Novel proline hydroxylase inhibitor as well as preparation method, composition and application thereof

Abstract

The invention discloses a novel proline hydroxylase (PHD) inhibitor and a preparation method, a pharmaceutical composition and application thereof. The novel proline hydroxylase (PHD) inhibitor can remarkably improve the activity of inhibiting PHDs, improve the effect of producing EPO, improve the bioavailability of a compound, reduce the dosage of a drug and reduce toxic and side effects.

Description

Technical Field

[0001] The present invention relates to a novel proline hydroxylase domain (PHDs) inhibitor, a preparation method thereof, a pharmaceutical composition and application thereof in the treatment of anemia. Background Art

[0002] Anemia occurs when a person does not have enough healthy red blood cells to deliver enough oxygen to the body's tissues. It often occurs in people with chronic kidney disease (CKD) because their kidneys do not produce enough erythropoietin (EPO). EPO, also known as erythrocyte stimulating factor or erythropoietin, is an endogenous glycoprotein hormone in the human body that stimulates the production of red blood cells. EPO is normally secreted by the kidneys, and endogenous EPO increases under conditions of reduced oxygen (hypoxia). Anemia caused by CKD can have a profound impact on a person's quality of life, causing fatigue, dizziness, shortness of breath, and cognitive dysfunction.

[0003] Anemia caused by chemotherapy for malignant tumors refers to anemia caused by chemotherapy for various malignant tumors other than hematopoietic tissues. The type and degree of anemia vary depending on the type of malignant tumor, the course of the disease, and the treatment method. The clinical manifestations vary with the type of tumor, the site of occurrence, and the degree of metastasis and spread. Cancer chemotherapy can cause anemia. There is also hemorrhagic anemia, and 20% of women may suffer from anemia.

[0004] Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor for cells to adapt to hypoxic environments. It is stably expressed in tissue anemia and inflammatory diseases and plays an important role in alleviating the disease. Proline Hydroxylase Domain (PHDs) can hydroxylate and degrade HIF and is the main protease for degrading HIF in the body. PHD inhibitors can effectively increase the content of HIF protein in the body, initiate the transcription of a series of genes related to lipid metabolism, angiogenesis, cell survival, etc., increase oxygen transport, reduce oxygen consumption, and enable cells to survive normally under hypoxic conditions, which has positive significance for the treatment of anemia and inflammatory diseases.

[0005] China is a country with a high incidence of chronic kidney disease, and more than half of CKD patients have anemia. It is estimated that the prevalence of chronic kidney disease in Chinese adults is 10.8%, and there are about 120 million adult chronic kidney disease patients. The incidence of chronic kidney disease is also similar worldwide, with a total of about 600-700 million CKD patients. Adding other types of anemia, the total number of anemia patients is even larger.

[0006] Injection of humanized erythropoietin (RH-EPO) is a common method for treating anemia caused by chronic kidney disease. In 1989, Amgen, a US company, developed a new erythropoietin drug, Epoetin alfa, using recombinant DNA technology and was approved by the US FDA for marketing. It is mainly used to treat pernicious anemia caused by long-term renal dialysis. In order to retain the activity of RH-EPO and reduce the frequency of administration, scientists have developed the second generation of EPO drugs. The representative drug is darbepoetin alfa, which has an elimination half-life of 25.3h, about three times that of Epoetin alfa. The optimal dosing frequency is once a week, and once every two weeks for patients with stable disease. This greatly improves patient compliance. The drug has been approved by the United States and the European Union for the treatment of anemia associated with chronic renal failure and anemia caused by chemotherapy in tumor patients. EPO is also used for anemia in cancer patients undergoing radiation and / or chemotherapy to reduce their need for blood transfusions. Erythropoeisis Stimulating Agent (ESA) therapy has also become an important method for treating tumor-related anemia. Recombinant human erythropoietin (HR-EPO) is the most commonly used and most studied ESA drug in clinical practice. Although the market for EPO therapy is growing, recombinant HR-EPO therapy requires intravenous injection 1 to 3 times a week for up to 12 weeks, which also increases the inconvenience of patient treatment. Therefore, the discovery and development of oral anemia treatment drugs is a long-term research goal of pharmaceutical scientists.

[0007] Proline hydroxylase (PHD) degrades hypoxia-inducible factor (HIF) through hydroxylation. Proline hydroxylase inhibitors can reduce the degradation of HIF by inhibiting PHD activity, increase the production of EPO in the body, and achieve the purpose of treating anemia.

[0008] Roxadustat, the world's first PHD inhibitor, was first launched in China in 2019, but was rejected by the FDA because its clinical safety did not reach non-inferiority to injection erythropoiesis-stimulating agent (ESA) treatment. Currently, another four PHD inhibitors (Daprodustat, Vadadustat, Molidustat and Enarodustat) have completed Phase III clinical trials and are being launched in Japan first. Although these inhibitors can achieve therapeutic effects, none of them are non-inferior to ESA. Therefore, it is very necessary to discover more effective, safer and long-acting PHD inhibitors as treatment drugs for anemia.

[0009]

[0010] Among these drugs, Vadadustat was non-inferior to Darbepoetin Alfa in both efficacy and cardiovascular safety in a Phase III clinical trial for the treatment of dialysis patients (N. Engl. J. Med. 2021, 384, 1601). In a Phase III clinical trial for the treatment of non-dialysis patients, although the efficacy was non-inferior, it was not non-inferior to Darbepoetin Alfa in terms of cardiovascular safety (N. Engl. J. Med. 2021, 384, 1589). Summarizing the clinical results, it was found that most of the reported clinical toxicities and side effects occurred in patients treated with high doses (J. Clin. Med. 2021, 10, 839). Therefore, for compounds of the same structural type, improving the drug's PHD inhibitory activity and reducing the dosage may be an important way to improve drug safety.

[0011] The kidneys control erythropoietin production in adults, and the anemia that accompanies renal failure is a major medical problem. The liver controls erythropoietin production during the fetal period, but this is suppressed shortly after birth (Science 2010, 329, 407). Systemic PHD2 inactivation (inhibition of PHD2) has been found to increase renal but not hepatic erythropoietin production. Simultaneous genetic inactivation of all three PHD paralogs (simultaneous inhibition of PHD1, PHD2, and PHD3, i.e., Pan-PHD or pan-PHD inhibitors) reactivates hepatic erythropoietin production. Pan-PHD inhibitors can activate liver production of EPO in cases where the kidneys are completely incapable of functioning, so this class of compounds is expected to be applicable to more patients and have greater development potential. Summary of the invention

[0012] In order to find a safer and more effective PHD inhibitor, the inventors designed and synthesized a series of novel Vadadustat derivatives, and tested their effects on inhibiting PHD activity and promoting EPO production. It was unexpectedly found that in Vadadustat analogs, the 3-chlorophenyl group was replaced with a bicyclic group, and the compound in which the hydroxyl group ortho-position on the pyridine ring was substituted by, for example, an alkyl group, can significantly improve its activity in inhibiting PHDs. For example, the activity of compound I-11 (MTB-1936, imidazole) in inhibiting PHD1, PHD2 and PHD3 was 106, 413 and 12.5 times higher than that of Vadadustat, respectively. The PHD2 inhibitory activity that can increase EPO production is the most critical, which can greatly reduce the dosage and improve the safety of clinical medication. In the case where the kidneys are completely unable to function, the simultaneous inhibition of the activities of PHD1, PHD2 and PHD3 can activate the liver to produce EPO.

[0013]

[0014] In view of this, this article provides a new type of proline hydroxylase (PHD) inhibitor, which can significantly improve the activity of inhibiting PHDs and improve the effect of EPO production, while improving the bioavailability of the compound, reducing the drug dosage and reducing toxic side effects.

[0015] In one aspect, there is provided a compound of formula I or a prodrug thereof, or a deuterated compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0016]

[0017]

[0018] in:

[0019] R 1 C 1-6 Alkyl, or C 3-7 Cycloalkyl; preferably methyl, ethyl, n-propyl, isopropyl, or cyclopropyl; more preferably methyl or ethyl; more preferably methyl;

[0020] R 2 Selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aryl, 5-11 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S, NH2, CN, halogen (such as F, Cl, Br, I), and OH; preferably selected from H, methyl, ethyl, n-propyl, isopropyl, and cyclopropyl; more preferably H.

[0021] Ar is a carbocyclic fused phenyl, a heterocyclic fused phenyl, a carbocyclic fused heteroaryl, or a heterocyclic fused heteroaryl, preferably a carbocyclic fused phenyl, or a heterocyclic fused phenyl; the carbocyclic ring is a saturated or unsaturated 5-membered or 6-membered carbocyclic ring, the heterocyclic ring is a saturated or unsaturated 5-membered or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S on the ring, and the heteroaryl is a 6-membered heteroaryl containing 1 or 2 N atoms on the ring; the carbocyclic fused phenyl, heterocyclic fused phenyl, carbocyclic fused heteroaryl, and heterocyclic fused heteroaryl are optionally substituted by 1 or more selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, OH, CN, NH2, mono- or di-C 1-6 Alkylamino, halogen substituents, preferably, the substituent is C 1-6 alkyl;

[0022] Preferably, Ar is selected from, but not limited to, the following groups:

[0023]

[0024]

[0025] Among them, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 Each independently selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, or isopropyl), C 3-7 Cycloalkyl (e.g., cyclopropyl), OH, CN, NH2, halogen (e.g., Cl, Br, I, or F), preferably, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 Each is independently selected from H, methyl, ethyl, and n-propyl, and more preferably each is independently H or methyl.

[0026] Preferably, Ar is selected from, but not limited to, the following groups:

[0027]

[0028] Preferably, the compound of formula I or its prodrug, or the deuterated product of the compound of formula I or its prodrug, or their pharmaceutically acceptable salts, is the following compound of formula I or its prodrug, or the deuterated product of the compound of formula I or its prodrug, or their pharmaceutically acceptable salts:

[0029]

[0030]

[0031]

[0032]

[0033] or

[0034] Herein, examples of "prodrugs" include, but are not limited to, for example, esters formed between a carboxyl group in Formula I and an alcohol, such as methanol, ethanol, propanol or isopropanol, and esters formed between a hydroxyl group and a carboxylic acid, such as acetic acid, propionic acid, isopropionic acid, butyric acid or isobutyric acid. The prodrugs can be prepared by conventional methods in the art.

[0035] Herein, examples of "pharmaceutically acceptable salts" include, but are not limited to, alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), or ammonium salts, etc. Alternatively, when the compound of formula I or its prodrug, or the deuterated substance of the compound of formula I or its prodrug has a basic functional group, examples thereof include, but are not limited to, salts formed with, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., as well as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. The pharmaceutically acceptable salts can be prepared by conventional methods in the art.

[0036] The compound of formula I or its prodrug, or the deuterated substance of the compound of formula I or its prodrug, or their pharmaceutically acceptable salts can be synthesized by a method comprising the following steps.

[0037]

[0038] Among them, R x C 1-6 Alkyl; R y H or C 1-6 Alkyl; R z C 1-6 Alkyl; Ar, R 1 , R 2 As defined above. Conventional methods can be used to convert bromide i into boride ii. Boride ii or boride iii reacts with dichloride iv to obtain monochloride v, which is alkoxylated to form alkoxy cyanide vi, which is then hydrolyzed to obtain carboxylic acid intermediate compound vii, which is reacted with glutamic acid alkyl ester to obtain compound viii, which is then dealkylated to obtain the target product.

[0039] Another aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned compound of formula I or a prodrug thereof, or a deuterated substance of the compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0040] The pharmaceutical composition can be used for preventing or treating anemia, preferably for preventing or treating anemia caused by chronic kidney disease, anemia caused by excessive blood loss, anemia caused by malignant tumors, or anemia caused by treatment of malignant tumors.

[0041] On the other hand, the present invention provides the use of the above-mentioned compound of formula I or its prodrug, or the deuterated product of the compound of formula I or its prodrug, or their pharmaceutically acceptable salts or the above-mentioned pharmaceutical composition for preparing a drug for preventing or treating anemia, preferably for preparing a drug for preventing or treating anemia caused by chronic kidney disease, anemia caused by excessive blood loss, anemia caused by malignant tumors, or anemia caused by treatment of malignant tumors.

[0042] On the other hand, the present invention provides a method for preventing or treating anemia, comprising administering to an individual in need thereof an effective amount of the compound of formula I or its prodrug, or a deuterated substance of the compound of formula I or its prodrug, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof; preferably, the anemia is anemia caused by chronic kidney disease, anemia caused by excessive blood loss, anemia caused by malignant tumors, or anemia caused by treatment of malignant tumors.

[0043] The compound of formula I or its prodrug, or the deuterated substance of the compound of formula I or its prodrug, or their pharmaceutically acceptable salts or pharmaceutical compositions described herein can be used alone or in combination with other drugs. DETAILED DESCRIPTION

[0044] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate the present invention by way of example and are not used to limit the present invention.

[0045] Example 1 Preparation of Compounds

[0046] 1.1. Preparation of Compound I-1

[0047]

[0048] Compound 1 (1.0 g, 5.07 mmol), diboronic acid pinacol ester (2.6 g, 10.14 mmol), AcOK (2.5 g, 25.35 mmol), PdCl2(dppf) (185 mg, 0.25 mmol)) was added with dioxane (20 mL) under nitrogen protection, reacted at 90 ° C for 4 h, cooled to room temperature, added with EA (100 mL) and H2O (20 mL), filtered through a celite pad, the aqueous layer was extracted with EA (2x20 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated, and the residue was purified by silica gel column to obtain white solid compound 2 (1.0 g, 80.8%). 1 H NMR (400MHz, CDCl3) δ7.69 (s, 1H), 7.60 (d, J = 7.4Hz, 1H), 7.25 (d, J = 7.4Hz, 1H), 2.91 (dd, J = 7.2Hz, 4H), 2.09-2.02 (m, 2H), 1.34 (s, 12H).

[0049]

[0050] Compound 2 (1.0 g, 4.10 mmol), compound 3 (844 mg, 4.51 mmol), K2CO3 (850 mg, 6.15 mmol), PdCl2 (dppf) (60 mg, 0.08 mmol) were added to DMF (20 mL) and water (2 mL), and the mixture was reacted at 130°C for 4 h under nitrogen protection. The mixture was cooled to room temperature, EA (100 mL) and water (20 mL) were added, and the mixture was filtered through a diatomaceous earth pad, extracted with EA (2x10 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The solid compound was purified by silica gel column, slurried with methanol (10 mL), and filtered to obtain a white solid 4 (410 mg, 37%). 1 H NMR (400MHz, CDCl3) δ8.41 (s, 1H), 7.34 (d, J = 7.6Hz, 1H), 7.14 (s, 1H), 7.04 (d, J = 7.6Hz, 1H), 3.04-2.93 (m, 4H), 2.41 (s, 3H), 2.20-2.08 (m, 2H).

[0051]

[0052] Sodium metal (352 mg, 15.3 mmol) was added to methanol (30 mL) in batches at room temperature. After it was completely converted into sodium methoxide, compound 4 (410 mg, 1.53 mmol) was added, and the mixture was refluxed for 16 h under nitrogen protection. Methanol was evaporated, and EtOH (20 mL), water (20 mL) and NaOH (612 mg, 15.3 mmol) were added and refluxed for 16 h. Ethanol was evaporated, and the pH was adjusted to 5-6 with 3N HCl, and extracted with DCM (3x20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain a white solid 6 (330 mg, 76%). MS m / z (ESI) [M+H] + =284.1.

[0053]

[0054] Compound 6 (330 mg, 1.16 mmol), glycine methyl ester hydrochloride (291 mg, 2.32 mmol), EDCI (334 mg, 1.74 mmol), HOBT (235 mg, 1.74 mmol), and DIPEA (1.0 mL, 5.8 mmol) were dissolved in DCM (10 mL). Under nitrogen protection, the mixture was reacted at room temperature overnight. The mixture was purified by column chromatography to give compound 7 (176 mg, 43%) as a colorless oil. 1H NMR (400MHz, CDCl3) δ8.34(t,J=5.3Hz,1H),8.22(s,1H),7.32(d,J=7.7Hz,1H),7.16(s,1H),7.07(dd,J=7.6,1.4Hz,1H) ,4.27(d,J=5.6Hz,2H),3.96(s,3H),3.79(s,3H),2.97(t,J=7.4Hz,4H),2.28(s,3H),2.18-2.10(m,2H).m / z(ESI)[M+H] + =355.2.

[0055]

[0056] Compound 7 (176 mg, 0.50 mmol) was dissolved in AcOH (10 mL), HBr / AcOH solution (33%, 3 mL) was added, and the mixture was reacted at 65 °C for 16 h under nitrogen protection. EA was added for slurrying, and the mixture was filtered. The filter cake was slurried with EA at 65 °C twice to obtain white solid compound 8 (92 mg, 56%). 1 H NMR (400MHz, DMSO) δ9.36(t,J=6.1Hz,1H),8.01(s,1H),7.36(d,J=7.7Hz,1H),7.28(s,1H),7.17(d,J=7 .6Hz,1H),4.01(d,J=6.2Hz,2H),2.93(t,J=6.9Hz,4H),2.16(s,3H),2.10-2.03(m,2H).m / z(ESI)[M+H] + =327.2.

[0057] 1.2. Preparation of Compound I-3

[0058]

[0059] Compound 9 (1.0 g, 6.1 mmol) and compound 3 (1.25 g, 6.71 mmol), potassium carbonate (1.26 g, 9.15 mmol) and PdCl2 (dppf) (89.3 mg, 0.122 mmol) were added to DMF (20 mL) and water (2 mL). The reaction was stirred at 120 ° C for 5 h, quenched with water at 0 ° C, extracted with EA (100 mL), washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated the solvent, added methanol (30 mL) for slurrying, filtered, and washed with cold methanol to obtain an off-white solid 10 (980 mg). 1H NMR (400MHz, CDCl3) δ8.42 (s, 1H), 7.14 (s, 1H), 7.05 (d, J = 8.2Hz, 1H), 6.92-6.90 (m,1H),4.69(t,J=8.8Hz,2H),3.32(t,J=8.8Hz,2H),2.44(s,3H); m / z(ESI)[M+H] + = 271. It was used directly in the next step without purification.

[0060]

[0061] Sodium turnings (833 mg, 36.2 mmol) were added to methanol (20 mL) in batches and stirred until the solution became clear. Compound 10 (980 mg, 3.6 mmol) was added and stirred at 65 °C for 16 h. Methanol was evaporated to dryness, water (10 mL) was added, and EA (100 mL) was extracted. The EA layer was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was removed, and vacuum dried to obtain a gray liquid 11 (680 mg). 1 H NMR (400MHz, CDCl3) δ8.30 (s, 1H), 7.15 (s, 1H), 7.06 (d, J = 8.1Hz, 1H), 6.91-6.89 (m, 1H) ,4.67(t,J=8.7Hz,2H),4.12(s,3H),3.31(t,J=8.8Hz,2H),2.29(s,3H); m / z(ESI)[M+H] + = 267. It was used directly in the next step without purification.

[0062]

[0063] Compound 11 (680 mg, 2.55 mmol) was added to 48% HBr aqueous solution (8 mL), heated to 100°C for 16 h, cooled to room temperature, and water was added to precipitate a white solid, which was filtered and washed with water to a pH of 5-6. The solid was washed twice with methanol and dried in vacuo to obtain compound 12 (690 mg, 99%). 1 H NMR(400MHz,DMSO)δ10.05(br s,1H), δ7.88(s,1H),7.28(s,1H),7.22(d,J=8.1Hz,1H),6.96(d,J=8.2Hz ,1H),3.72(t,J=7.6Hz,2H),3.13(t,J=7.4Hz,2H),2.30(s,3H); m / z(ESI)

[0064] [M+H] + =272.

[0065]

[0066] Compound 12 (760 mg, 2.8 mmol), EDCI (805 mg, 4.2 mmol), HOBT (568 mg, 4.2 mmol), glycine methyl ester hydrochloride (1.06 g, 8.4 mmol) and DIPEA (2.3 mL, 14.0 mmol) were added with DCM (15 mL) and reacted at room temperature for 16 h. Water was added at 0°C to quench the reaction and the mixture was extracted with DCM (50 mL). The organic phase was washed twice with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and purified by silica gel column chromatography to give solid compound 13 (182 mg, 19%). 1 H NMR (400MHz, CDCl3) δ8.49(t,J=5.7Hz,1H),7.97(s,1H),7.17(s,1H),7.09-7.07(m,1H),6.89(d,J=8.1Hz,1H) ,4.67(t,J=8.5Hz,2H),4.28(d,J=5.8Hz,2H),3.83(s,3H),3.31(t,J=8.8Hz,2H),2.25(s,3H); m / z(ESI)[M+H] + =343.

[0067]

[0068] Compound 13 (182 mg, 0.53 mmol) was added to THF (5 mL) and water (5 mL), and then NaOH (74.4 mg, 1.86 mmol) was added, and the mixture was reacted at room temperature for 2 h under nitrogen protection. 1 M HCl was added at 0°C to adjust the pH to 2-3, and a white solid was precipitated, which was filtered, washed with water until neutral, and washed twice with petroleum ether. The solid was recrystallized with petroleum ether and ethyl acetate, and dried in vacuo to obtain solid compound 14 (85 mg, 49%). 1 H NMR (400MHz, DMSO) δ12.77(s,1H),9.30(t,J=5.7Hz,1H),8.01(s,1H),7.32(s,1H),7.16(d,J=8.1Hz,1H),6.89( d,J=8.2Hz,1H),4.60(t,J=8.7Hz,2H),3.98(d,J=6.0Hz,2H),3.26(t,J=8.8Hz,2H),2.17(s,3H); m / z(ESI)[M+H] + =329.

[0069] 1.3. Compound I-9

[0070]

[0071] Compound 15 (2 g, 11.11 mmol), compound 3 (2.3 g, 12.22 mmol), K2CO3 (2.3 g, 16.66 mmol), and PdCl2 (dppf) (163 mg, 0.22 mmol) were added to DMF (30 mL) and water (3 mL), and the mixture was reacted at 130°C for 4 h under nitrogen protection. The mixture was cooled to room temperature, EA (100 mL) and water (20 mL) were added, and the mixture was filtered through a diatomaceous earth pad and extracted with EA (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The obtained solid was slurried with methanol (20 mL) and filtered to obtain a gray solid compound 16 (1.93 g, 60.6%). 1 H NMR (400MHz, CDCl3) δ8.40(s,1H),6.98(d,J=8.3Hz,1H),6.81(d,J=2.1Hz,1H ),6.76(dd,J=8.3,2.2Hz,1H),4.38-4.25(m,4H),2.41(s,3H).m / z(ESI)[M+H] + =287.1.

[0072]

[0073] Sodium metal (1.55 g, 67.3 mmol) was added to methanol (40 mL) in batches at room temperature. After it was completely converted into sodium methoxide, compound 16 (1.93 g, 6.73 mmol) was added. Under nitrogen protection, the mixture was refluxed for 16 h. A large amount of methanol was evaporated. EtOH (20 mL) and water (20 mL) were added. NaOH (2.7 g, 67.33 mmol) was added. The mixture was refluxed for 16 h. Ethanol was evaporated. The pH was adjusted to 5-6 with 3N HCl. DCM (3x20 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain yellow solid compound 18 (2 g, 98%). MS m / z (ESI) [M+H] + =302.1.

[0074]

[0075] Compound 18 (2.0 g, 6.64 mmol), glycine methyl ester hydrochloride (1.7 g, 13.28 mmol), EDCI (1.9 g, 9.96 mmol), HOBT (1.3 g, 9.96 mmol), and DIPEA (5.9 mL, 33.2 mmol) were dissolved in DCM (30 mL). The mixture was reacted at room temperature for 16 h under nitrogen protection. The mixture was purified by silica gel column chromatography to give a light yellow solid 19 (0.8 g, 32%). 1H NMR (400MHz, CDCl3) δ8.32(t,J=5.4Hz,1H),8.20(s,1H),6.95(d,J=8.2Hz,1H),6.83(d,J=2.1Hz,1H),6.78(dd,J =8.3,2.1Hz,1H),4.34-4.29(m,4H),4.27(d,J=5.6Hz,2H),3.95(s,3H),3.79(s,3H),2.28(s,3H).m / z(ESI)[M+H] + =373.2.

[0076]

[0077] Compound 19 (0.8 g, 2.15 mmol) was dissolved in AcOH (20 mL), and HBr / AcOH solution (33%, 5 mL) was added. The mixture was reacted at 65°C for 16 h under nitrogen protection. The solvent was evaporated, and EA (100 mL) was added for slurrying. The mixture was filtered and the filter cake was slurried twice with EA at 65°C to give a yellow solid compound 20 (390 mg, 52.6%). 1 H NMR (400MHz, DMSO) δ9.35(t,J=6.1Hz,1H),8.01(s,1H),6.99(d,J=8.3Hz,1H),6.96(d,J=2.0Hz,1H) ,6.89(dd,J=8.3,2.1Hz,1H),4.27-4.32(m,4H),4.01(d,J=6.2Hz,2H),2.17(s,3H).m / z(ESI)[M+H] + =345.2.

[0078] 1.4. Preparation of Compound I-11

[0079]

[0080] Sodium turnings (2.2 g, 46.3 mmol) were slowly added into methanol (40 mL). After the solution became clear, compound 21 (1.31 g, 4.63 mmol) was added. The mixture was stirred at 65 °C for 16 h. The methanol was evaporated and the residue was used directly in the next step without purification.

[0081]

[0082] Compound 22 (1.29 g, 4.63 mmol) was added to EtOH (20 mL) and water (5 mL), and then NaOH (1.85 g, 46.3 mmol) was added, and the mixture was heated to 100°C for 16 h. The ethanol was evaporated, and the pH was adjusted to 5-6 with concentrated hydrochloric acid, and the mixture was concentrated and co-evaporated with toluene twice. The residue was dried under vacuum to obtain compound 23. MS m / z (ESI) [M+H] + = 298. It was used directly in the next step without purification.

[0083]

[0084] Compound 23 (1.38 g, 4.63 mmol), EDCI (1.33 g, 6.95 mmol) and HOBT (939 mg, 6.95 mmol), glycine methyl ester hydrochloride (1.16 g, 9.26 mmol) and DIPEA (3.83 mL, 23.2 mmol) were added with DCM (20 mL) and reacted at room temperature for 16 h. Water was added at 0°C to quench the mixture and the mixture was extracted with DCM (2x20 mL). The organic phase was washed twice with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography to obtain yellow oily compound 24 (1.0 g, 58.6%). 1 HNMR (400MHz, CDCl3) δ8.31(s,1H),7.97(s,1H),7.17(s,1H),7.51(d,J=8.1Hz,1H),7.28(dd,J=1.6, 8.3Hz,1H),4.30(d,J=5.6Hz,2H),4.00(s,3H),3.93(s,3H),3.81(s,3H),2.31(s,3H); m / z(ESI)[M+H] + =369.

[0085]

[0086] Compound 24 (1.0 g, 2.71 mmol) was added to HBr / HOAc (33%, 5 mL) and glacial acetic acid (20 mL) and reacted at 65°C for 16 h. The solvent was evaporated, a small amount of EA was added, and the solid was slurried to obtain a gray solid, which was recrystallized from petroleum ether and ethyl acetate and dried in vacuo to obtain compound 25 (240 mg, 31%). 1H NMR (400MHz, DMSO) δ12.78 (s, 2H), 9.37 (t, J = 6.1Hz, 1H), 8.48 (s, 1H), 8.10 (s, 1H), 7.78-7.75 (m,2H),7.39(d,J=8.4Hz,1H),4.03(d,J=6.0Hz,2H),3.94(s,3H),2.19(s,3H); m / z(ESI)[M+H] + =341.

[0087] 1.5. Preparation of Compound I-12

[0088]

[0089] Compound 26 (2 g, 7.75 mmol), compound 3 (1.74 g, 9.30 mmol), K2CO3 (1.6 g, 11.63 mmol), PdCl2 (dppf) (113 mg, 0.16 mmol) were added to DMF (30 mL) and water (3 mL), and the mixture was reacted at 120°C for 4 h under nitrogen protection. The mixture was cooled to room temperature, EA (100 mL) and water (20 mL) were added, and the mixture was filtered through a diatomaceous earth pad, extracted with EA (50 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The solid compound 27 was purified by silica gel column chromatography, and the solid was slurried with methanol (10 mL) and filtered to obtain a gray solid 27 (877 mg, 40%). 1 H NMR (400MHz, CDCl3) δ8.49(s,1H),7.98(s,1H),7.91(d,J=8.3Hz,1H),7.32(d,J= 1.1Hz,1H),7.19(dd,J=8.3,1.6Hz,1H),3.90(s,3H),2.42(s,3H).m / z(ESI)[M+H] + =283.0.

[0090]

[0091] Sodium metal (1.1 g, 46.5 mmol) was added to methanol (40 mL) in batches at room temperature. After it was completely converted into sodium methoxide, compound 27 (877 mg, 3.1 mmol) was added. Under nitrogen protection, the mixture was refluxed for 16 h. Methanol was evaporated. EtOH (20 mL) and water (20 mL) were added. The mixture was refluxed for 4 h. Ethanol was evaporated. The pH was adjusted to 5-6 with concentrated HCl, evaporated to dryness, and toluene was evaporated 3 times. The obtained product 29 was used directly in the next step without purification. MS m / z (ESI) [M+H] + =298.1.

[0092]

[0093] Compound 29 (922 mg, 3.1 mmol), glycine methyl ester hydrochloride (778 mg, 6.2 mmol), EDCI (891 mg, 4.65 mmol), HOBT (628 mg, 4.65 mmol), DIPEA (2.7 mL, 15.5 mmol) were dissolved in DCM (20 mL), reacted at room temperature for 16 h under nitrogen protection, and purified by silica gel column chromatography to obtain a yellow solid 30 (690 mg). MS m / z (ESI) [M+H] + =369.1. It was used directly in the next reaction without purification.

[0094]

[0095] Compound 30 (690 mg) was dissolved in AcOH (20 mL), and HBr / AcOH (33%, 4 mL) solution was added. The mixture was reacted at 65°C for 16 h under nitrogen protection. The solvent was evaporated, and methanol (10 mL) was added. The mixture was refluxed for 2 h. The solvent was evaporated and the residue was purified by silica gel column chromatography to obtain white solid compound 31 (492 mg, two-step yield 44.8%). 1 H NMR (400MHz, DMSO) δ12.76(s,1H),9.72(s,1H),9.56(t,J=6.2Hz,1H),8.17(d,J=0.8Hz,1H),8.14(s,1H ),8.02(dd,J=8.5,0.4Hz,1H),7.71(dd,J=8.5,1.5Hz,1H),4.15-4.12(m,5H),3.69(s,3H),2.20(s,3H). MS m / z(ESI)

[0096] [M+H] + =355.1.

[0097]

[0098] Compound 31 (492 mg, 1.39 mmol) was dissolved in THF (5 mL), and then NaOH (167 mg, 4.17 mmol) and water (5 mL) were added. The mixture was reacted at room temperature for 2 h, the solvent was evaporated, 1N HCl was added to adjust the pH to 5-6, the mixture was filtered, washed with water, and dried to obtain yellow solid compound 32 (176 mg, 37%). 1H NMR (400MHz, DMSO) δ12.85(s,1H),9.28(t,J=6.1Hz,1H),8.28(s,1H),8.12(s,1H),7.77(d,J=8.3Hz,1 H),7.68(s,1H),7.26(d,J=8.2Hz,1H),3.98(d,J=5.7Hz,2H),3.89(s,3H),2.21(s,3H).m / z(ESI)[M+H] + =341.1.

[0099] 1.6. Preparation of Compound I-15

[0100]

[0101] Compound 33 (3 g, 17.14 mmol), compound 3 (3.8 g, 20.57 mmol), K2CO3 (3.6 g, 25.71 mmol), PdCl2 (dppf) (251 mg, 0.34 mmol) were added to DMF (50 mL) and water (5 mL), and the mixture was reacted at 120°C for 4 h under nitrogen protection. The mixture was cooled to room temperature, EA (100 mL) and water (10 mL) were added, and the mixture was filtered through a diatomaceous earth pad and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The mixture was purified by silica gel column chromatography, and the obtained solid was slurried with methanol (20 mL) and filtered to obtain a gray solid compound 34 (2.26 g, 46.8%). 1 H NMR (400MHz, CDCl3) δ8.49 (s, 1H), 7.56-7.52 (m, 1H), 7.43 (d, J = 8.5Hz, 1H), 7.17 (d, J = 3.1Hz, 1H), 7.12(dd,J=8.4,1.7Hz,1H),6.56(dd,J=3.1,0.8Hz,1H),3.86(s,3H),2.44(s,3H).m / z(ESI)[M+H] + =282.0.

[0102]

[0103] Sodium metal (3.7 g, 160.4 mmol) was added to methanol (60 mL) in batches at room temperature. After it was completely converted into sodium methoxide, compound 34 (2.26 g, 8.02 mmol) was added. Under nitrogen protection, the reaction was refluxed for 16 h. Methanol was evaporated, EA (100 mL) and water (10 mL) were added, the organic phase was washed with water and saturated sodium chloride solution, the solvent was evaporated, HBr aqueous solution (48%, 30 mL) was added, the reaction was carried out at 100 ° C for 5 h, cooled to room temperature, water (500 mL) was added, filtered, the solid was washed with water, and dried to obtain red solid compound 36 (1.8 g, 79.7%). MS m / z (ESI) [M+H] + =283.1. It was used directly in the next step without purification.

[0104]

[0105] Compound 36 (830 mg, 2.94 mmol), glycine methyl ester hydrochloride (715 mg, 4.41 mmol), PyBOP (2.3 g, 4.41 mmol) and Et3N (2.0 mL, 14.7 mmol) were dissolved in DCM (30 mL). Under nitrogen protection, the mixture was reacted at room temperature for 16 h. The solvent was evaporated and the residue was purified by silica gel column chromatography to give yellow solid compound 37 (89 mg, 8.6%). 1 H NMR (400MHz, CDCl3) δ12.09(s,1H),8.49(t,J=5.4Hz,1H),8.05(s,1H),7.62-7.55(m,1H),7.41(d,J=8.4Hz,1H),7.17(dd,J=8.4,1.6H z,1H),7.13(d,J=3.1Hz,1H),6.55(dd,J=3.1,0.7Hz,1H),4.27(d,J=5.8Hz,2H),3.85(s,3H),3.82(s,3H),2.26(s,3H).m / z(ESI)[M+H] + =354.1.

[0106]

[0107] Compound 37 (89 mg, 0.25 mmol) was dissolved in THF (5 mL), and then NaOH (30 mg, 0.75 mmol) and water (5 mL) were added. The mixture was reacted at room temperature for 2 h. THF was evaporated, and 1N HCl was added to adjust the pH to 2-3. The mixture was filtered, washed with water, and dried to give yellow solid compound 38 (45 mg, 53%). 1H NMR (400MHz, DMSO) δ12.80(s,1H),12.76(s,1H),9.35(t,J=6.1Hz,1H),8.09(s,1H),7.61(d,J=1.0Hz,1H),7.57(d,J=8.5Hz,1H),7.4 3(d,J=3.0Hz,1H),7.21(dd,J=8.4,1.5Hz,1H),6.51(d,J=3.0Hz,1H),4.02(d,J=6.1Hz,2H),3.85(s,3H),2.20(s,3H).m / z(ESI)[M+H] + =340.1.

[0108] 1.7. Preparation of Compound I-17

[0109]

[0110] Compound 39 (3.0 g, 11.67 mmol), compound 3 (2.62 g, 14.0 mmol), potassium carbonate (2.42 g, 17.51 ​​mmol) and PdCl2 (dppf) (170.8 mg, 0.233 mmol) were dissolved in DMF (30 mL) and water (3 mL). The mixture was stirred at 120 °C for 5 h. Water was added to quench the mixture at 0 °C, and the mixture was extracted with EA (100 mL), washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness. Methanol (30 mL) was added to make a pulp, filtered, and washed with cold methanol to obtain an off-white solid 40 (1.9 g). MS m / z (ESI) [M+H] + = 282. It was used directly in the next step without purification.

[0111]

[0112] Sodium turnings (3.11 g, 135.4 mmol) were slowly added to methanol (50 mL). When the solution became clear, compound 40 (1.9 g, 6.77 mmol) was added. The mixture was stirred at 65 °C for 16 h. The methanol was evaporated to dryness, water (10 mL) was added, and the mixture was extracted with EA (100 mL). The EA layer was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated, and dried in vacuo to obtain a gray liquid 41 (1.4 g). MS m / z (ESI) [M+H] + =278.

[0113] It was directly used in the next reaction without purification.

[0114]

[0115] Compound 41 (1.4 g, 5.05 mmol) was added to HBr aqueous solution (15 mL, 48%), heated to 100 °C for 16 h, cooled to room temperature, and water was added to precipitate a white solid, which was filtered and washed with water to a pH of 5-6, washed twice with methanol, and the solid was vacuum dried to obtain a crude compound 42 (1.04 g). MS m / z (ESI) [M+H] + =283.

[0116] It was directly used in the next reaction without purification.

[0117]

[0118] Compound 42 (840 mg, 2.98 mmol), cystine methyl ester hydrochloride (561 mg, 4.47 mmol) and PyBOP (2.33 g, 4.47 mmol) were added to DCM (15 mL) and Et3N (2.07 mL, 14.9 mmol), reacted at room temperature for 16 h, evaporated the solvent, and purified by silica gel column chromatography to obtain compound 43 (30 mg, 16.7%). 1 H NMR (400MHz, CDCl3) δ12.14(s,1H),8.53(t,J=5.4Hz,1H),8.10(s,1H),7.72(d,J=8.1Hz,1H),7.29-7.28(m,1H),7.16(d,J=3.0Hz,1H ),7.09(dd,J=1.5,8.3Hz,1H),6.57(dd,J=0.8,3.0Hz,1H),4.30(d,J=5.8Hz,2H),3.85(d,J=4.4Hz,6H),2.30(s,3H); m / z(ESI)[M+H] + =354.

[0119]

[0120] Compound 43 (30 mg, 0.085 mmol) was added to THF (2 mL) and water (2 mL), and NaOH (12 mg, 0.3 mmol) was added, and the mixture was reacted at room temperature for 2 hours under nitrogen protection. 1 M HCl was added at 0°C to adjust the pH to 2-3, and a white solid was precipitated, which was filtered, washed with water until neutral, and washed twice with petroleum ether. The solid was recrystallized with petroleum ether and ethyl acetate, and dried in vacuo to obtain compound 44 (15 mg, 52%). 1H NMR (400MHz, DMSO) δ12.77(s,1H),9.37(t,J=6.0Hz,1H),8.13(s,1H),7.67(d,J=8.3Hz,1H),7.53(s,1H),7.43(d,J=3.0Hz,1 H),7.08(dd,J=1.5,8.0Hz,1H),6.50(dd,J=0.8,3.0Hz,1H),4.02(d,J=6.0Hz,2H),3.84(s,3H),2.23(s,3H); m / z(ESI)[M+H] + =340.1.

[0121] 1.8 Preparation of other analogs

[0122] The analogs of the present invention can be prepared using similar methods and different starting materials.

[0123] 1.9 Preparation of sodium carboxylate

[0124]

[0125] Compound I-1 (326 mg, 1 mmol) was dissolved in THF (5 mL), and 2N NaOH aqueous solution was added at room temperature. The mixture was stirred for 3 h. The precipitated solid was filtered, washed with THF, and dried under vacuum at 50° C. to obtain compound I-1a (320 mg, 92%).

[0126] 2.0 Using the method shown in 1.9, sodium salts of other carboxylic acids were prepared;

[0127]

[0128] 2.1 The corresponding carboxylate salts shown in the following formula can be prepared by reacting carboxylic acid with other bases using the method shown in 1.9 or other similar methods;

[0129]

[0130] Where R 1 , R 2 and Ar is as described above, and M is a metal or ammonium cation.

[0131] Example 2, biological test (Chem. Sci. 2017, 8, 7651)

[0132] The structural formulas of compounds I-33, I-34 and I-35 used as comparative compounds are as follows:

[0133]

[0134] 2.1. Enzymatic evaluation of the inhibitory effect of compounds on proline hydroxylase (PHD1, PHD2 or PHD3)

[0135] 2.1.1. Specific steps for testing the inhibition of PHD1, PHD2 or PHD3 activity:

[0136] a) Use Echo 665 to transfer 40 nL of compound dilution into a 384-well assay plate;

[0137] b) Seal the test plate and centrifuge at 1000 rpm for 1 minute;

[0138] c) Prepare 4× detection working solution (AlphaScreenStreptavidinDonor beads, AlphaScreen Protein A Acceptor beads and Hydroxy-HIF-1α(Pro564)(D43B5)) using pre-cooled 1× reaction buffer Rabbit mAb) was placed in a 25°C incubator and incubated in the dark;

[0139] d) Prepare 2× PHD1 (or PHD2 or PHD3) working solution, add 4 μL 2× prepared PHD1

[0140] (or PHD2 or PHD3) working solution into the 384 experimental plate;

[0141] e) Seal the test plate, centrifuge at 1000 rpm for 1 minute, and incubate in a 25°C incubator for 30 minutes;

[0142] f) Prepare 2× substrate working solution and add 4 μL of substrate working solution to the 384 assay plate to start the reaction;

[0143] g) Seal the test plate, centrifuge at 1000 rpm for 1 minute, and incubate in a 25°C incubator for 30 minutes; h) Prepare 4× stop working solution, add 4 μL of the prepared stop working solution to the 384 test plate to terminate the reaction. Add 4 μL of the detection working solution (step c) to the 384 test plate;

[0144] i) Seal the test plate, centrifuge at 1000 rpm for 1 minute, and incubate in a 25°C incubator for 30 minutes;

[0145] j) using Envision 2104 multi-label Reader to detect fluorescence signals;

[0146] 2.1.2 Data Analysis

[0147] Calculation IC 50And fitting compound dose-effect curve: Graphad 8.0 was used to obtain the IC of the compound using the following nonlinear fitting formula: 50 (Tables 1 to 3).

[0148] Cytotoxicity assay method

[0149] a) Cell culture

[0150] Hep 3B cells were cultured in MEM medium, supplemented with 1% double antibody and 10% FBS, and cultured at 37°C and 5% CO2.

[0151] b) Cell plating

[0152] The cells were routinely cultured until the cell saturation reached 80%-90%. When the number reached the required level, the cells were harvested. Resuspended with the corresponding culture medium, counted, and prepared into a cell suspension of appropriate density. 30 μL of the cell suspension containing appropriate cells was added to each well of a 384-well plate. Hela, 786-O, and Hep 3B cells were cultured overnight in a 37°C, 5% CO2 incubator.

[0153] c) Preparation of compounds

[0154] The compound to be tested was diluted 3-fold with DMSO from a 20mM stock solution to 10 concentrations. Staurosporine was diluted with DMSO from 20mM to 2mM, and then 3-fold diluted to 10 concentrations. 150nL DMSO was added to the cells as a high reading control well. Cell-free culture medium (Blank) was used as a low reading control well.

[0155] d) Compound treatment of cells

[0156] 1. 24 hours after cell plating, add 150 nL of the compound prepared in step 3.3, centrifuge at 1000 rpm for 1 min, and place the cells in a 37°C, 5% CO2 incubator.

[0157] 2. Final concentration of test compound:

[0158] Concentration of test compound: 100000, 33333, 11111, 3703, 1234, 411, 137, 45.7, 15.2, 5.1 nM

[0159] Staurosporine concentration: 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.6, 1.5, 0.5 nM

[0160] 3. Place the Hep 3B cell plate in a 37°C, 5% CO2 incubator for 24 hours.

[0161] e) CTG method detection

[0162] 1. Add 30 μL CTG reagent (CelltiterGlo kit) to each well, place on a fast shaker for 3 minutes, centrifuge at 1000 rpm for 1 minute, and place at room temperature away from light for 30 minutes.

[0163] 2. Read the chemiluminescent signal value using the Envision instrument.

[0164] f) Data analysis

[0165] 1. Calculate CC using GraphPad Prism 8 software 50 , the following nonlinear fitting formula is used to obtain the CC of the compound 50 (Drug concentration required to inhibit half of the cells, Table 1-3):

[0166] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0167] Y: inhibition rate X: log value of compound concentration

[0168] Inhibition rate (%) = 100-(compound well reading value-low reading control well reading value) / (high reading control well reading value-low reading control well reading value)*100

[0169] High reading control well: cells plus 150nL DMSO

[0170] Low reading control wells: medium without cells (Blank).

[0171] Table 1 IC values ​​of compounds for inhibition of PHD2 50 and CC 50

[0172]

[0173] Table 2 IC values ​​of compounds for inhibition of PHD1 50 and CC 50

[0174]

[0175]

[0176] Table 3 IC values ​​of compounds for inhibition of PHD3 50 and CC 50

[0177]

[0178] The test results showed that the ortho-hydroxyl group was replaced by a methyl group and the chlorophenyl group was replaced by a bicyclic group, which could significantly improve the activity of inhibiting PHD2. The activity of compounds (I-1, I-3, I-9, I-11, I-12, I-15 and I-17) in inhibiting PHD2 (IC 50 ) is 22-413 times higher than Vadadustat. The activity of compounds I-3, I-9 and I-15 in inhibiting PHD2 is 146, 28 and 45 times higher than that of compounds I-34, I-35 and I-33, respectively. It can be seen that the compounds can be used at significantly reduced doses, which can improve their clinical safety and have better development potential.

[0179] The compounds also showed inhibitory activity against PHD1 and PHD3 and could activate the liver to produce EPO when the kidneys were completely inoperative.

[0180] Example 3. Pharmacokinetics

[0181] Each group consisted of 3 male SD rats, with a total of 4 groups. Each group of animals was given a single oral administration of 0.3 mmol / kg of compounds I-3, I-9, I-34 and I-35, respectively. Plasma samples were collected from each group of animals before administration (0 hours) and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 24 and 48 hours after administration. The concentration of the corresponding compound in the plasma sample was determined by LC-MS / MS method.

[0182] Table 4 Pharmacokinetic parameters

[0183]

[0184] After a single oral administration of compounds I-3, I-9, I-34 and I-35 to male SD rats, the C max and AUC 0-24 Compared with I-34 and I-35, the bioavailability is significantly improved.

Claims

1. A compound of formula I or a prodrug thereof, or a deuterated compound of said compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt thereof, in: R 1 C 1-6 Alkyl, or C 3-7 Cycloalkyl; preferably methyl, ethyl, n-propyl, isopropyl, or cyclopropyl; more preferably methyl or ethyl; more preferably methyl; R 2 Selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aryl, 5-11 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S, NH2, CN, halogen (such as F, Cl, Br, I), and OH; preferably selected from H, methyl, ethyl, n-propyl, isopropyl, and cyclopropyl; more preferably H; Ar is a carbocyclic fused phenyl, a heterocyclic fused phenyl, a carbocyclic fused heteroaryl, or a heterocyclic fused heteroaryl, preferably a carbocyclic fused phenyl, or a heterocyclic fused phenyl; the carbocyclic ring is a saturated or unsaturated 5-membered or 6-membered carbocyclic ring, the heterocyclic ring is a saturated or unsaturated 5-membered or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S on the ring, and the heteroaryl is a 6-membered heteroaryl containing 1 or 2 N atoms on the ring; the carbocyclic fused phenyl, heterocyclic fused phenyl, carbocyclic fused heteroaryl, and heterocyclic fused heteroaryl are optionally substituted by 1 or more selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, OH, CN, NH2, mono- or di-C 1-6 Alkylamino, halogen substituents, preferably, the substituent is C 1-6 alkyl.

2. The compound of formula I or its prodrug according to claim 1, or a deuterated compound of the compound of formula I or its prodrug, or a pharmaceutically acceptable salt thereof, wherein: Ar is selected from the following groups: Among them, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 Each independently selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, or isopropyl), C 3-7 Cycloalkyl (e.g., cyclopropyl), OH, CN, NH2, halogen (e.g., Cl, Br, I, or F), preferably, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 Each is independently selected from H, methyl, ethyl, and n-propyl, and more preferably each is independently H or methyl.

3. The compound of formula I or its prodrug according to claim 1, or a deuterated compound of the compound of formula I or its prodrug, or a pharmaceutically acceptable salt thereof, wherein: Ar is selected from the following groups:

4. The following compounds of formula I or their prodrugs, or deuterated compounds of said compounds of formula I or their prodrugs, or their pharmaceutically acceptable salts:

5. The compound of formula I or a prodrug thereof, or a deuterated compound of the compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: The prodrug is an ester formed by a carboxyl group in the compound of formula I and an alcohol (such as methanol, ethanol, propanol or isopropanol), or an ester formed by a hydroxyl group in the compound of formula I and a carboxylic acid (such as acetic acid, propionic acid, isopropionic acid, butyric acid or isobutyric acid).

6. A compound of formula I or a prodrug thereof, or a deuterated product of the compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the pharmaceutically acceptable salt is an alkali metal salt (e.g., sodium salt, potassium salt), an alkaline earth metal salt (e.g., calcium salt, magnesium salt), or an ammonium salt; or, when the compound of formula I or a prodrug thereof, or a deuterated product of the compound of formula I or a prodrug thereof has a basic functional group, the pharmaceutically acceptable salt is a salt formed by the compound of formula I or a prodrug thereof, or a deuterated product of the compound of formula I or a prodrug thereof with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid.

7. A method for preparing a compound of formula I or a prodrug thereof, or a deuterated product of the compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6, comprising: The step of reacting boride ii or boride iii with dichloride iv to obtain monochloride v; The steps of alkoxylating monochloride v to generate alkoxy cyanide vi; hydrolyzing alkoxy cyanide vi to obtain carboxylic acid intermediate compound vii; reacting carboxylic acid intermediate compound vii with alkyl glutamate to obtain compound viii; and dealkylating compound viii to obtain a target product; Its synthetic route is as follows: Optionally, the boride ii is obtained by converting the bromide i, and the structural formula of the bromide i is Ar-Br; Among them, R x C 1-6 Alkyl; R y H or C 1-6 Alkyl; R z C 1-6 Alkyl; Ar, R 1 , R 2 As defined in any one of claims 1 to 6.

8. A pharmaceutical composition comprising the compound of formula I or a prodrug thereof according to any one of claims 1 to 6, or a deuterated product of the compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

9. Use of the compound of formula I or its prodrug according to any one of claims 1 to 6, or a deuterated product of the compound of formula I or its prodrug, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, for preparing a medicament for preventing or treating anemia.

10. The use according to claim 9, wherein the anemia is anemia caused by chronic kidney disease, anemia caused by excessive blood loss, anemia caused by malignant tumors, or anemia caused by treatment of malignant tumors.

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