency HIF-PHD inhibitor.
  • the present invention also provides the use of pyridazine derivatives in the preparation of drugs for preventing and/or treating indications related to HIF regulation.
  • the pyridazine derivatives of the present invention are ideal and highly effective HIF-PHD inhibitors, and can be used to treat or prevent disorders or diseases related to HIF regulation, such as anemia and ischemia.
  • the present invention adopts the following technical solution:
  • R 1 is selected from hydrogen, C 1-6 alkyl or substituted C 1-6 alkyl
  • R 2 is selected from C 1-6 alkyl, substituted C 1-6 alkyl, carboxyl or -CH 2 COOH;
  • R 3 and R 4 are independently selected from hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, fluorine, chlorine, bromine, iodine, and hydroxyl;
  • R 5 is unsubstituted or selected from fluorine, chlorine, bromine, iodine, hydroxy, carboxy, nitro, C 1-6 hydrocarbon, C 1-6 alkoxy, cyano, ester, amide and sulfonate C 1-20 alkyl, C 5-20 aryl or C 5-20 heteroaryl substituted by one, two, three, four or more substituents in the acyl group;
  • X is selected from N or CH
  • Y is selected from NH, CH 2 , O, CO, SO 2 , SO.
  • R 1 is hydrogen
  • R 2 is carboxyl or -CH 2 COOH
  • R 3 is hydroxyl
  • R 4 is different from R 3 .
  • R 3 is hydroxyl and R 4 is hydrogen, C 1-6 alkyl, fluorine, chlorine, bromine or iodine.
  • C 1-6 hydrocarbon groups include C 1-6 alkyl groups, C 2-6 alkenyl groups, and C 2-6 alkynyl groups.
  • the C 1-6 alkyl group includes methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclic Butyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl.
  • the C 2-6 alkynyl group includes CH ⁇ C-, CH ⁇ C-CH 2 -, CH ⁇ C-CH 2 -CH 2 -, CH ⁇ C-CH 2- CH 2 -CH 2 -, CH 3 -C ⁇ C-CH 2 -, CH 3 -C ⁇ C-CH 2 -CH 2 -, etc.
  • the C 1-6 alkoxy group includes methoxy, ethoxy, propoxy, butoxy, pentoxy, isobutoxy, tert-butoxy, etc. .
  • the heteroatom in the C 5-20 heteroaryl group is selected from one or more of nitrogen, oxygen and sulfur.
  • R 5 when R 5 is a substituted C 5-20 aryl or C 5-20 heteroaryl, the substitution on the C 5-20 aryl or C 5-20 heteroaryl is The group is in the non-ortho position of the carbon to which the C 5-20 aryl group or C 5-20 heteroaryl group is connected to Y, for example, in the meta position or the para position.
  • R 5 is unsubstituted or substituted C 1-6 alkyl, C 5-10 aryl or C 5-10 heteroaryl.
  • R 5 is unsubstituted or substituted monocyclic aryl or monocyclic heteroaryl.
  • R 5 is Or; wherein, R 6 is selected from C 1-6 alkoxy, and R 7 is selected from fluorine, chlorine, bromine or iodine.
  • the pyridazine derivative has a structure represented by the general formula (II):
  • R 2 is selected from C 1-6 alkyl, substituted C 1-6 alkyl, carboxyl or -CH 2 COOH;
  • R 3 and R 4 are independently selected from hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, fluorine, chlorine, bromine, iodine, and hydroxyl;
  • R 5 is unsubstituted or selected from fluorine, chlorine, bromine, iodine, hydroxy, carboxy, nitro, C 1-6 hydrocarbon, C 1-6 alkoxy, cyano, ester, amide and sulfonate C 1-20 alkyl, C 5-20 aryl or C 5-20 heteroaryl substituted by one, two, three, four or more substituents in the acyl group;
  • X is selected from N or CH
  • Y is selected from NH, CH 2 , O, CO, SO 2 , SO.
  • the R 2 in the general formula (II) is selected from a carboxyl group or -CH 2 COOH;
  • R 3 is selected from hydroxyl
  • R 4 is selected from hydrogen, C 1-6 alkyl, fluorine or chlorine;
  • R 5 is selected from
  • X is selected from N or CH
  • Y is selected from NH or O.
  • the pyridazine derivative has the following structure:
  • the pyridazine derivative is one of the compounds represented by the following structural formula:
  • the pyridazine derivative compound includes not only a single compound form, but also a mixture form of multiple compounds meeting the requirements of general formula (I), and different isomers of the same compound Forms such as racemates, enantiomers, diastereomers and the like.
  • Prodrug of a compound of general formula (I) refers to a substance that, when administered by an appropriate method, can undergo metabolic or chemical reactions in the body of a subject to be converted into at least one compound of general formula (I) .
  • the preparation method of the pyridazine derivative of the present invention includes the following steps:
  • Z is selected from Cl, Br, I, OTf;
  • PG is benzyl
  • n 0 or 1
  • R 4 is selected from hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, fluorine, chlorine, bromine, iodine, and hydroxyl;
  • X is selected from N or CH
  • Y is selected from NH, CH 2 , O, CO, SO 2 , SO.
  • the invention also relates to the use of the above-mentioned pyridazine derivatives in the preparation of drugs for preventing and/or treating indications related to HIF regulation.
  • the conditions or diseases related to HIF regulation include anemia and ischemia, and the indications related to HIF regulation also include other diseases related to the HIF-PHD inhibition mechanism.
  • Another technical solution adopted by the present invention a medicine for preventing and/or treating indications related to HIF-PHD inhibition, containing the above-mentioned pyridazine derivative.
  • the present invention also relates to the use of the above-mentioned pyridazine derivatives as medicines.
  • the present invention has the following advantages compared with the prior art:
  • the pyridazine derivatives provided by the present invention have a strong inhibitory effect on HIF-PHD, so the compounds of the present invention can be used to prepare drugs for the treatment or prevention of various indications related to HIF regulation.
  • unsubstituted when it is used to define a certain group, means that the defined group is not substituted by other groups other than hydrogen atoms, in which case the certain group has Those of ordinary skill in the art generally understand the same meaning.
  • an unsubstituted C 1-6 alkyl group is a methyl group, an ethyl group, etc. as commonly understood by those skilled in the art.
  • substituted when used to define a certain group, means that one or more hydrogen atoms on the defined group are replaced by substituents, and the meaning of the certain group should be Understand in combination with substituents.
  • substituted when referring to “substituted”, it means that the hydrogen atom in the group defined by it is replaced by one or more substituents selected from the following:
  • the above-mentioned substituents are selected from deuterium, cyano, halogen (preferably F, Cl, Br), hydroxyl, carboxyl, ester, sulfone, sulfonylamino, carbonylamino, carbonyl, C 1-6 hydrocarbyl sulfinyl Acylamino, amino, hydrazinoyl, C 1-6 hydrocarbyl, halogenated C 1-6 hydrocarbyl, hydroxyl-substituted C 1-6 hydrocarbyl, amide-substituted C 1-6 hydrocarbyl, C 1-6 hydrocarbyloxy, Halogenated C 1-6 hydrocarbyloxy group, C 1-6 hydrocarbyloxy C 1-6 hydrocarbyl group, C 1-6 hydrocarbyloxy C 1-6 hydrocarbyloxy group.
  • halogen preferably F, Cl, Br
  • the above-mentioned substituents are selected from deuterium, cyano, F, Cl, Br, hydroxyl, carboxyl, ester, sulfone, sulfonamide, amide, carbonyl, methylsulfinylamino, ethyl sulfinyl Sulfonylamino, isopropylsulfinylamino, tert-butylsulfinylamino, amino, hydrazinoyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl Base, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, halomethyl (e.g.
  • haloethyl halo-n-propyl
  • hydrocarbyl refers to alkyl, alkenylalkyl and alkynylalkyl groups.
  • alkyl refers to a linear, branched or cyclic saturated substituent composed of carbon and hydrogen.
  • the alkyl group specifically includes, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl , Cyclohexyl, n-hexyl, isohexyl, 2,2,-methylbutyl and 2,3-dimethylbutyl, 16-alkyl, 18-alkyl.
  • C 1-20 alkyl refers to a linear, branched or cyclic saturated hydrocarbon group containing 1-20 carbon atoms.
  • the substituent may be substituted at any available point of attachment, and the substituent may be mono- or poly-substituted.
  • substituents can be alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxy, ester, cyano, cycloalkyl, Aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo.
  • C 1-3 alkoxy C 3-8 cycloalkyl C 1-6 alkyl refers to C 1-6 alkyl, It is substituted by a C 3-8 cycloalkyl group, and the C 3-8 cycloalkyl group is substituted by a C 1-3 alkoxy group.
  • the structural formula of methoxycyclobutyl methyl is:
  • alkenyl and alkynyl respectively refer to linear, branched or cyclic unsaturated hydrocarbon groups containing double and triple bonds, preferably 2-20 carbon atoms, more preferably 2-12 carbon atoms.
  • the substituent can be substituted at any available point of attachment, and the substituent can be mono- or poly-substituted.
  • the substituent may be selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxy, ester, cyano, cycloalkane Group, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo.
  • aryl is a carbocyclic aryl group
  • heteroaryl refers to a group of a heteroaromatic system containing 1-10 heteroatoms, including monocyclic heteroaryl groups and condensed ring heteroaryl groups. Heteroatoms include oxygen, sulfur, nitrogen, phosphorus, etc.
  • monocyclic heteroaryl groups include but are not limited to furan, thiophene, pyrrole, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazole, Oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, isoxa Oxazoline etc.
  • Fused ring heteroaryl groups include, but are not limited to, quinoline, isoquinoline, indole, benzofuran, benzothiophene, purine, acridine, carbazole, fluorene, chromenone, fluorenone, quinoxaline, 3, 4-phthalone, dibenzofuran, hydrogenated dibenzofuran, benzoxazolyl, etc.
  • Heteroaryl groups can be substituted and unsubstituted.
  • Substituents are, for example, selected from alkyl, cycloalkyl (such as cyclopropyl, cyclobutanyl, cyclopentyl, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio , Alkylamino, halogen, mercaptan, hydroxy, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, alkane Silicon-based, etc.
  • deuterium is an isotope of hydrogen, the atomic mass is twice that of the latter, and the bond with carbon is stronger.
  • Deuterated and deuterium mean that hydrogen is replaced with deuterium at a specified position.
  • a “deuterated substituent” is a substituent in which at least one hydrogen is replaced by deuterium enriched in a specified percentage.
  • the raw materials or reagents used in the present invention can be synthesized by conventional methods or commercially available.
  • the compound of formula Ia can be obtained by the following synthetic route:
  • the preparation method of the compound of formula Ia specifically includes the following steps:
  • the compound of formula Ia was prepared: compound f (5g, 9.1mmol) was added to 500mL of methanol, then Pd/C (500mg, 10% W) was added, and hydrogen gas was reacted at room temperature under normal pressure for 48 hours. The reaction liquid was filtered through a pad of Celite, concentrated under reduced pressure, and then beaten with methanol twice to obtain compound Ia (2 g, yield 60.6%) as a white powder.
  • the obtained target product Ia was subjected to hydrogen nuclear magnetic resonance 1 H-NMR (500MHz, DMSO) and mass spectrometry.
  • the results are as follows:
  • Example 1 Using the method of Example 1 or a similar method, other compounds of this application can be prepared.
  • Detecting the test compound using the FP assay method respectively (the concentration required for 50% inhibition of enzyme activity of the compound) IC 50 concentration for the half PHD1, PHD2, and PHD3 suppressed.
  • the target compound (Ia) has a very strong inhibitory effect on PHD1, PHD2 and PHD3, with IC 50 values less than 100 nM.
  • This strong inhibitory effect has important therapeutic significance for the treatment of diseases or diseases related to HIF-PHD regulation, such as anemia and ischemia.
  • mice male mice, weighing 21-22g;
  • the target compound Ia was prepared as 0.4 mg/mL (for intravenous administration) and 1.0 mg/mL (for oral administration), and then used. Route of administration: oral/intravenous injection. Dosing volume and frequency: 5mL/kg (intravenous injection) or 10mL/kg (oral), single dose.
  • Sample collection Blood was collected at the following time points, 5min, 15min, 30min, 1hr, 2hr, 4hr, 8hr and 24hr after administration.
  • Sample analysis Use the LC-MS/MS method to detect the collected samples.
  • the instrument model used is LCMSMS-035 (triple quadruple, 6500+).
  • Pharmacokinetic data analysis Use WinNolin according to the non-compartmental model method to fit and calculate the obtained blood drug concentration data. Part of the results are summarized in the following table.
  • test results show that the compound of the present invention has good pharmacokinetic characteristics.
  • the compounds of the present invention are ideal and highly effective HIF-PHD inhibitors, and can be expected to be used to treat or prevent diseases or diseases related to HIF-PHD regulation, such as anemia and ischemia, and achieve very good results. It can also be made into oral preparations (tablets or capsules, etc.). The tablets or capsules made with the compounds of the present invention can be taken once or multiple times a day. The compound of the present invention can also be combined with other drugs to prepare a compound preparation.

Abstract

Provided is a pyridazine derivative as shown in formula (I), and a use thereof in preparing a drug for the prevention and/or treatment of indications related to HIF modulation. The pyridazine derivative is an ideal, highly-effective HIF-PHD inhibitor, and may be used in the treatment or prevention of disorders or diseases related to HIF modulation, for instance anemia and ischemia.

Description

一种哒嗪衍生物及其制备方法和医药用途A kind of pyridazine derivative and its preparation method and medical use 技术领域Technical field
本发明涉及一种哒嗪衍生物及其在制备预防和/或治疗与HIF调节有关的适应症的药物中的用途和药物组合物。The invention relates to a pyridazine derivative and its use and pharmaceutical composition in the preparation of a medicine for preventing and/or treating indications related to HIF regulation.
背景技术Background technique
贫血是由各种原因导致的外周血红细胞或血红蛋白容量低于正常的临床综合征，包括虚弱、眩晕、疲劳和呼吸短促等。红细胞的主要作用是将氧带到全身各组织器官。在贫血发生时红细胞数或血红蛋白浓度减低，这种带氧的作用受到影响，从而导致出现组织器官缺氧的一系列表现。Anemia is a clinical syndrome in which peripheral red blood cell or hemoglobin volume is lower than normal due to various reasons, including weakness, dizziness, fatigue, and shortness of breath. The main role of red blood cells is to carry oxygen to all tissues and organs throughout the body. When anemia occurs, the number of red blood cells or the concentration of hemoglobin decreases, and this oxygen-carrying effect is affected, resulting in a series of hypoxia in tissues and organs.
组织缺氧的早期反应是诱导产生缺氧诱导因子(Hypoxia-inducible factor，HIF)。HIF是一种α/β异二聚体基因转录因子，与红细胞生成、血管生成、糖酵解能量代谢和凋亡相关。HIF细胞水平是通过其α亚基上的脯氨酸残基被脯氨酰羟化酶(HIF-PHD)羟基化来得到代谢调节的。在有氧条件下HIF的半衰期很短，因为HIF的α亚基可被以分子氧作为底物的HIF-PHD氧化降解；缺氧条件或抑制HIF-PHD的三种同种型(PHD-1、PHD-2、PHD-3)则可以稳定HIF，从而刺激红细胞的产生。The early response of tissue hypoxia is to induce the production of Hypoxia-inducible factor (HIF). HIF is an α/β heterodimer gene transcription factor, which is related to erythropoiesis, angiogenesis, glycolytic energy metabolism and apoptosis. The cellular level of HIF is metabolically regulated by the hydroxylation of proline residues on its alpha subunit by prolyl hydroxylase (HIF-PHD). Under aerobic conditions, the half-life of HIF is very short, because the α subunit of HIF can be oxidatively degraded by HIF-PHD with molecular oxygen as a substrate; hypoxic conditions may inhibit the three isoforms of HIF-PHD (PHD-1 , PHD-2, PHD-3) can stabilize HIF, thereby stimulating the production of red blood cells.
因此，通过抑制HIF-PHD能够稳定HIF细胞水平，进而可以预防和/或治疗与HIF调节有关的病症或疾病，例如贫血和缺血等。本领域需要开发对HIF-PHD具有强效抑制作用的药物。Therefore, inhibiting HIF-PHD can stabilize HIF cell levels, thereby preventing and/or treating disorders or diseases related to HIF regulation, such as anemia and ischemia. There is a need in this field to develop drugs with a strong inhibitory effect on HIF-PHD.
发明内容Summary of the invention
本发明提供了一种哒嗪衍生物，其是理想的高效HIF-PHD抑制剂。The present invention provides a pyridazine derivative, which is an ideal high-efficiency HIF-PHD inhibitor.
本发明同时还提供哒嗪衍生物在制备预防和/或治疗与HIF调节有关的适应症的药物中的用途。The present invention also provides the use of pyridazine derivatives in the preparation of drugs for preventing and/or treating indications related to HIF regulation.
本发明的哒嗪衍生物是理想的高效HIF-PHD抑制剂，可用于治疗或预防与HIF调节有关的病症或疾病，例如贫血和缺血。The pyridazine derivatives of the present invention are ideal and highly effective HIF-PHD inhibitors, and can be used to treat or prevent disorders or diseases related to HIF regulation, such as anemia and ischemia.
为解决以上技术问题，本发明采取如下一种技术方案：To solve the above technical problems, the present invention adopts the following technical solution:
一种具有通式(I)所示结构的哒嗪衍生物，A pyridazine derivative with the structure represented by the general formula (I),
Figure PCTCN2020074212-appb-000001
Figure PCTCN2020074212-appb-000001
其中：among them:
R 1选自氢、C 1-6烷基或取代的C 1-6烷基； R 1 is selected from hydrogen, C 1-6 alkyl or substituted C 1-6 alkyl;
R 2选自C 1-6烷基、取代的C 1-6烷基、羧基或-CH 2COOH； R 2 is selected from C 1-6 alkyl, substituted C 1-6 alkyl, carboxyl or -CH 2 COOH;
R 3、R 4独自地选自氢、C 1-6烷基、取代的C 1-6烷基、氟、氯、溴、碘、羟基； R 3 and R 4 are independently selected from hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, fluorine, chlorine, bromine, iodine, and hydroxyl;
R 5为未取代的，或被选自氟、氯、溴、碘、羟基、羧基、硝基、C 1-6烃基、C 1-6烷氧基、氰基、酯基、酰胺基和磺酰基中的一个、两个、三个、四个或更多个取代基所取代的C 1-20烷基、C 5-20芳基或C 5-20杂芳基； R 5 is unsubstituted or selected from fluorine, chlorine, bromine, iodine, hydroxy, carboxy, nitro, C 1-6 hydrocarbon, C 1-6 alkoxy, cyano, ester, amide and sulfonate C 1-20 alkyl, C 5-20 aryl or C 5-20 heteroaryl substituted by one, two, three, four or more substituents in the acyl group;
X选自N或CH；X is selected from N or CH;
Y选自NH、CH 2、O、CO、SO 2、SO。 Y is selected from NH, CH 2 , O, CO, SO 2 , SO.
根据本发明的一些优选方面，R 1为氢，R 2为羧基或-CH 2COOH，R 3为羟基。 According to some preferred aspects of the present invention, R 1 is hydrogen, R 2 is carboxyl or -CH 2 COOH, and R 3 is hydroxyl.
根据本发明的一些优选方面，R 4与R 3不同。 According to some preferred aspects of the present invention, R 4 is different from R 3 .
在本发明的一些实施方式中，R 3为羟基，R 4为氢、C 1-6烷基、氟、氯、溴或碘。 In some embodiments of the present invention, R 3 is hydroxyl and R 4 is hydrogen, C 1-6 alkyl, fluorine, chlorine, bromine or iodine.
根据本发明，C 1-6烃基包括C 1-6烷基、C 2-6烯基、C 2-6炔基。 According to the present invention, C 1-6 hydrocarbon groups include C 1-6 alkyl groups, C 2-6 alkenyl groups, and C 2-6 alkynyl groups.
在本发明的一些实施方式中，所述的C 1-6烷基包括甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、新戊基、环己基、正己基。 In some embodiments of the present invention, the C 1-6 alkyl group includes methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclic Butyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl.
在本发明的一些实施方式中，所述的C 2-6烯基包括CH 2＝CH-、CH 2＝CH-CH 2-、CH 2＝CH-CH 2-CH 2-、CH 2＝CH-CH 2-CH 2-CH 2-、CH 3-CH＝CH-CH 2-、CH 3-CH＝CH-CH 2-CH 2-等。 In some embodiments of the present invention, the C 2-6 alkenyl group includes CH 2 =CH-, CH 2 =CH-CH 2 -, CH 2 =CH-CH 2 -CH 2 -, CH 2 =CH -CH 2 -CH 2 -CH 2 -, CH 3 -CH=CH-CH 2 -, CH 3 -CH=CH-CH 2 -CH 2 -, etc.
在本发明的一些实施方式中，所述的C 2-6炔基包括CH≡C-、CH≡C-CH 2-、CH≡C-CH 2-CH 2-、CH≡C-CH 2-CH 2-CH 2-、CH 3-C≡C-CH 2-、CH 3-C≡C-CH 2-CH 2-等。 In some embodiments of the present invention, the C 2-6 alkynyl group includes CH≡C-, CH≡C-CH 2 -, CH≡C-CH 2 -CH 2 -, CH≡C-CH 2- CH 2 -CH 2 -, CH 3 -C≡C-CH 2 -, CH 3 -C≡C-CH 2 -CH 2 -, etc.
在本发明的一些实施方式中，所述的C 1-6烷氧基包括甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、异丁氧基、叔丁氧基等。 In some embodiments of the present invention, the C 1-6 alkoxy group includes methoxy, ethoxy, propoxy, butoxy, pentoxy, isobutoxy, tert-butoxy, etc. .
根据本发明的一些优选方面，所述的C 5-20杂芳基中杂原子选自氮、氧和硫中的一个或多个。 According to some preferred aspects of the present invention, the heteroatom in the C 5-20 heteroaryl group is selected from one or more of nitrogen, oxygen and sulfur.
根据本发明的一些优选方面，当R 5为取代的C 5-20芳基或C 5-20杂芳基时，所述的C 5-20芳基或C 5-20杂芳基上的取代基处于所述的C 5-20芳基或C 5-20杂芳基与Y相连的碳的非邻位，例如在间位、对位。 According to some preferred aspects of the present invention, when R 5 is a substituted C 5-20 aryl or C 5-20 heteroaryl, the substitution on the C 5-20 aryl or C 5-20 heteroaryl is The group is in the non-ortho position of the carbon to which the C 5-20 aryl group or C 5-20 heteroaryl group is connected to Y, for example, in the meta position or the para position.
根据本发明的一些具体且优选的方面，R 5为未取代的，或取代的C 1-6烷基、C 5-10芳基或C 5-10杂芳基。 According to some specific and preferred aspects of the present invention, R 5 is unsubstituted or substituted C 1-6 alkyl, C 5-10 aryl or C 5-10 heteroaryl.
在本发明的一些实施方式中，R 5为未取代的，或取代的单环芳基或单环杂芳基。 In some embodiments of the present invention, R 5 is unsubstituted or substituted monocyclic aryl or monocyclic heteroaryl.
根据本发明的一些优选方面，R 5为
Figure PCTCN2020074212-appb-000002
Figure PCTCN2020074212-appb-000003
或；其中，R 6选自C 1-6烷氧基，R 7选自氟、氯、溴或碘。 According to some preferred aspects of the present invention, R 5 is
Figure PCTCN2020074212-appb-000002
Figure PCTCN2020074212-appb-000003
Or; wherein, R 6 is selected from C 1-6 alkoxy, and R 7 is selected from fluorine, chlorine, bromine or iodine.
在本发明的一些实施方式中，所述的哒嗪衍生物具有通式(II)所示的结构：In some embodiments of the present invention, the pyridazine derivative has a structure represented by the general formula (II):
Figure PCTCN2020074212-appb-000004
Figure PCTCN2020074212-appb-000004
其中：among them:
R 2选自C 1-6烷基、取代的C 1-6烷基、羧基或-CH 2COOH； R 2 is selected from C 1-6 alkyl, substituted C 1-6 alkyl, carboxyl or -CH 2 COOH;
R 3、R 4独自地选自氢、C 1-6烷基、取代的C 1-6烷基、氟、氯、溴、碘、羟基； R 3 and R 4 are independently selected from hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, fluorine, chlorine, bromine, iodine, and hydroxyl;
R 5为未取代的，或被选自氟、氯、溴、碘、羟基、羧基、硝基、C 1-6烃基、C 1-6烷氧基、氰基、酯基、酰胺基和磺酰基中的一个、两个、三个、四个或更多个取代基所取代的C 1-20烷基、C 5-20芳基或C 5-20杂芳基； R 5 is unsubstituted or selected from fluorine, chlorine, bromine, iodine, hydroxy, carboxy, nitro, C 1-6 hydrocarbon, C 1-6 alkoxy, cyano, ester, amide and sulfonate C 1-20 alkyl, C 5-20 aryl or C 5-20 heteroaryl substituted by one, two, three, four or more substituents in the acyl group;
X选自N或CH；X is selected from N or CH;
Y选自NH、CH 2、O、CO、SO 2、SO。 Y is selected from NH, CH 2 , O, CO, SO 2 , SO.
根据本发明的一些优选方面，通式(II)中所述R 2选自羧基或-CH 2COOH； According to some preferred aspects of the present invention, the R 2 in the general formula (II) is selected from a carboxyl group or -CH 2 COOH;
R 3选自羟基； R 3 is selected from hydroxyl;
R 4选自氢、C 1-6烷基、氟或氯； R 4 is selected from hydrogen, C 1-6 alkyl, fluorine or chlorine;
R 5选自
Figure PCTCN2020074212-appb-000005
R 5 is selected from
Figure PCTCN2020074212-appb-000005
X选自N或CH；X is selected from N or CH;
Y选自NH或O。Y is selected from NH or O.
根据本发明的一些优选方面，所述的哒嗪衍生物具有如下结构：According to some preferred aspects of the present invention, the pyridazine derivative has the following structure:
Figure PCTCN2020074212-appb-000006
Figure PCTCN2020074212-appb-000006
根据本发明的一些具体且优选的方面，所述的哒嗪衍生物为如下结构式表示的化合物中的一种：According to some specific and preferred aspects of the present invention, the pyridazine derivative is one of the compounds represented by the following structural formula:
Figure PCTCN2020074212-appb-000007
Figure PCTCN2020074212-appb-000007
Figure PCTCN2020074212-appb-000008
Figure PCTCN2020074212-appb-000008
Figure PCTCN2020074212-appb-000009
Figure PCTCN2020074212-appb-000009
根据本发明，所述的哒嗪衍生物的化合物，其不仅包括单一的某种化合物形式，还包括多种结构满足通式(Ⅰ)要求的化合物的混合物形式，以及同一化合物的不同异构体形式例如外消旋体、对映异构体、非对映异构体等。“具有通式(Ⅰ)的化合物的前药”指一种物质，当采用适当的方法施用后，可在受试者体内进行代谢或化学反应而转变成通式(Ⅰ)的至少一种化合物。According to the present invention, the pyridazine derivative compound includes not only a single compound form, but also a mixture form of multiple compounds meeting the requirements of general formula (I), and different isomers of the same compound Forms such as racemates, enantiomers, diastereomers and the like. "Prodrug of a compound of general formula (I)" refers to a substance that, when administered by an appropriate method, can undergo metabolic or chemical reactions in the body of a subject to be converted into at least one compound of general formula (I) .
本发明哒嗪衍生物的制备方法，包括以下步骤：The preparation method of the pyridazine derivative of the present invention includes the following steps:
Figure PCTCN2020074212-appb-000010
Figure PCTCN2020074212-appb-000010
(1)化合物A和化合物B经Suzuki偶联，得到化合物C；(1) Compound A and compound B are coupled by Suzuki to obtain compound C;
(2)化合物C在碱性条件下水解，得到羧酸化合物D；(2) Compound C is hydrolyzed under alkaline conditions to obtain carboxylic acid compound D;
(3)羧酸化合物D与化合物E发生酯化反应，再去除保护基得到目标化合物；其中，(3) The carboxylic acid compound D and the compound E undergo an esterification reaction, and then the protective group is removed to obtain the target compound; wherein,
Z选自Cl、Br、I、OTf；Z is selected from Cl, Br, I, OTf;
PG为苄基；PG is benzyl;
n为0或1；n is 0 or 1;
其它基团定义如下：Other groups are defined as follows:
R 4选自氢、C 1-6烷基、取代的C 1-6烷基、氟、氯、溴、碘、羟基； R 4 is selected from hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, fluorine, chlorine, bromine, iodine, and hydroxyl;
R 5为
Figure PCTCN2020074212-appb-000011
R 5 is
Figure PCTCN2020074212-appb-000011
X选自N或CH；X is selected from N or CH;
Y选自NH、CH 2、O、CO、SO 2、SO。 Y is selected from NH, CH 2 , O, CO, SO 2 , SO.
本发明还涉及上述哒嗪衍生物在制备预防和/或治疗与HIF调节有关的适应症的药物中的用途。The invention also relates to the use of the above-mentioned pyridazine derivatives in the preparation of drugs for preventing and/or treating indications related to HIF regulation.
所述与HIF调节有关的病症或疾病包括贫血和缺血，所述与HIF调节有关的适应症还包括其他和HIF-PHD抑制机理相关的疾病。The conditions or diseases related to HIF regulation include anemia and ischemia, and the indications related to HIF regulation also include other diseases related to the HIF-PHD inhibition mechanism.
本发明采用的又一技术方案：一种预防和/或治疗与HIF-PHD抑制有关的适应症的药物，含有上述的哒嗪衍生物。Another technical solution adopted by the present invention: a medicine for preventing and/or treating indications related to HIF-PHD inhibition, containing the above-mentioned pyridazine derivative.
本发明还涉及上述的哒嗪衍生物作为药物的用途。The present invention also relates to the use of the above-mentioned pyridazine derivatives as medicines.
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:
本发明提供的哒嗪衍生物对HIF-PHD具有强效的抑制作用，因此本发明化合物可用于制备治疗或预防各种与HIF调节有关的适应症的药物。The pyridazine derivatives provided by the present invention have a strong inhibitory effect on HIF-PHD, so the compounds of the present invention can be used to prepare drugs for the treatment or prevention of various indications related to HIF regulation.
术语定义Definition of Terms
除非另外定义，本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs.
术语“未取代的”，当其用于限定某个基团时，意思是，该限定的基团没有为氢原子之外的其他基团所取代，此时该某个基团具有按照本发明所属领域的普通技术人员通常理解的相同的含义。例如未取代的C 1-6烷基即本领域技术人员通常所理解的甲基、乙基等。 The term "unsubstituted", when it is used to define a certain group, means that the defined group is not substituted by other groups other than hydrogen atoms, in which case the certain group has Those of ordinary skill in the art generally understand the same meaning. For example, an unsubstituted C 1-6 alkyl group is a methyl group, an ethyl group, etc. as commonly understood by those skilled in the art.
术语“取代的”，当其用于限定某个基团时，意思是，其限定的基团上的某一个或多个氢原子被取代基所取代，此时该某个基团的含义应结合取代基来理解。本发明中，除非特别说明，当提及“取代的”，意指由其限定的基团中的氢原子由选自下列中的某一个或多个取代基所取代：The term "substituted", when used to define a certain group, means that one or more hydrogen atoms on the defined group are replaced by substituents, and the meaning of the certain group should be Understand in combination with substituents. In the present invention, unless otherwise specified, when referring to "substituted", it means that the hydrogen atom in the group defined by it is replaced by one or more substituents selected from the following:
氘、氰基、卤素、羟基、羧基、酯基、砜基、磺酰胺基、酰胺基、羰基(-C(＝O)-)、C 1-6烃基S(＝O)(＝NH)-、胺基、肼酰基、C 1-6烃基、卤代的C 1-6烃基、羟基取代的C 1-6烃基、酰胺取代的C 1-6烃基、C 1-6烃氧基、卤代的C 1-6烃氧基、C 1-6烃氧基C 1-6烃基、C 1-6烃氧基C 1-6烃氧基、C 1-6烃胺基、C 1-6烃巯基、C 1-6烃基羰基、C 1-6烃基胺酰基、C 1-6烃基酰胺基、卤代C 1-6烃基酰胺基、C 1-6烃基氧酰基、C 1-6烃基胺酰胺基、C 1-6烃基砜基、C 1-6烃基磺酰胺基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、卤代C 3-6环烷氧基、C 3-6环烷基C 1-6烃基、C 3-6环烷基氧C 1-6烃基、C 3-6环烷基C 1-6烃氧基、C 3-6环烷基C 1-6烃氧基C 1-6烃氧基、C 3-6环烷胺基、C 3-6环烷基C 1-6烃胺基、C 3-6环烷巯基、卤代C 3-6环烷巯基、C 3-6环烷基C 1-6烃巯基、C 3-6环烷基砜基、C 3-6环烷基C 1-6烃砜基、C 3-6环烷基磺酰胺基、C 3-6环烷基C 1-6烃基磺酰胺基、C 3-6环烷羰基、C 3-6环烷基C 1-6烃基羰基、C 3-6环烷胺酰基、C 3-6环烷基C 1-6烃基胺酰基、C 3-6环烷酰胺基、C 3-6环烷基C 1-6烃基酰胺基、C 3-6环烷胺酰胺基、C 4-8杂环烷基、C 4-8杂环烷基氧基、卤代C 4-8杂环烷基氧基、C 4-8杂环烷基氧C 1-6烃基、卤代C 4-8杂环烷基氧C 1-6烃基、C 4-8杂环烷基C 1-6烃氧基、卤代C 4-8杂环烷基C 1-6烃氧基、C 4-8杂环烷基C 1-6烃基、C 4-8杂环烷基C 1-6烃氧基C 1-6烃基、C 4-8杂环烷胺基、C 4-8杂环烷巯基、C 4-8杂环烷基C 1-6烃基巯基、C 4-8杂环烷基砜基、 C 4-8杂环烷基C 1-6烃砜基、C 4-8杂环烷基磺酰胺基、C 4-8杂环烷基C 1-6烃基磺酰胺基、C 4-8杂环烷基羰基、C 4-8杂环烷基C 1-6烃基羰基、C 4-8杂环烷基被羰基取代、C 4-8杂环烷基胺酰基、C 4-8杂环烷基酰胺基、C 4-8杂环烷基C 1-6烃基酰胺基、C 5-10芳基、C 5-10芳氧基、C 5-10芳氧基C 1-6烃基、C 5-10芳基C 1-6烃基、C 5-10芳基C 1-6烃氧基、C 5-10芳胺基、C 5-10芳巯基、C 5-10芳基C 1-6烃巯基、C 5-10芳基砜基、C 5-10芳基C 1-6烃砜基、C 5-10芳基磺酰胺基、C 5-10芳基C 1-6烃基磺酰胺基、C 5-10芳羰基、C 5-10芳基C 1-6烃基羰基、C 5-10芳胺酰基、C 5-10芳酰胺基或C 5-10芳胺酰胺基。 Deuterium, cyano, halogen, hydroxyl, carboxyl, ester, sulfone, sulfonamide, amide, carbonyl (-C(=O)-), C 1-6 hydrocarbon group S(=O)(=NH)- , Amine, hydrazinoyl, C 1-6 hydrocarbyl, halogenated C 1-6 hydrocarbyl, hydroxy substituted C 1-6 hydrocarbyl, amide substituted C 1-6 hydrocarbyl, C 1-6 hydrocarbyloxy, halogenated a C 1-6 hydrocarbon group, C 1-6 hydrocarbyloxy C 1-6 hydrocarbyl, C 1-6 hydrocarbyloxy C 1-6 hydrocarbon group, C 1-6 hydrocarbon group, C 1-6 hydrocarbon Mercapto group, C 1-6 hydrocarbyl carbonyl group, C 1-6 hydrocarbyl amino acyl group, C 1-6 hydrocarbyl amide group, halogenated C 1-6 hydrocarbyl amide group, C 1-6 hydrocarbyl oxyacyl group, C 1-6 hydrocarbyl amine amide Group, C 1-6 hydrocarbyl sulfone group, C 1-6 hydrocarbyl sulfonamide group, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 cycloalkoxy, halogenated C 3 -6 cycloalkoxy, C 3-6 cycloalkyl C 1-6 hydrocarbyl, C 3-6 cycloalkyloxy C 1-6 hydrocarbyl, C 3-6 cycloalkyl C 1-6 hydrocarbyloxy, C 3-6 cycloalkyl C 1-6 hydrocarbyloxy C 1-6 hydrocarbyloxy group, C 3-6 cycloalkylamino group, C 3-6 cycloalkyl C 1-6 hydrocarbylamino group, C 3-6 ring Alkyl mercapto group, halogenated C 3-6 cycloalkyl mercapto group, C 3-6 cycloalkyl C 1-6 hydrocarbon mercapto group, C 3-6 cycloalkyl sulfone group, C 3-6 cycloalkyl C 1-6 hydrocarbon sulfone Group, C 3-6 cycloalkylsulfonamide group, C 3-6 cycloalkyl C 1-6 hydrocarbyl sulfonamide group, C 3-6 cycloalkane carbonyl group, C 3-6 cycloalkyl C 1-6 hydrocarbyl carbonyl group , C 3-6 cycloalkylamino acyl group, C 3-6 cycloalkyl C 1-6 hydrocarbyl amino acyl group, C 3-6 cycloalkanamide group, C 3-6 cycloalkyl C 1-6 hydrocarbyl amide group, C 3-6 cycloalkylamino amide group, C 4-8 heterocycloalkyl, C 4-8 heterocycloalkyloxy, halogenated C 4-8 heterocycloalkyloxy, C 4-8 heterocycloalkyl Oxygen C 1-6 hydrocarbon group, halogenated C 4-8 heterocycloalkyloxy C 1-6 hydrocarbon group, C 4-8 heterocycloalkyl C 1-6 hydrocarbonoxy group, halogenated C 4-8 heterocycloalkyl group C 1-6 hydrocarbyloxy group, C 4-8 heterocycloalkyl C 1-6 hydrocarbyl group, C 4-8 heterocycloalkyl C 1-6 hydrocarbyloxy C 1-6 hydrocarbyl group, C 4-8 heterocycloalkane Amino group, C 4-8 heterocycloalkane mercapto group, C 4-8 heterocycloalkyl C 1-6 hydrocarbyl mercapto group, C 4-8 heterocycloalkylsulfone group, C 4-8 heterocycloalkyl C 1-6 Hydrocarbyl sulfone group, C 4-8 heterocycloalkylsulfonamide group, C 4-8 heterocycloalkyl C 1-6 hydrocarbyl sulfonamide group, C 4-8 heterocycloalkylcarbonyl group, C 4-8 heterocycloalkane C 1-6 hydrocarbylcarbonyl, C 4-8 heterocycloalkyl substituted by carbonyl, C 4-8 heterocycloalkylamino acyl, C 4-8 heterocycloalkylamido, C 4-8 heterocycloalkyl C 1-6 hydrocarbyl amide group, C 5-10 aryl group, C 5-10 aryloxy group, C 5-10 aryloxy group C 1-6 alkyl, C 5-10 aryl, C 1-6 alkyl, C 5-10 aryl, C 1-6 alkyloxy, C 5-10 arylamino, C 5-10 aryl mercapto, C 5-10 Aryl C 1-6 hydrocarbon mercapto group, C 5-10 aryl sulfone group, C 5-10 aryl C 1-6 hydrocarbon sulfone group, C 5-10 aryl sulfonamide group, C 5-10 aryl C 1 -6 alkyl sulfonamide group, C 5-10 aryl carbonyl group, C 5-10 aryl group, C 1-6 alkyl carbonyl group, C 5-10 arylamino group, C 5-10 aryl amide group or C 5-10 aryl amide base.
作为优选，上述的取代基选自氘、氰基、卤素(优选F、Cl、Br)、羟基、羧基、酯基、砜基、磺酰基氨基、羰基氨基、羰基、C 1-6烃基亚磺酰基氨基、胺基、肼酰基、C 1-6烃基、卤代的C 1-6烃基、羟基取代的C 1-6烃基、酰胺取代的C 1-6烃基、C 1-6烃氧基、卤代的C 1-6烃氧基、C 1-6烃氧基C 1-6烃基、C 1-6烃氧基C 1-6烃氧基。 Preferably, the above-mentioned substituents are selected from deuterium, cyano, halogen (preferably F, Cl, Br), hydroxyl, carboxyl, ester, sulfone, sulfonylamino, carbonylamino, carbonyl, C 1-6 hydrocarbyl sulfinyl Acylamino, amino, hydrazinoyl, C 1-6 hydrocarbyl, halogenated C 1-6 hydrocarbyl, hydroxyl-substituted C 1-6 hydrocarbyl, amide-substituted C 1-6 hydrocarbyl, C 1-6 hydrocarbyloxy, Halogenated C 1-6 hydrocarbyloxy group, C 1-6 hydrocarbyloxy C 1-6 hydrocarbyl group, C 1-6 hydrocarbyloxy C 1-6 hydrocarbyloxy group.
进一步优选地，上述的取代基选自氘、氰基、F、Cl、Br、羟基、羧基、酯基、砜基、磺酰胺基、酰胺基、羰基、甲基亚磺酰基氨基、乙基亚磺酰基氨基、异丙基亚磺酰基氨基、叔丁基亚磺酰基氨基、胺基、肼酰基、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、新戊基、环己基、卤代甲基(具体例如三氟甲基)、卤代乙基、卤代正丙基、卤代异丙基、卤代环丙基、卤代正丁基、卤代异丁基、卤代叔丁基、卤代环丁基、羟基甲基、羟基乙基、羟基正丙基、羟基异丙基、羟基环丙基、羟基正丁基、羟基异丁基、羟基叔丁基、羟基环丁基、羟基正戊基、羟基异戊基、羟基新戊基、羟基环己基、甲氧基、乙氧基、丙氧基。Further preferably, the above-mentioned substituents are selected from deuterium, cyano, F, Cl, Br, hydroxyl, carboxyl, ester, sulfone, sulfonamide, amide, carbonyl, methylsulfinylamino, ethyl sulfinyl Sulfonylamino, isopropylsulfinylamino, tert-butylsulfinylamino, amino, hydrazinoyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl Base, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, halomethyl (e.g. trifluoromethyl), haloethyl, halo-n-propyl, halo Substituted isopropyl, halogenated cyclopropyl, halogenated n-butyl, halogenated isobutyl, halogenated tert-butyl, halogenated cyclobutyl, hydroxymethyl, hydroxyethyl, hydroxyn-propyl, hydroxyiso Propyl, hydroxycyclopropyl, hydroxyn-butyl, hydroxyisobutyl, hydroxytert-butyl, hydroxycyclobutyl, hydroxyn-pentyl, hydroxyisopentyl, hydroxyneopentyl, hydroxycyclohexyl, methoxy , Ethoxy, Propoxy.
术语“烃基”是指烷基，烯基烷基和炔基烷基。The term "hydrocarbyl" refers to alkyl, alkenylalkyl and alkynylalkyl groups.
术语“烷基”是指直链、支链或环状的饱和的由碳和氢构成的取代基。烷基具体包括例如甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、新戊基、环己基、正己基、异己基、2,2,-甲基丁基和2,3-二甲基丁基、16-烷基、18-烷基。术语“C 1-20烷基”是指含有1-20个碳原子的直链、支链或环状的饱和烃基。当烷基被取代时，取代基可以在任何可使用的连接点上取代，取代基可以是单取代或多取代。例如取代基可以是烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、氘、卤素、硫醇、羟基、硝基、羧基、酯基、氰基，环烷基、芳基、杂芳基、环烷氧基、杂环烷 氧基、环烷硫基、氧代。 The term "alkyl" refers to a linear, branched or cyclic saturated substituent composed of carbon and hydrogen. The alkyl group specifically includes, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl , Cyclohexyl, n-hexyl, isohexyl, 2,2,-methylbutyl and 2,3-dimethylbutyl, 16-alkyl, 18-alkyl. The term "C 1-20 alkyl" refers to a linear, branched or cyclic saturated hydrocarbon group containing 1-20 carbon atoms. When the alkyl group is substituted, the substituent may be substituted at any available point of attachment, and the substituent may be mono- or poly-substituted. For example, substituents can be alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxy, ester, cyano, cycloalkyl, Aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo.
在涉及到具体命名时，取代基通常置于被取代的基团之前，例如“C 1-3烷氧基C 3-8环烷基C 1-6烷基”指C 1-6烷基，其被C 3-8环烷基取代，而该C 3-8环烷基又为C 1-3烷氧基取代，举例：甲氧基环丁基甲基的结构式为： When referring to specific naming, the substituent is usually placed before the substituted group. For example, "C 1-3 alkoxy C 3-8 cycloalkyl C 1-6 alkyl" refers to C 1-6 alkyl, It is substituted by a C 3-8 cycloalkyl group, and the C 3-8 cycloalkyl group is substituted by a C 1-3 alkoxy group. For example, the structural formula of methoxycyclobutyl methyl is:
Figure PCTCN2020074212-appb-000012
Figure PCTCN2020074212-appb-000012
术语“烯基”和“炔基”分别是指直链、支链或环状的含有双键和三键的不饱和烃基，优选2-20个碳原子，更优选2-12个碳原子。当被取代时，取代基可以在任何可使用的连接点上取代，取代基可以是单取代或多取代。例如取代基可以是选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、氘、卤素、硫醇、羟基、硝基、羧基、酯基、氰基，环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、氧代。The terms "alkenyl" and "alkynyl" respectively refer to linear, branched or cyclic unsaturated hydrocarbon groups containing double and triple bonds, preferably 2-20 carbon atoms, more preferably 2-12 carbon atoms. When substituted, the substituent can be substituted at any available point of attachment, and the substituent can be mono- or poly-substituted. For example, the substituent may be selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxy, ester, cyano, cycloalkane Group, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo.
术语“芳基”为碳环芳基，术语“杂芳基”指包含1-10个杂原子的杂芳香体系的基团，包括单环杂芳基和稠环杂芳基。杂原子包括氧，硫，氮，磷等。其中单环杂芳基包括但不限于呋喃、噻吩、吡咯、噻唑、咪唑、1,2,3-三氮唑、1,2,4-三氮唑、1,2,3-噻二唑，噁唑、1,2,4-噁二唑、1,3,4-噁二唑、吡啶、嘧啶、哒嗪、吡嗪、四氢呋喃、四氢吡咯、哌啶、哌嗪、吗啉、异噁唑啉等。稠环杂芳基包括但不限于喹啉、异喹啉、吲哚、苯并呋喃、苯并噻吩、嘌呤、吖啶、咔唑、芴、色烯酮、芴酮、喹喔啉、3,4-二氢萘酮、二苯并呋喃、氢化二苯并呋喃、苯并噁唑基等。杂芳基可以是取代的和未取代的。取代基例如是选自烷基、环烷基(如环丙烷基、环丁烷基和环戊烷基等)、烯基、炔基、叠氮、氨基、氘、烷氧基、烷硫基、烷基氨基，卤素、硫醇、羟基，硝基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、烷基硅基等。The term "aryl" is a carbocyclic aryl group, and the term "heteroaryl" refers to a group of a heteroaromatic system containing 1-10 heteroatoms, including monocyclic heteroaryl groups and condensed ring heteroaryl groups. Heteroatoms include oxygen, sulfur, nitrogen, phosphorus, etc. Wherein monocyclic heteroaryl groups include but are not limited to furan, thiophene, pyrrole, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazole, Oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, isoxa Oxazoline etc. Fused ring heteroaryl groups include, but are not limited to, quinoline, isoquinoline, indole, benzofuran, benzothiophene, purine, acridine, carbazole, fluorene, chromenone, fluorenone, quinoxaline, 3, 4-phthalone, dibenzofuran, hydrogenated dibenzofuran, benzoxazolyl, etc. Heteroaryl groups can be substituted and unsubstituted. Substituents are, for example, selected from alkyl, cycloalkyl (such as cyclopropyl, cyclobutanyl, cyclopentyl, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio , Alkylamino, halogen, mercaptan, hydroxy, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, alkane Silicon-based, etc.
术语“氘”是氢的同位素，原子质量是后者的2倍，与碳的结合更强。氘化“和”氘“表示氢在指定位置被替换为氘。一个“氘化的取代基”是取代基，其中至少一个氢被以指定的百分比富集的氘取代。The term "deuterium" is an isotope of hydrogen, the atomic mass is twice that of the latter, and the bond with carbon is stronger. "Deuterated" and "deuterium" mean that hydrogen is replaced with deuterium at a specified position. A "deuterated substituent" is a substituent in which at least one hydrogen is replaced by deuterium enriched in a specified percentage.
具体实施方式detailed description
下面结合具体实施例对本发明做进一步详细的说明，但本发明并不限于以下实施例。The present invention will be further described in detail below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.
本发明所用原料或试剂可通过常规方法合成或市售购得。The raw materials or reagents used in the present invention can be synthesized by conventional methods or commercially available.
实施例1Example 1
本实施例提供式Ia化合物，其化学结构如下：This example provides a compound of formula Ia, the chemical structure of which is as follows:
Figure PCTCN2020074212-appb-000013
Figure PCTCN2020074212-appb-000013
式Ia化合物可通过如下合成路线获得：The compound of formula Ia can be obtained by the following synthetic route:
Figure PCTCN2020074212-appb-000014
Figure PCTCN2020074212-appb-000014
式Ia化合物的制备方法具体包括如下步骤：The preparation method of the compound of formula Ia specifically includes the following steps:
制备化合物a’：将化合物a(40g,0.124mol)加入到400mL的1,4-二氧六环中，再分别加入联硼酸频那醇酯(47.4g,0.186mol)，醋酸钾(24.4g，0.249mol)，最后加入Pb(dppf)Cl 2(4g，10％W)，氮气保护下，加热到80℃反应2小时。减压浓缩去除溶剂，得化合物a’粗品。 Preparation of compound a': add compound a (40g, 0.124mol) to 400mL of 1,4-dioxane, then add pinacol diborate (47.4g, 0.186mol), potassium acetate (24.4g) , 0.249mol), and finally add Pb(dppf)Cl 2 (4g, 10% W), under the protection of nitrogen, heat to 80°C and react for 2 hours. The solvent was removed by concentration under reduced pressure to obtain crude compound a'.
制备化合物c：将化合物a’粗品(0.124mol)加入到400mL甲苯和100mL水的混合液中，再加入化合物b(48g，0.186mol)，碳酸钠(26.4g，0.249mol)，最后加入(PPh 3) 4Pd(4g，10％W)。氮气保护下加热到100℃反应过夜。将反应液冷却至室温，垫硅藻土过滤，减压浓缩，残留物经柱层析纯化得化合物c粗品26g，两步产率50.3％。 Preparation of compound c: add the crude compound a'(0.124mol) to a mixture of 400mL toluene and 100mL water, then add compound b (48g, 0.186mol), sodium carbonate (26.4g, 0.249mol), and finally add (PPh 3 ) 4 Pd (4g, 10% W). Under the protection of nitrogen, it was heated to 100°C and reacted overnight. The reaction solution was cooled to room temperature, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 26 g of crude compound c, with a two-step yield of 50.3%.
制备化合物d：将化合物c(26g，0.0628mol)加入到300mL的MeOH/H 2O的混合液中，再加入LiOH·H 2O(3.2g，0.075mol)，加热到40℃ 反应过夜。将反应液倒入水中，用3M的盐酸将体系调至pH约为3，有固体析出，过滤，将固体减压下去除残留溶剂，得化合物d(16g，64％)，为灰白色粉末。 Preparation of compound d: Compound c (26g, 0.0628mol) was added to 300mL of a MeOH/H 2 O mixture, and LiOH·H 2 O (3.2g, 0.075 mol) was added, and heated to 40°C for overnight reaction. The reaction solution was poured into water, the system was adjusted to pH about 3 with 3M hydrochloric acid, a solid was precipitated, filtered, and the solid was removed under reduced pressure to remove residual solvent to obtain compound d (16 g, 64%) as an off-white powder.
制备化合物f：将化合物d(7.2g，18.04mmol)加入到70mL的DCM中，再分别加入化合物e(4.3g，21.64mmol)，EDCI(5.2g，27.06mmol)，HOBT(3.6g，27.06mmol)，最后加入三乙胺(5.5g，54.12mmol)，室温下反应3小时。将反应液倒入水中，用DCM萃取，将有机相减压浓缩，残留物经柱层析纯化得化合物f(7g，71.4％)，为白色粉末。Preparation of compound f: Compound d (7.2g, 18.04mmol) was added to 70mL of DCM, then compound e (4.3g, 21.64mmol), EDCI (5.2g, 27.06mmol), HOBT (3.6g, 27.06mmol) were added separately ), finally add triethylamine (5.5g, 54.12mmol), and react at room temperature for 3 hours. The reaction solution was poured into water, extracted with DCM, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound f (7g, 71.4%) as a white powder.
制备式Ia化合物：将化合物f(5g，9.1mmol)加入到500mL的甲醇中，再加入Pd/C(500mg，10％W)，常压氢气室温反应48小时。将反应液垫硅藻土过滤，减压浓缩，再用甲醇打浆2次，得Ia化合物(2g，产率60.6％)，为白色粉末。The compound of formula Ia was prepared: compound f (5g, 9.1mmol) was added to 500mL of methanol, then Pd/C (500mg, 10% W) was added, and hydrogen gas was reacted at room temperature under normal pressure for 48 hours. The reaction liquid was filtered through a pad of Celite, concentrated under reduced pressure, and then beaten with methanol twice to obtain compound Ia (2 g, yield 60.6%) as a white powder.
对得到的目标产品Ia进行了氢核磁共振 1H-NMR(500MHz，DMSO)和质谱测试，结果如下： The obtained target product Ia was subjected to hydrogen nuclear magnetic resonance 1 H-NMR (500MHz, DMSO) and mass spectrometry. The results are as follows:
1H-NMR谱图中吸收峰：δ＝12.81(s,1H),12.43(s,1H),9.47(t,J＝6.1Hz,1H),8.91(d,J＝1.8Hz,1H),8.51(d,J＝9.3Hz,1H),8.09(d,J＝1.8Hz,1H),7.65(d,J＝9.3Hz,1H),7.53–7.45(m,2H),7.34–7.25(m,3H),4.02(d,J＝6.1Hz,2H). 1 H-NMR spectrum absorption peak: δ = 12.81 (s, 1H), 12.43 (s, 1H), 9.47 (t, J = 6.1 Hz, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.51(d,J=9.3Hz,1H), 8.09(d,J=1.8Hz,1H), 7.65(d,J=9.3Hz,1H),7.53-7.45(m,2H),7.34-7.25(m ,3H),4.02(d,J=6.1Hz,2H).
m/z[MH] +:367.1。计算得出产品具有分子式C 18H 14N 4O 5，精确分子质量(exact mass)为366.096。 m/z[MH] + : 367.1. The calculated product has a molecular formula of C 18 H 14 N 4 O 5 and an exact mass of 366.096.
以实施例1的方法或相近的方法，可以制备得到本申请其他化合物。Using the method of Example 1 or a similar method, other compounds of this application can be prepared.
药效等试验Drug efficacy and other tests
一、化合物活性测试：1. Compound activity test:
1、试验方法1. Test method
利用FP assay方法检测受试化合物分别对PHD1、PHD2和PHD3的半抑制浓度IC 50(把酶活性抑制至50％时所需的化合物的浓度)。 Detecting the test compound using the FP assay method, respectively (the concentration required for 50% inhibition of enzyme activity of the compound) IC 50 concentration for the half PHD1, PHD2, and PHD3 suppressed.
2、试验结果2. Test results
结果显示目标化合物(Ia)对PHD1、PHD2和PHD3具有非常强的抑制作用，IC 50值均小于100nM。这一强抑制作用对与HIF-PHD调节有关的病症或疾病，例如贫血和缺血等疾病的治疗具有重要的治疗意义。 The results show that the target compound (Ia) has a very strong inhibitory effect on PHD1, PHD2 and PHD3, with IC 50 values less than 100 nM. This strong inhibitory effect has important therapeutic significance for the treatment of diseases or diseases related to HIF-PHD regulation, such as anemia and ischemia.
二、药物动力学实验2. Pharmacokinetic experiment
1、实验方法：1. Experimental method:
实验动物：雄性小鼠，体重21-22g；Experimental animals: male mice, weighing 21-22g;
供试品配制：将目标化合物Ia配制成0.4mg/mL(为静脉给药用)和1.0mg/mL(为口服给药用)，待用。给药途径：口服/静脉注射。给药容量及频率：5mL/kg(静脉注射)或10mL/kg(口服)，单次给药。Preparation of the test product: The target compound Ia was prepared as 0.4 mg/mL (for intravenous administration) and 1.0 mg/mL (for oral administration), and then used. Route of administration: oral/intravenous injection. Dosing volume and frequency: 5mL/kg (intravenous injection) or 10mL/kg (oral), single dose.
样品采集：按照下列时间点采集血液，给药后5min、15min、30min、1hr、2hr、4hr、8hr和24hr取血。Sample collection: Blood was collected at the following time points, 5min, 15min, 30min, 1hr, 2hr, 4hr, 8hr and 24hr after administration.
2、样品分析及结果2. Sample analysis and results
样品分析：使用LC-MS/MS方法对采集样品进行检测。使用仪器型号为LCMSMS-035(triple quadruple，6500+)。Sample analysis: Use the LC-MS/MS method to detect the collected samples. The instrument model used is LCMSMS-035 (triple quadruple, 6500+).
药物动力学数据分析：使用WinNolin按照非房室模型法对所得血药浓度数据进行拟合和计算，部分结果总结在以下表中。Pharmacokinetic data analysis: Use WinNolin according to the non-compartmental model method to fit and calculate the obtained blood drug concentration data. Part of the results are summarized in the following table.
按照非房室模型法计算出的目标化合物药物动力学参数The pharmacokinetic parameters of the target compound calculated according to the non-compartmental model method
Figure PCTCN2020074212-appb-000015
Figure PCTCN2020074212-appb-000015
Figure PCTCN2020074212-appb-000016
Figure PCTCN2020074212-appb-000016
试验结果表明本发明化合物具有良好的药物动力学特征。The test results show that the compound of the present invention has good pharmacokinetic characteristics.
以上实施例仅是代表性的。通过上述实施例可见，本发明的化合物是理想的高效HIF-PHD抑制剂，可期望用于治疗或预防与HIF-PHD调节有关的病症或疾病，例如贫血和缺血等疾病，并取得非常好的效果，其还可以制成口服制剂(片剂或胶囊等)。用本发明化合物制成的片剂或胶囊可被服用每日一次或多次。本发明化合物还可和其他它药物结合制成复方制剂。The above embodiments are only representative. It can be seen from the above examples that the compounds of the present invention are ideal and highly effective HIF-PHD inhibitors, and can be expected to be used to treat or prevent diseases or diseases related to HIF-PHD regulation, such as anemia and ischemia, and achieve very good results. It can also be made into oral preparations (tablets or capsules, etc.). The tablets or capsules made with the compounds of the present invention can be taken once or multiple times a day. The compound of the present invention can also be combined with other drugs to prepare a compound preparation.
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。The above-mentioned embodiments are only to illustrate the technical concept and features of the present invention, and their purpose is to enable those familiar with the art to understand the content of the present invention and implement them accordingly, and cannot limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention should be covered by the protection scope of the present invention.

Claims (14)

  1. 一种具有通式(I)所示结构的哒嗪衍生物，A pyridazine derivative with the structure represented by the general formula (I),
    Figure PCTCN2020074212-appb-100001
    Figure PCTCN2020074212-appb-100001
    其中：among them:
    R 1选自氢、C 1-6烷基或取代的C 1-6烷基； R 1 is selected from hydrogen, C 1-6 alkyl or substituted C 1-6 alkyl;
    R 2选自C 1-6烷基、取代的C 1-6烷基、羧基或-CH 2COOH； R 2 is selected from C 1-6 alkyl, substituted C 1-6 alkyl, carboxyl or -CH 2 COOH;
    R 3、R 4独自地选自氢、C 1-6烷基、取代的C 1-6烷基、氟、氯、溴、碘、羟基； R 3 and R 4 are independently selected from hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, fluorine, chlorine, bromine, iodine, and hydroxyl;
    R 5为未取代的，或被选自氟、氯、溴、碘、羟基、羧基、硝基、C 1-6烃基、C 1-6烷氧基、氰基、酯基、酰胺基和磺酰基中的一个、两个、三个、四个或更多个取代基所取代的C 1-20烷基、C 5-20芳基或C 5-20杂芳基； R 5 is unsubstituted or selected from fluorine, chlorine, bromine, iodine, hydroxy, carboxy, nitro, C 1-6 hydrocarbon, C 1-6 alkoxy, cyano, ester, amide and sulfonate C 1-20 alkyl, C 5-20 aryl or C 5-20 heteroaryl substituted by one, two, three, four or more substituents in the acyl group;
    X选自N或CH；X is selected from N or CH;
    Y选自NH、CH 2、O、CO、SO 2、SO。 Y is selected from NH, CH 2 , O, CO, SO 2 , SO.
  2. 根据权利要求1所述的具有通式(I)所示结构的哒嗪衍生物，其特征在于：R 1为氢，R 2为羧基或-CH 2COOH，R 3为羟基。 The pyridazine derivative with the structure represented by the general formula (I) according to claim 1, characterized in that: R 1 is hydrogen, R 2 is carboxyl or -CH 2 COOH, and R 3 is hydroxyl.
  3. 根据权利要求1或2所述的具有通式(I)所示结构的哒嗪衍生物，其特征在于：R 4与R 3不同，优选地，R 3为羟基，R 4为氢、C 1-6烷基、氟、氯、溴或碘。 The pyridazine derivative having the structure represented by the general formula (I) according to claim 1 or 2, characterized in that: R 4 is different from R 3 , preferably, R 3 is a hydroxyl group, R 4 is hydrogen, and C 1 -6 alkyl, fluorine, chlorine, bromine or iodine.
  4. 根据权利要求1至3任一项所述的具有通式(I)所示结构的哒嗪衍生物，其特征在于：所述的C 5-20杂芳基中杂原子选自氮、氧和硫中的一个或多个。 The pyridazine derivative with the structure represented by the general formula (I) according to any one of claims 1 to 3, wherein the heteroatom in the C 5-20 heteroaryl group is selected from nitrogen, oxygen and One or more of sulfur.
  5. 根据权利要求1至4任一项所述的具有通式(I)所示结构的哒嗪衍生物，其特征在于：当R 5为取代的C 5-20芳基或C 5-20杂芳基时，所述的C 5-20芳基或C 5-20杂芳基上的取代基处于所述的C 5-20芳基或C 5-20杂芳基与Y相连的碳的非邻位。 The pyridazine derivative having the structure represented by the general formula (I) according to any one of claims 1 to 4, characterized in that: when R 5 is a substituted C 5-20 aryl or C 5-20 heteroaryl group, substituted on the C 5-20 aryl group or C 5-20 heteroaryl group is attached to the non-ortho-C 5-20 aryl group or C 5-20 heteroaryl with carbon Y Bit.
  6. 根据权利要求1至5任一项所述的具有通式(I)所示结构的哒嗪衍生 物，其特征在于：R 5为
    Figure PCTCN2020074212-appb-100002
    Figure PCTCN2020074212-appb-100003
    其中，R 6选自C 1-6烷氧基，R 7选自氟、氯、溴或碘。     The pyridazine derivative having the structure represented by the general formula (I) according to any one of claims 1 to 5, characterized in that: R 5 is
    Figure PCTCN2020074212-appb-100002
    Figure PCTCN2020074212-appb-100003
    Wherein, R 6 is selected from C 1-6 alkoxy, and R 7 is selected from fluorine, chlorine, bromine or iodine.
  7. 根据权利要求1所述的具有通式(I)所示结构的哒嗪衍生物，其特征在于：所述的哒嗪衍生物具有通式(II)所示的结构：The pyridazine derivative having the structure represented by the general formula (I) according to claim 1, wherein the pyridazine derivative has the structure represented by the general formula (II):
    Figure PCTCN2020074212-appb-100004
    Figure PCTCN2020074212-appb-100004
    其中：among them:
    R 2选自C 1-6烷基、取代的C 1-6烷基、羧基或-CH 2COOH； R 2 is selected from C 1-6 alkyl, substituted C 1-6 alkyl, carboxyl or -CH 2 COOH;
    R 3、R 4独自地选自氢、C 1-6烷基、取代的C 1-6烷基、氟、氯、溴、碘、羟基； R 3 and R 4 are independently selected from hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, fluorine, chlorine, bromine, iodine, and hydroxyl;
    R 5为未取代的，或被选自氟、氯、溴、碘、羟基、羧基、硝基、C 1-6烃基、C 1-6烷氧基、氰基、酯基、酰胺基和磺酰基中的一个、两个、三个、四个或更多个取代基所取代的C 1-20烷基、C 5-20芳基或C 5-20杂芳基； R 5 is unsubstituted or selected from fluorine, chlorine, bromine, iodine, hydroxy, carboxy, nitro, C 1-6 hydrocarbon, C 1-6 alkoxy, cyano, ester, amide and sulfonate C 1-20 alkyl, C 5-20 aryl or C 5-20 heteroaryl substituted by one, two, three, four or more substituents in the acyl group;
    X选自N或CH；X is selected from N or CH;
    Y选自NH、CH 2、O、CO、SO 2、SO。 Y is selected from NH, CH 2 , O, CO, SO 2 , SO.
  8. 根据权利要求7所述的具有通式(I)所示结构的哒嗪衍生物，其特征在于：The pyridazine derivative having the structure represented by the general formula (I) according to claim 7, characterized in that:
    R 2为羧基或-CH 2COOH； R 2 is a carboxyl group or -CH 2 COOH;
    R 3为羟基； R 3 is a hydroxyl group;
    R 4选自氢、C 1-6烷基、氟或氯； R 4 is selected from hydrogen, C 1-6 alkyl, fluorine or chlorine;
    R 5选自
    Figure PCTCN2020074212-appb-100005
    R 5 is selected from
    Figure PCTCN2020074212-appb-100005
    X选自N或CH；X is selected from N or CH;
    Y选自NH或O。Y is selected from NH or O.
  9. 根据权利要求8所述的具有通式(I)所示结构的哒嗪衍生物，其特征在于：所述的哒嗪衍生物具有如下结构：The pyridazine derivative with the structure represented by the general formula (I) according to claim 8, wherein the pyridazine derivative has the following structure:
    Figure PCTCN2020074212-appb-100006
    Figure PCTCN2020074212-appb-100006
  10. 根据权利要求1至8任一项所述的具有通式(I)所示结构的哒嗪衍生物，其特征在于：所述的哒嗪衍生物为选自如下结构式表示的化合物中的一种：The pyridazine derivative having the structure represented by the general formula (I) according to any one of claims 1 to 8, characterized in that: the pyridazine derivative is one selected from the group of compounds represented by the following structural formulas :
    Figure PCTCN2020074212-appb-100007
    Figure PCTCN2020074212-appb-100007
    Figure PCTCN2020074212-appb-100008
    Figure PCTCN2020074212-appb-100008
    Figure PCTCN2020074212-appb-100009
    Figure PCTCN2020074212-appb-100009
    Figure PCTCN2020074212-appb-100010
    Figure PCTCN2020074212-appb-100010
    Figure PCTCN2020074212-appb-100011
    Figure PCTCN2020074212-appb-100011
  11. 一种制备如权利要求8至10任一项所述的哒嗪衍生物的制备方法，包括以下步骤：A method for preparing the pyridazine derivative according to any one of claims 8 to 10, comprising the following steps:
    Figure PCTCN2020074212-appb-100012
    Figure PCTCN2020074212-appb-100012
    (1)化合物A和化合物B经Suzuki偶联，得到化合物C；(1) Compound A and compound B are coupled by Suzuki to obtain compound C;
    (2)化合物C在碱性条件下水解，得到羧酸化合物D；(2) Compound C is hydrolyzed under alkaline conditions to obtain carboxylic acid compound D;
    (3)羧酸化合物D与化合物E发生酯化反应，再去除保护基得到目标化合物；其中，(3) The carboxylic acid compound D and the compound E undergo an esterification reaction, and then the protective group is removed to obtain the target compound; wherein,
    Z选自Cl、Br、I、OTf；Z is selected from Cl, Br, I, OTf;
    PG选自苄基；PG is selected from benzyl;
    n为0或1；n is 0 or 1;
    R 4、R 5、X和Y的定义同权利要求8。 The definitions of R 4 , R 5 , X and Y are the same as in claim 8.
  12. 如权利要求1至10中任一项权利要求所述的具有通式(I)所示结构的哒嗪衍生物在制备预防和/或治疗与HIF调节有关的适应症的药物中的用途。The use of the pyridazine derivative having the structure represented by the general formula (I) according to any one of claims 1 to 10 in the preparation of a medicine for preventing and/or treating indications related to HIF regulation.
  13. 根据权利要求12所述的用途，其特征在于：所述与HIF调节有关的适应症包括贫血和缺血。The use according to claim 12, wherein the indications related to HIF regulation include anemia and ischemia.
  14. 一种预防和/或治疗与HIF调节有关的适应症的药物，其特征在于：含有如权利要求1至10中任一项权利要求所述的具有通式(I)所示结构的哒嗪衍生物。A medicine for preventing and/or treating indications related to HIF regulation, characterized in that it contains the pyridazine derivative with the structure represented by the general formula (I) as claimed in any one of claims 1 to 10 Things.
PCT/CN2020/074212 2019-02-02 2020-02-03 Pyridazine derivative, and preparation method and medicinal use thereof WO2020156571A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10010422A1 (en) * 2000-03-03 2001-09-06 Bayer Ag New 6-(4-carboxy-phenyl)-dihydropyridazinone esters or amides, having erythropoietin sensitizing and erythropoiesis stimulating activity, useful for treating anemia
CN101506149A (en) * 2006-06-26 2009-08-12 宝洁公司 Prolyl hydroxylase inhibitors and methods of use
CN102526044A (en) * 2001-12-06 2012-07-04 法布罗根股份有限公司 Methods of increasing endogenous erythropoietin EPO
CN107417605A (en) * 2017-08-02 2017-12-01 江苏艾立康药业股份有限公司 Act on the pyridine derivative compound of prolyl hydroxylase

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102977016B (en) * 2003-06-06 2015-01-14 菲布罗根有限公司 Nitrogen-containing heteroaryl compounds and their use in increasing endogeneous erythropoietin
JP5557832B2 (en) * 2008-03-18 2014-07-23 メルク・シャープ・アンド・ドーム・コーポレーション Substituted 4-hydroxypyridine-5-carboxamide
MX2011013879A (en) * 2009-06-30 2012-02-01 Merck Sharp & Dohme Substituted 4-hydroxypyrimidine-5-carboxamides.
US9040522B2 (en) * 2013-03-29 2015-05-26 Takeda Pharmaceutical Company Limited 6-(5-hydroxy-1H-pyrazol-1-yl)nicotinamide inhibitors of PHD

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10010422A1 (en) * 2000-03-03 2001-09-06 Bayer Ag New 6-(4-carboxy-phenyl)-dihydropyridazinone esters or amides, having erythropoietin sensitizing and erythropoiesis stimulating activity, useful for treating anemia
CN102526044A (en) * 2001-12-06 2012-07-04 法布罗根股份有限公司 Methods of increasing endogenous erythropoietin EPO
CN101506149A (en) * 2006-06-26 2009-08-12 宝洁公司 Prolyl hydroxylase inhibitors and methods of use
CN107417605A (en) * 2017-08-02 2017-12-01 江苏艾立康药业股份有限公司 Act on the pyridine derivative compound of prolyl hydroxylase

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"CAS RN 1112002-47-7 1112021-80-3 1112021-85-8", STN REGISTRY, 26 February 2009 (2009-02-26), DOI: 20200308150637X *
"CAS RN 1358651-85-0 1358800-51-7", STN REGISTRY, 29 February 2012 (2012-02-29), DOI: 20200308150602X *
"CAS RN 1359032-85-1 1359497-93-0", STN REGISTRY, 1 March 2012 (2012-03-01), DOI: 20200308150637X *

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