Long-acting oral medication containing hypoxia-inducible factor-prolyl hydroxylase inhibitors and its use

Abstract

This invention relates to a long-acting oral pharmaceutical preparation containing a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) and its use. Specifically, it relates to a long-acting oral pharmaceutical preparation comprising a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, adjuvants, or excipients, and said long-acting oral pharmaceutical preparation is suitable for long-term administration in the treatment of chronic anemia because it is suitable for administration at intervals of one week or more.

Description

[Technical Field]

[0001] This application claims priority to Chinese invention patent application 202311391445.2, filed on 24 October 2023, with the title of the invention "Long-acting oral pharmaceutical containing a hypoxia-inducible factor-prolyl hydroxylase inhibitor and its use," the entire contents of said application are incorporated herein by reference.

[0002] This application belongs to the pharmaceutical field, and in particular, relates to the treatment of proline hydroxylase-related diseases (e.g., anemia). [Background technology]

[0003] Anemia is a disease caused by a decrease in the number of red blood cells or a decrease in the hemoglobin content of red blood cells. Since the main function of hemoglobin is to transport and utilize oxygen to various organs, low levels of hemoglobin directly cause oxygen deficiency in the body's organs. Because all normal physiological activities depend on sufficient oxygen utilization, different degrees of anemia cause a variety of clinical symptoms. Common secondary effects of anemia include cardiovascular diseases (heart failure, atrial fibrillation, angina pectoris, etc.), urinary tract diseases (renal failure, proteinuria), neurological disorders (dizziness, headache, tinnitus, blurred vision, mental malaise, drowsiness, discomfort, anxiety, difficulty concentrating; syncope may occur in severe cases of anemia), digestive disorders (loss of appetite, constipation), and reproductive disorders (decreased libido, menstrual irregularities). Anemia not only has a serious impact on a patient's physical health and quality of life, but if it is not treated promptly, it can even threaten the patient's life safety.

[0004] Anemia has many causes, usually resulting from decreased production of erythropoietin (EPO). Chronic kidney disease (CKD) causes decreased erythropoietin synthesis, so most patients with CKD suffer from anemia, or chronic renal anemia (CKD anemia). There are mainly two types of pharmaceutical treatments for chronic renal anemia. The first type is based on erythropoiesis stimulating agents (ESAs) with EPO or similar functions, both of which must be administered by injection. In recent years, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI), another medication that can be administered orally to treat chronic renal anemia, have been gradually approved by several monitoring agencies. HIF-PHI is a novel small molecule oral drug for the treatment of renal anemia that stabilizes HIF levels in the body by inhibiting hypoxia-inducible factor prolyl hydroxylase, and promotes EPO production by regulating multiple downstream target genes, thereby exhibiting a renal anemia therapeutic effect similar to that of ESA. Several HIF-PHIs are disclosed in literature such as WO2004108681, WO2007070359, WO2007150011, WO2008076425, WO2011007856, WO201206472, WO2013043621, WO2014102818, and WO2018205928.

[0005] Whether using the injectable ESA or orally administered HIF-PHI drugs mentioned above, the treatment of renal anemia basically requires two stages. The first stage is the fixing period, which generally does not exceed two months, and its purpose is to raise or adjust the hemoglobin level of the anemic patient to the interval specified by each monitoring mechanism. The second stage is the titration period, which involves treating and maintaining the patient's hemoglobin level within the interval specified by each monitoring mechanism over a long period of time. This is a long-term stage, and the patient will need to take the medication for an extended period.

[0006] Studies have shown that for chronic diseases requiring long-term treatment (e.g., diabetes, chronic renal anemia), treatment efficacy is highly correlated with patient adherence to medication, and patient adherence to medication is closely related to the frequency or interval between doses. For example, for medications such as insulin (Diabetes Spectr 2016,29(3),166-170) and GLP-1 agonists (Int J Clin Pract.2021,75:e14060), which must be administered by injection such as subcutaneous or intramuscular injection, it has been demonstrated that longer intervals between doses are associated with better patient adherence and better long-term treatment efficacy. In the field of chronic renal anemia, as is evident from existing research on injectable ESA drugs (Cureus 2020, 12(9):e10358), patients with longer administration cycles (longer intervals between two adjacent administrations) exhibit better adherence and superior long-term therapeutic efficacy with so-called long-acting ESAs.

[0007] Regarding injectable drugs, conventional technology offers methods to extend the time interval between two adjacent doses. However, extending the time interval between two adjacent doses of oral drugs presents a significant challenge. In conventional technology, because the elimination half-life (t1 / 2) of oral drugs is generally short, it is rare for the medication interval (cycle) to be once a week or more. Regarding HIF-PHI for the treatment of chronic renal anemia, oral drugs already on the market or in clinical trials generally include daprodustat (for patients with chronic renal anemia, t1 / 2). 1 / 2 :~7h; See Am J Kidney Dis. 2016, 67(6), 861-871), Vadadustat (t 1 / 2 :4.7~9.1h; See Adv Chronic Kidney Dis. 2019, 26(4), 253-266), Enarodustad 1 / 2 :8.2~8.7h; see Drugs 2021, 81, 169-174), Molidustat (t 1 / 2 It is administered once daily, such as 4-10 hours (see Adv Chronic Kidney Dis. 2019, 26(4), 253-266), or roxadustat (Roxadustat, t 1 / 2 :12~15h; See Adv Chronic Kidney Dis. 2019, 26(4), 253-266), Desidustat, t 1 / 2 It is administered three times a week, as shown in 6-15 hours (see Drugs2022, 82(11), 1207-1212).

[0008] These conventional dosing regimens for oral HIF-PHI drugs all have dosing cycles (intervals) that are without exception substantially shorter than one week (7 days). For diseases requiring long-term medication such as chronic renal anemia, a once-weekly oral dosing regimen enables better patient adherence to medication and facilitates easier disease management than once-daily or three-times-weekly oral dosing regimens. Meanwhile, most patients with chronic renal anemia concurrently suffer from hypertension, diabetes, hyperphosphatemia, hyperkalemia, hypercholesterolemia, hyperlipidemia and other diseases. The once-weekly dosing regimen makes it easier to avoid interactions between the drug for treating anemia and drugs that the patient is taking for diseases such as hypertension, diabetes, hyperphosphatemia, hyperkalemia, hypercholesterolemia or hyperlipidemia; for example, the administration time of HIF-PHI and other drugs can be staggered (once-daily or three-times-weekly administration greatly increases the difficulty for patients to stagger administration times).

[0009] Therefore, long-acting orally administered drugs that are useful for the treatment of chronic anemia (e.g., chronic renal anemia, etc.) are highly desirable. SUMMARY OF THE INVENTION

[0010] The reason why there is a lack of long-acting oral drugs for chronic renal anemia in the prior art is that according to conventional pharmaceutical theory, after 5 t 1 / 2 have passed since a patient takes the drug, it is generally considered that the drug has been almost completely eliminated from the patient's blood. Therefore, the time interval between two adjacent administrations (dosing cycle) of a drug for treating a chronic disease generally must not exceed 5 elimination half-lives. In practical practice, in order to ensure therapeutic effect, it is generally rare for the dosing interval (dosing cycle) to exceed 3 elimination half-lives. According to pharmaceutical theory, when it is desired that the dosing interval of an orally administered drug is once per week or longer, that is, the dosing cycle is one week or longer, the elimination half-life of the drug should be 24h×7 / 5 or longer, that is, t 1 / 2 is 33.6 hours or longer. For example, trelagliptin, an oral DPP-4 inhibitor approved in Japan for once-weekly administration to treat diabetes, has a drug elimination half-life t 1 / 2This range is 38.44 to 54.26 hours (J Diabetes Investig 2018, 9, 354-359).

[0011] The inventors of this application have unexpectedly found, through animal and human clinical trials, that hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) drugs have a reduced excretion half-life t 1 / 2 Even with intervals much shorter than 33.6 hours, it was still demonstrated that hemoglobin could be maintained within the desired range with once-weekly or longer-interval oral administration during the dose adjustment period for chronic anemia. This unexpected finding could improve adherence to medical treatment in patients with chronic renal anemia using novel administration methods, thereby improving treatment efficacy and making chronic diseases easier to manage over the long term.

[0012] A first aspect of this application provides a long-acting oral pharmaceutical formulation comprising a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, adjuvants, or excipients, wherein the long-acting oral pharmaceutical formulation is suitable for administration at intervals of one week or more. In particular, this application has surprisingly found that a once-weekly administration frequency during the titration period reduces patient adverse reactions more than a three-times-weekly administration frequency.

[0013] A second aspect of this application provides a pharmaceutical product comprising a packaging container, a drug information sheet, and a pharmaceutical preparation contained in the packaging container, wherein the pharmaceutical preparation comprises a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, adjuvants, or excipients, and the drug information sheet includes a description indicating that the pharmaceutical preparation is suitable for oral administration at intervals of one week or more.

[0014] A third aspect of this application provides the use of a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof in the manufacture of a long-acting oral pharmaceutical for the treatment of chronic anemia, wherein the long-acting oral pharmaceutical is suitable for administration at intervals of one week or more.

[0015] A fourth aspect of this application provides a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof for the oral treatment of chronic anemia, wherein the oral treatment is administered at intervals of at least one week.

[0016] A fifth aspect of this application provides the use of a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof in the treatment of chronic anemia, wherein the HIF-PHI or a pharmaceutically acceptable salt thereof is administered orally at intervals of at least one week.

[0017] A sixth aspect of this application provides a method for treating chronic anemia, comprising orally administering to a patient in need of treatment a therapeutically effective dose of a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof at intervals of at least one week. [Brief explanation of the drawing]

[0018] [Figure 1] The following shows a comparison of hemoglobin histograms of rats in each group in Example 3 at days 0, 7, 14, 21, and 28.

[0019] [Figure 2] This example shows a comparison of hemoglobin histograms of rats in each group at day 28 and the statistical significance of each group. [Modes for carrying out the invention]

[0020] (1) Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI) or their pharmaceutically acceptable salts. In various aspects of this application and in various embodiments of various aspects, the hypoxia-inducible factor-prolyl hydroxylase inhibitor may be in the form of various hypoxia-inducible factor-prolyl hydroxylase inhibitor compounds known in the art, or pharmaceutically acceptable salts thereof. In some embodiments, the HIF-PHI or a pharmaceutically acceptable salt thereof may be t 1 / 2 The duration is less than 33.6 hours, less than 24 hours, less than 16 hours, or less than 10 hours.

[0021] In some preferred embodiments of this application, the hypoxia-inducible factor-prolyl hydroxylase inhibitor may be an HIF-PHI compound or a pharmaceutically acceptable salt thereof that is approved for clinical use or is in clinical trials. For example, the HIF-PHI can be selected from roxadustat, daprodustat, vadadustat, molidustat, enarodustat, desidustat, HIF117 (SSS17), HEC53856, and DDO-3055.

[0022] In some embodiments, the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is roxadustat or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is daprodustat or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is vadadustat or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is molidustat or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is enarodustat or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is desidustat or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is HIF117 (SSS17) or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is HEC53856 or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is DDO-3055 or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is a compound of formula I of WO2018205928 or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is any mixture of the above HIF-PHIs.

[0033] In this application, unless otherwise specified, any compound such as “compound of formula I” (synonymous with “compound represented by general formula I”), “roxadustat”, or “(6'-hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indolidine]-7'-carbonyl)glycine” or any pharmaceutically acceptable salt thereof, when referred to or indicated by a structural formula, name, or symbol, encompasses various forms of these compounds, such as their tautomers, optical isomers, geometric isomers, or mixtures of isomers (e.g., racemic mixtures), their isotopically modified compounds, solvates or hydrates of these compounds, and various solid forms of these (e.g., various crystalline or amorphous forms).

[0034] The term "optical isomer" means that if a compound has one or more chiral centers, each chiral center may have either an R or S configuration, and the various isomers formed thereby are optical isomers. Optical isomers include all forms of diastereomers, enantiomers, meso compounds, racemates, or mixtures thereof. For example, optical isomers can be separated by chiral column chromatography or chiral synthesis.

[0035] The term "geometric isomer" means that, if a double bond is present in the compound, the compound may be a cis isomer, a trans isomer, an E isomer, or a Z isomer. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers, or mixtures thereof.

[0036] The term "tautomer" refers to an isomer resulting from the rapid movement of an atom in a molecule between two positions. Those skilled in the art will understand that tautomers can transition to one another and coexist in equilibrium under certain conditions. For example, the "compound of formula I" as described herein also includes any tautomer of the compound of general formula I. Specifically, the inventors have found that the compound of formula I may have the following tautomers Ia, Ib, Ic, or Id.

[0037] [ka]

[0038] An "isotope-modified compound" means a compound in which any atom of the compound is replaced with its isotopic atom. In this application, an "isotope-modified compound" includes all pharmaceutically acceptable isotope-modified compounds of the compound, in which one or more atoms are replaced with atoms that have the same atomic number as atoms normally found in nature but have a different atomic mass or mass number.

[0039] Examples of isotopes contained in the compound of this application include, 2 H(D), 3 Hydrogen isotopes such as H(T), 11 C, 13 C, 14 Isotopes of carbon such as C, 36 Chlorine isotopes such as Cl, 18 Fluorine isotopes such as F, 123 I, 125 Iodine isotopes such as I 13 N, 15 Nitrogen isotopes such as N, 15 O, 17 O, 18 Oxygen isotopes such as O, 35 Examples include sulfur isotopes such as S.

[0040] Some isotope-modified compounds (e.g., those containing radioactive isotopes) can be used in pharmaceutical and / or substrate tissue distribution studies. Considering the ease of introduction and the convenience of detection methods, isotope deuterium (i.e.) 2 H), tritium (that is, 3 H) and carbon-14 (i.e.) 14 C) is particularly useful for this purpose.

[0041] Deuterium (that is 2 H) or tritium (i.e.) 3Substitution with relatively heavy isotopes, such as H), may be preferable in some cases because it can offer therapeutic advantages through greater metabolic stability (e.g., increased half-life in the body or reduced dose).

[0042] Positron-emitting isotopes (for example) 11 C, 18 F, 15 O and 13 Substitution with N) can be used in positron emission topography (PET) studies to detect the occupancy state of substrate receptors.

[0043] Isotope-modified compounds can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the examples and preparations attached herein, using appropriate isotope-labeled reagents instead of previously used unlabeled reagents.

[0044] The compounds described in this application may exist in both non-solvated and solvated (including hydrated) forms.

[0045] Some of the compounds of this application may exist in different crystalline or amorphous forms, and whatever form they exist in, they are included within the scope of this application.

[0046] In this application, “pharmaceutically acceptable salt” means an inorganic or organic acid addition salt of the compound, or an organic base or inorganic base addition salt, that is suitable for use in the body of a mammal (i.e., has safety and efficacy at the time of use). These salts can be prepared in situ during the final separation and purification of the compound, or by reacting the free form of the pure compound with a suitable organic or inorganic acid or base, respectively, and separating the resulting salt. Typical salts include hydrogen bromide, hydrogen chloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, glucoheptonate, lactate, laurylsulfonate, and the like. These salts may include salts based on alkali metals and alkaline earth metals (e.g., sodium, lithium, potassium, calcium, magnesium, etc.), and salts based on non-toxic ammonium, quaternary ammonium, and amine cations (including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.).

[0047] In some preferred embodiments of this application, the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is in the form of a compound of formula I disclosed in WO2018205928 or a pharmaceutically acceptable salt thereof.

[0048] [ka]

[0049] In some embodiments, in a compound represented by general formula I, R 1 and R 2The group is independently selected from cyano, alkyl, heterocyclic, alkenyl, alkynyl, aryl, heteroaryl, and acyl groups, and the alkyl, heterocyclic, alkenyl, alkynyl, aryl, heteroaryl, and acyl groups are optionally substituted with one or more substituents, the substituents being halogen, cyano, hydroxyl, amino, carboxyl, acyl, alkyl, heterocyclic, alkenyl, alkynyl, aryl, heteroaryl, =O, =S, -SH, and R. 10 O-, R 10 S-, R 10 (O=)S- and R 10 (O=)2S- is independently selected, and of those R 10 is an alkyl group, heterocyclic group, alkenyl group, alkynyl group, aryl group, or heteroaryl group, or R 1 and R 2 They form a ring together, R 3 This is selected from alkyl groups, heterocyclic groups, alkenyl groups, alkynyl groups, aryl groups, and heteroaryl groups. R 4 and R 5 It is hydrogen, R 6 and R 6’ It is hydrogen, R 7 It is hydrogen, R 8 It is selected from hydrogen and alkyl groups, X is an oxygen atom.

[0050] In some embodiments, in a compound represented by general formula I, R 1 and R 2This is independently selected from a cyano group, a C1-C12 acyclic alkyl group, a C2-C12 acyclic alkenyl group, a C2-C12 acyclic alkynyl group, a C6-C14 aryl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkenyl group, a heterocycloalkyl group having 3-8 ring atoms, a heterocycloalkenyl group having 3-8 ring atoms, a heteroaryl group having 5-14 ring atoms, a C1-C12 acyclic alkyl group-C(=O)-, and a C2-C12 acyclic alkenyl group-C(=O)-, and the above C1-C12 acyclic alkyl group C2-C12 acyclic alkenyl groups, C2-C12 acyclic alkynyl groups, C6-C14 aryl groups, C3-C8 cycloalkyl groups, C3-C8 cycloalkenyl groups, heterocycloalkyl groups having 3-8 ring atoms, heterocycloalkenyl groups having 3-8 ring atoms, heteroaryl groups having 5-14 ring atoms, C1-C12 acyclic alkyl groups -C(=O)-, and C2-C12 acyclic alkenyl groups -C(=O)- are optionally substituted with 1-3 substituents, among which substituents are hydroxyl groups, halogens, cyano groups, amino groups, and carboxyl groups. Xyl group, C1-C6 acyclic alkyl group, C3-C8 cycloalkyl group, C2-C6 acyclic alkenyl group-, C2-C6 acyclic alkynyl group-, C3-C8 cycloalkyl group, C3-C8 cycloalkenyl group, C6-C14 aryl group, heteroaryl group having 5-14 ring atoms, C1-C6 acyclic alkyl group-O-, C3-C8 cycloalkyl group-O-, C2-C6 acyclic alkenyl group-O-, C2-C6 acyclic alkynyl group-O-, C3-C8 cycloalkenyl group-O-, C6-C14 aryl group-O-, 5-14 ring atoms The heteroaryl group having -O-, C1-C6 acyclic alkyl group -S-, C3-C8 cycloalkyl group -S-, C2-C6 acyclic alkenyl group -S-, C2-C6 acyclic alkynyl group -S-, C3-C8 cycloalkenyl group -S-, C6-C14 aryl group -S-, heteroaryl group having 5 to 14 ring atoms -S-, heterocycloalkyl group having 3 to 8 ring atoms, heterocycloalkenyl group having 3 to 8 ring atoms, =O, =S, -SH, -CF3, -CO2C1-C6 acyclic alkyl group, C1-C6 acyclic alkyl group -S-,Independently selected from C1-C6 acyclic alkyl groups (O=)S- and C1-C6 acyclic alkyl groups (O=)2S-, or R 1 and R 2 Together they form an arbitrarily substituted cycloalkane ring, cycloalkene ring, heterocycloalkane ring, or heterocycloalkene ring having 3 to 8 ring atoms. R 3The group is selected from C1-C12 acyclic alkyl groups, C2-C12 acyclic alkenyl groups, C2-C12 acyclic alkynyl groups, C6-C14 aryl groups, C3-C8 cycloalkyl groups, C3-C8 cycloalkenyl groups, heterocycloalkyl groups having 3-8 ring atoms, heterocycloalkenyl groups having 3-8 ring atoms, and heteroaryl groups having 5-14 ring atoms. The C3-C8 cycloalkyl group, C3-C8 cycloalkenyl group, heterocycloalkyl group having 3-8 ring atoms, heterocycloalkenyl group having 3-8 ring atoms, and heteroaryl group having 5-14 ring atoms are optionally substituted with 1-3 substituents, among which substituents are hydroxyl group, halogen, cyano group, amino group, carboxyl group, C1-C6 acyclic alkyl group, C3-C8 cycloalkyl group, C2-C6 acyclic alkenyl group, C2-C6 acyclic alkynyl group, and C3-C8 cycloalkyl group. C3-C8 cycloalkenyl group, C6-C14 aryl group, heteroaryl group having 5-14 ring atoms, C1-C6 acyclic alkyl group-O-, C3-C8 cycloalkyl group-O-, C2-C6 acyclic alkenyl group-O-, C2-C6 acyclic alkynyl group-O-, C3-C8 cycloalkenyl group-O-, C6-C14 aryl group-O-, heteroaryl group having 5-14 ring atoms-O-, C1-C6 acyclic alkyl group-S-, C3-C8 cycloalkyl group-S-, C2-C6 acyclic alkenyl group-S - Independently selected from C2-C6 acyclic alkynyl group -S-, C3-C8 cycloalkenyl group -S-, C6-C14 aryl group -S-, heteroaryl group having 5-14 ring atoms -S-, heterocycloalkyl group having 3-8 ring atoms, heterocycloalkenyl group having 3-8 ring atoms, =O, =S, -SH, -CF3, -CO2C1-C6 acyclic alkyl group, C1-C6 acyclic alkyl group -S-, C1-C6 acyclic alkyl group (O=)S-, and C1-C6 acyclic alkyl group (O=)2S-, R 4 and R 5 It is hydrogen, R 6 and R 6’ It is hydrogen, R 7 It is hydrogen, R 8 The C1-C12 acyclic alkyl groups and C3-C8 cycloalkyl groups are selected from hydrogen, C1-C12 acyclic alkyl groups and C3-C8 cycloalkyl groups, and the C1-C12 acyclic alkyl groups and C3-C8 cycloalkyl groups are optionally substituted with 1 to 3 substituents, of which substituents are hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 acyclic alkyl groups, C3-C8 cycloalkyl groups, C2-C6 acyclic alkenyl groups, C2-C6 acyclic alkynyl groups, and C3-C8 Independently selected from cycloalkyl groups, C3-C8 cycloalkenyl groups, C6-C14 aryl groups, heteroaryl groups having 5 to 14 ring atoms, C1-C6 acyclic alkyl groups-O-, C3-C8 cycloalkyl groups-O-, C2-C6 acyclic alkenyl groups-O-, C2-C6 acyclic alkynyl groups-O-, C3-C8 cycloalkenyl groups-O-, C6-C14 aryl groups-O-, and heteroaryl groups having 5 to 14 ring atoms-O-, X is an oxygen atom.

[0051] In some preferred embodiments of this application, in a compound represented by general formula I, R 1 and R 2 R is independently selected from a cyano group and an unsubstituted C1-C6 acyclic alkyl group, or 1 and R 2 These together form an optionally substituted cycloalkane ring or heterocycloalkane ring having 3 to 8 ring atoms.

[0052] In some preferred embodiments of this application, in a compound represented by general formula I, R 1 and R 2 is independently selected from methyl and ethyl groups, or R 1 and R 2Together they form a cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, methylcyclohexane ring, cycloheptane ring, tetrahydrofuran ring, or tetrahydropyran ring.

[0053] In some preferred embodiments of this application, in a compound represented by general formula I, R 1 and R 2 This is independently selected from cyano groups and unsubstituted C1-C6 acyclic alkyl groups.

[0054] In some preferred embodiments of this application, in a compound represented by general formula I, R 1 and R 2 The group is independently selected from methyl and ethyl groups.

[0055] In some preferred embodiments of this application, in a compound represented by general formula I, R 1 and R 2 Together, they form an arbitrarily substituted heterocycloalkane ring having 3 to 8 ring atoms.

[0056] In some preferred embodiments of this application, in a compound represented by general formula I, R 1 and R 2 Together they form a tetrahydrofuran ring or a tetrahydropyran ring.

[0057] In some preferred embodiments of this application, in a compound represented by general formula I, R 1 and R 2 Together, they form an arbitrarily substituted cycloalkane ring having 3 to 8 ring atoms.

[0058] In some preferred embodiments of this application, in a compound represented by general formula I, R 1 and R 2 Together they form a clopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, methylcyclohexane ring, or cycloheptane ring.

[0059] In some preferred embodiments of this application, in a compound represented by general formula I, R 3 The group is selected from C1-C6 acyclic alkyl groups, C6-C14 aryl groups, C3-C8 cycloalkyl groups, and heteroaryl groups having 5 to 14 ring atoms. The above C1-C6 acyclic alkyl groups, C6-C14 aryl groups, and C3-C8 cycloalkyl groups are optionally substituted with 1 to 3 substituents, the substituents of which are independently selected from hydroxyl groups, halogens, cyano groups, amino groups, carboxyl groups, C6-C14 aryl groups, and C1-C6 acyclic alkyl groups.

[0060] In some preferred embodiments of this application, in a compound represented by general formula I, R 3 The group is selected from methyl, ethyl, propyl, butyl, phenyl, benzyl, tolyl, methoxyphenyl, chlorophenyl, fluorophenyl, bromophenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and pyridyl groups.

[0061] In some preferred embodiments of this application, in a compound represented by general formula I, R 3 The C1-C6 acyclic alkyl group is selected from a C1-C6 acyclic alkyl group, and the above C1-C6 acyclic alkyl group is optionally substituted with 1 to 3 substituents, the substituents of which are independently selected from a hydroxyl group, halogen, cyano group, amino group, carboxyl group, C6-C14 aryl group, and C1-C6 acyclic alkyl group.

[0062] In some preferred embodiments of this application, in a compound represented by general formula I, R 3 The methyl, ethyl, propyl, and butyl compounds are selected from methyl, ethyl, propyl, and butyl compounds.

[0063] In some preferred embodiments of this application, in a compound represented by general formula I, R 3is selected from a C6-C14 aryl group, wherein the C6-C14 aryl group is optionally substituted with 1 to 3 substituents, and the substituents are independently selected from a hydroxy group, halogen, a cyano group, an amino group, a carboxyl group, a C6-C14 aryl group, and a C1-C6 acyclic alkyl group.

[0064] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 is selected from a phenyl group, a benzyl group, a tolyl group, a methoxyphenyl group, a chlorophenyl group, a fluorophenyl group and a bromophenyl group, preferably selected from a phenyl group.

[0065] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 is selected from a C3-C8 cycloalkyl group, wherein the C3-C8 cycloalkyl group is optionally substituted with 1 to 3 substituents, and the substituents are independently selected from a hydroxy group, halogen, a cyano group, an amino group, a carboxyl group, a C6-C14 aryl group, and a C1-C6 acyclic alkyl group.

[0066] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 is selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0067] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 is selected from a heteroaryl group having 5 to 14 ring atoms.

[0068] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 is selected from a pyridyl group.

[0069] In some preferred embodiments of the present application, in the compound represented by general formula I, R 8is selected from hydrogen and a C1-C6 acyclic alkyl group, wherein the C1-C6 acyclic alkyl group is optionally substituted with 1 to 3 substituents, and the substituents are independently selected from a hydroxy group, halogen, a cyano group, an amino group, a carboxyl group, a C1-C6 acyclic alkyl group, and a C1-C6 acyclic alkyl group-O-.

[0070] In some preferred embodiments of the present application, in the compound represented by general formula I, R 8 is selected from hydrogen, methyl, ethyl, propyl, butyl, and pentyl.

[0071] In some preferred embodiments of the present application, in the compound represented by general formula I, R 8 is selected from hydrogen.

[0072] In some preferred embodiments of the present application, in the compound represented by general formula I, R 8 is selected from a C1-C6 acyclic alkyl group, wherein the C1-C6 acyclic alkyl group is optionally substituted with 1 to 3 substituents, and the substituents are independently selected from a hydroxy group, halogen, a cyano group, an amino group, a carboxyl group, a C1-C6 acyclic alkyl group, and a C1-C6 acyclic alkyl group-O-.

[0073] In some preferred embodiments of the present application, in the compound represented by general formula I, R 8 is selected from methyl, ethyl, propyl, butyl, and pentyl.

[0074] In some preferred embodiments of the present application, in the compound represented by general formula I, R 1 and R 2 together form an optionally substituted cycloalkane ring having 3 to 8 ring atoms, and R 3R is selected from C6-C14 aryl groups, and the above C6-C14 aryl group is optionally substituted with 1 to 3 substituents, the substituents of which are independently selected from hydroxyl groups, halogens, cyano groups, amino groups, carboxyl groups, C6-C14 aryl groups, and C1-C6 acyclic alkyl groups. 8 The substituent is selected from hydrogen and a C1-C6 acyclic alkyl group, and the C1-C6 acyclic alkyl group is optionally substituted with 1 to 3 substituents, the substituents of which are independently selected from a hydroxyl group, halogen, cyano group, amino group, carboxyl group, C1-C6 acyclic alkyl group, and C1-C6 acyclic alkyl group-O-.

[0075] In some preferred embodiments of this application, in a compound represented by general formula I, R 1 and R 2 Each of the C1-C6 acyclic alkyl groups is independently selected, and the above C1-C6 acyclic alkyl groups are optionally substituted with 1 to 3 C1-C6 acyclic alkyl substituents, or R 1 and R 2 Together they form a cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, methylcyclohexane ring, cycloheptane ring, or tetrahydropyran ring, R 3 R is selected from C6-C14 aryl groups, and the above C6-C14 aryl group is optionally substituted with 1 to 3 substituents, the substituents of which are independently selected from hydroxyl groups, halogens, cyano groups, amino groups, carboxyl groups, C6-C14 aryl groups, and C1-C6 acyclic alkyl groups. 8 The substituent is selected from hydrogen and a C1-C6 acyclic alkyl group, and the C1-C6 acyclic alkyl group is optionally substituted with 1 to 3 substituents, the substituents of which are independently selected from a hydroxyl group, halogen, cyano group, amino group, carboxyl group, C1-C6 acyclic alkyl group, and C1-C6 acyclic alkyl group-O-.

[0076] In some preferred embodiments of this application, in a compound represented by general formula I, R 1 and R2 Together they form a cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, methylcyclohexane ring, or cycloheptane ring, R 3 R is selected from C6-C14 aryl groups, and the above C6-C14 aryl group is optionally substituted with 1 to 3 substituents, the substituents of which are independently selected from hydroxyl groups, halogens, cyano groups, amino groups, carboxyl groups, C6-C14 aryl groups, and C1-C6 acyclic alkyl groups. 8 It is selected from hydrogen.

[0077] In some particularly preferred embodiments of this application, the compound represented by general formula I is the compound (6'-hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indridine]-7'-carbonyl)glycine, i.e., R 1 and R 2 These, along with the C atoms bonded to them, form a cyclopentane ring (i.e., R 1 and R 2 (is -CH2CH2CH2CH2-), R 3 is a phenyl group, R 4 and R 5 is hydrogen, R 6 and R 6’ is hydrogen, R 7 is hydrogen, R 8 It is a compound of formula I, where is hydrogen and X is an oxygen atom.

[0078] In the above different preferred embodiments, the preferred options for each substituent can be combined with each other, and all of these various combinations are within the scope of the present invention.

[0079] To avoid ambiguity, various terms used herein are defined below. Unless otherwise specified, the meanings of terms used herein are as follows:

[0080] The term "hydroxyl group" means -OH.

[0081] The term "halogen" or "halo" means -F, -Cl, -Br, or -I.

[0082] The term "amino group" refers to -NH2.

[0083] The term "cyano group" means -CN.

[0084] The term "carboxyl group" refers to -C(=O)OH.

[0085] The term "substitution" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in the group are independently substituted by a corresponding number of substituents.

[0086] The term "independently" means that if there is more than one substituent, these substituents may be identical or different.

[0087] The terms "optional" or "optional" indicate that the event described may or may not occur. For example, "optionally substituted" for a group means that the group may or may not be substituted.

[0088] As used herein, the term “heteroatom” refers to oxygen (O), nitrogen (N), or S(O). m (m represents 0, 1, or 2, i.e., a sulfur atom S, a sulfinyl group SO, or a sulfonyl group S(O)2).

[0089] The term “alkyl group” refers to a group formed at any carbon atom after a saturated hydrocarbon consisting of only two elements, C and H, has lost one hydrogen atom. “Alkyl groups” as used herein include acyclic alkyl groups such as linear alkyl groups and branched alkyl groups, and also include cycloalkyl groups such as monocyclic alkyl groups, spirocyclic alkyl groups, fused alkyl groups, and crosslinked alkyl groups. Preferably, “alkyl group” in this application means an acyclic alkyl group. Alkyl groups may be unsubstituted or substituted.

[0090] The “alkyl group” as described herein includes optionally substituted acyclic alkyl groups, preferably having 1 to 20 carbon atoms, more preferably 1 to 12 carbon atoms, and most preferably 1 to 6 carbon atoms, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group, chloromethyl group, fluoroethyl group, trifluoromethyl group, or 1,1,1-trifluoroethyl group.

[0091] The term "alkyl group" as used herein includes optionally substituted cycloalkyl groups (e.g., C3-C20 cycloalkyl groups, C3-C12 cycloalkyl groups, or C3-C8 cycloalkyl groups), and also includes, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, decahydronaphthyl group, norpinanyl group, adamantyl group, fluorocyclopropyl group, 2-iodocyclobutyl group, 2,3-dimethylcyclopentyl group, 2,2-dimethoxycyclohexyl group, and 3-phenylcyclopentyl group.

[0092] "C1-C6 acyclic alkyl groups," also known as "lower acyclic alkyl groups," refer to a subset of alkyl groups, meaning linear and branched alkyl groups having 1 to 6 carbon atoms, including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl groups.

[0093] The "alkyl group" as described herein may be substituted with one or more substituents, including halogen, cyano group, nitrate group (-NO2), hydroxyl group, amino group, carboxyl group, acyl group, alkyl group, heterocyclic group, alkenyl group, alkynyl group, aryl group, heteroaryl group, =O, =S, -SH, R 16 O-, R 16 S-, R 16 (O=)S-, and R 16 (O=)2S- is independently selected, and of those R 16 This includes alkyl groups, heterocyclic groups, alkenyl groups, alkynyl groups, aryl groups, or heteroaryl groups.

[0094] Preferably, the "alkyl group" as described herein is optionally substituted with 1 to 3 substituents, the substituents being a hydroxyl group, halogen, nitrate group, cyano group, amino group, carboxyl group, C1-C6 acyclic alkyl group, C3-C8 cycloalkyl group, C2-C6 acyclic alkenyl group-, C2-C6 acyclic alkynyl group-, C3-C8 cycloalkyl group, C3-C8 cycloalkenyl group, C6-C14 aryl group, heteroaryl group having 5 to 14 ring atoms, C1-C6 acyclic alkyl group-O-, C3-C8 cycloalkyl group-O-, C2-C6 acyclic alkenyl group-O-, C2-C6 acyclic alkynyl group-O-, C3-C8 cycloalkenyl group-O-, C6-C14 aryl group-O- Independently selected from a heteroaryl group (-O-) having 5 to 14 ring atoms, a C1-C6 acyclic alkyl group (-S-), a C3-C8 cycloalkyl group (-S-), a C2-C6 acyclic alkenyl group (-S-), a C2-C6 acyclic alkynyl group (-S-), a C3-C8 cycloalkenyl group (-S-), a C6-C14 aryl group (-S-), a heteroaryl group (-S-) having 5 to 14 ring atoms, a heterocycloalkyl group (-S-) having 3 to 8 ring atoms, a heterocycloalkenyl group (-S-) having 3 to 8 ring atoms, a =O, =S, -SH, -CF3, -CO2C1-C6 acyclic alkyl group (-S-), a C1-C6 acyclic alkyl group (-S-), a C1-C6 acyclic alkyl group (-O=)S-, and a C1-C6 acyclic alkyl group (-O=)2S-.

[0095] The term "alkenyl group" refers to a group formed after any carbon atom loses one hydrogen atom in a hydrocarbon that consists of only two elements, C and H, and contains one or more carbon-carbon double bonds but does not contain carbon-carbon triple bonds or aromatic bonds. The "alkenyl groups" as used herein include acyclic alkenyl groups such as linear alkenyl groups and branched alkenyl groups, as well as cycloalkenes such as monocyclic alkenyl groups, spirocyclic alkenyl groups, fused cyclic alkenyl groups, and bridging cyclic alkenyl groups. Alkenyl groups may be unsubstituted or substituted.

[0096] The “alkenyl group” described herein includes optionally substituted acyclic alkenyl groups, preferably having 2 to 20 carbon atoms, more preferably 2 to 12 carbon atoms, and most preferably 2 to 6 carbon atoms. Examples include vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, isobutenyl group, 1-pentenyl group, 2-pentenyl group, isopentenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, isohexyl group, 1-heptenyl group, 2-heptenyl group, 3-heptenyl group, 1-octenyl group, 2-octenyl group, 3-octenyl group, 4-octenyl group, 1-nonenyl group, 1-decenyl group, 1-undecenyl group, and 1-dodecenyl group.

[0097] The term "alkenyl group" as used herein includes optionally substituted cycloalkenyl groups (e.g., C3-C20 cycloalkenyl groups, C3-C12 cycloalkenyl groups, or C3-C8 cycloalkenyl groups), and also includes, for example, cyclobutenyl groups, cyclopentenyl groups, cyclohexenyl groups, cycloheptenyl groups, cyclobutadienyl groups, cyclopentadienyl groups, cycloheptatrienyl groups, and the like.

[0098] The “alkenyl group” described herein may be substituted with one or more (e.g., 1 to 3) substituents, and the selection and preferred range of substituents are the same as those for the substituents of the “alkyl group”.

[0099] The term "alkynyl group" refers to a group formed after a hydrocarbon consisting of only two elements, C and H, containing one or more carbon-carbon triple bonds but no aromatic bonds, loses one hydrogen atom from any carbon atom. As used in this text, "alkynyl groups" include acyclic alkynyl groups such as linear alkynyl groups and branched alkynyl groups, as well as cycloalkynyl groups such as monocyclic alkynyl groups, spirocyclic alkynyl groups, fused cyclic alkynyl groups, and bridging cyclic alkynyl groups. Alkynyl groups may optionally contain one or more carbon-carbon double bonds. Alkynyl groups may be unsubstituted or substituted.

[0100] The "alkynyl group" described herein includes optionally substituted acyclic alkynyl groups, preferably having 2 to 20 carbon atoms, more preferably 2 to 12 carbon atoms, and most preferably 2 to 6 carbon atoms. Examples include ethynyl group, propynyl group, 1-butynyl group, 2-butynyl group, isobutynyl group, 1-pentynyl group, 2-pentynyl group, isopentinyl group, 3-methyl-3-butynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 3-heptynyl group, l-octinyl group, 1-noninyl group, 1-decynyl group, 1-undecynyl group, and 1-dodecynyl group.

[0101] The term "alkynyl group" as used herein includes optionally substituted cycloalkynyl groups (e.g., C8-C18 cycloalkynyl groups), as well as cyclooctinyl groups, for example.

[0102] The "alkynyl group" described herein may be optionally substituted with one or more (e.g., 1 to 3) substituents, and the selection and preferred range of substituents are the same as those for the substituents of the "alkyl group".

[0103] The term "heterocyclic group" means a monocyclic or polycyclic compound substituent containing a saturated or carbon-carbon double bond or carbon-carbon triple bond, which comprises 3 to 20 ring atoms (preferably 3 to 12 ring atoms, more preferably 3 to 8 ring atoms), of which one or more ring atoms are selected from heteroatoms, and the remaining ring atoms are carbon, none of which rings are aromatic. The "heterocyclic group" as used herein also includes spiroheterocyclic groups, fused heterocyclic groups, and bridging heterocyclic groups. Heterocyclic groups may be unsubstituted or substituted. Heterocyclic groups may be heterocycloalkyl groups, heterocycloalkenyl groups, or heterocycloalkynyl groups. Suitable examples of monocyclic heterocycles include, but are not limited to, piperidinyl, pyrrolidinyl, piperazinyl, azetidinyl, azetidinyl, morpholinyl, azetidinyl, oxocyclopentyl (tetrahydrofuranyl), and oxacyclohexyl (tetrahydropyranyl) groups.

[0104] It should be understood that the “heterocyclic group” as described herein may be optionally substituted with one or more (e.g., 1 to 3) substituents, and the selection and preferred range of substituents are the same as those for the substituents of the “alkyl group”.

[0105] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic group having a conjugated π-electron system. The aryl ring may be fused with heteroaromatic rings, heterocycles, cycloalkanes, spirocycloalkanes, fused cycloalkanes, bridged cycloalkanes, cycloalkenes, spirocycloalkenes, fused cycloalkenes, bridged cycloalkenes, cycloalkynes, spirocycloalkynes, fused cycloalkynes, or bridged cycloalkynes. The aryl group may be unsubstituted or substituted. Examples include phenyl group, naphthyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, methoxyphenyl group (e.g., 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group), chlorophenyl group (e.g., 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group), fluorophenyl group (e.g., 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group), bromophenyl group (e.g., 2-bromophenyl group, 3-bromophenyl group), This includes, but is not limited to, the following groups: 4-bromophenyl group, 2-chloro-3-methylphenyl group, 2-chloro-4-methylphenyl group, 2-chloro-5-methylphenyl group, 3-chloro-2-methylphenyl group, 3-chloro-4-methylphenyl group, 4-chloro-2-methylphenyl group, 4-chloro-3-methylphenyl group, 5-chloro-2-methylphenyl group, 2,3-dichlorophenyl group, 2,5-dichlorophenyl group, 3,4-dichlorophenyl group, 2,3-dimethylphenyl group, 3,4-dimethylphenyl group, etc.

[0106] The “aryl group” as described herein may be optionally substituted with 1 to 4 or 1 to 3 substituents, and the selection and preferred range of substituents are the same as those for the substituents of the “alkyl group”.

[0107] The term "heteroaryl group" refers to an aromatic system containing 5 to 18 ring atoms (preferably 5 to 14 ring atoms), wherein 1 to 4 ring atoms are heteroatoms selected from oxygen, nitrogen, and sulfur. The heteroaryl group itself may be condensed with an aromatic ring, heteroring, cycloalkane, spirocycloalkane, condensed cycloalkane, bridged cycloalkane, cycloalkene, spirocycloalkene, condensed cycloalkene, bridged cycloalkene, cycloalkyne, spirocycloalkyne, condensed cycloalkyne, or bridged cycloalkyne. It may be unsubstituted or substituted. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazolyl, pyrazinyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzimidazolyl, indolyl, quinolyl, isoquinolyl, and quinazolinyl groups.

[0108] The "heteroaryl group" described herein is optionally substituted with 1 to 4 or 1 to 3 substituents, and the selection and preferred range of substituents are the same as those for the substituents of the "alkyl group".

[0109] As used herein, the term “acyl group” means RC(=O)-, where R is a C1-C18 (preferably C1-C12, and more preferably C1-C6) alkyl group. Examples of “acyl groups” include, but are not limited to, formyl, acetyl, benzoyl, nicotinoyl, propionyl, isobutyryl, and oxalyl groups.

[0110] The acyl group RC(=O)- may be optionally substituted with one or more substituents (e.g., 1 to 3), and the selection and preferred range of substituents are the same as those for the alkyl group substituents.

[0111] As used herein, the term "ring formation" means the formation of a cyclic structure such as a cycloalkane ring, cycloalkene ring, cycloalkyne ring, aromatic ring, heterocycloalkane ring, heterocycloalkene ring, heterocycloalkyne ring, or heteroaromatic ring, and such cyclic structure may be monocyclic, dicyclic, or polycyclic, and includes fused rings, bridging rings, and spiro-ring structures. In particular, substituent R 1 and R 2 The ring formed by this is preferably 3-12 membered, with 3-12 membered cycloalkane rings, cycloalkene rings, heterocycloalkane rings, and heterocycloalkene rings being particularly preferred, and most preferably 3-8 membered cycloalkane rings, cycloalkene rings, heterocycloalkane rings, and heterocycloalkene rings, such as cyclopropane rings, cyclobutane rings, cyclopentane rings, cyclohexane rings, cycloheptane rings, tetrahydrofuran rings, and tetrahydropyran rings. The ring structure is optionally substituted with one or more (e.g., 1-3) substituents, and the selection and preferred range of substituents are the same as for the substituents of the "alkyl group".

[0112] In this specification, ranges of numbers related to the number of substituents, carbon atoms, and ring atoms refer to listing all integers within that range exactly as they are, and the range is merely a simplified notation. For example, "1 to 4 substituents" means 1, 2, 3, or 4 substituents. "1 to 3 substituents" means 1, 2, or 3 substituents. "3-12 member ring" means a ring with 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 members. "3-8 member ring" means a ring with 3, 4, 5, 6, 7, or 8 members. "1 to 12 carbon atoms" or "C1-C12" means 1 (C1), 2 (C2), 3 (C3), 4 (C4), 5 (C5), 6 (C6), 7 (C7), 8 (C8), 9 (C9), 10 (C10), 11 (C11), or 12 (C12) carbon atoms. "1 to 6 carbon atoms" or "C1-C6" means 1 (C1), 2 (C2), 3 (C3), 4 (C4), 5 (C5), or 6 (C6) carbon atoms. "2-6 carbon atoms" or "C2-C6" means 2 (C2), 3 (C3), 4 (C4), 5 (C5), or 6 (C6) carbon atoms. "C3-C8" means 3 (C3), 4 (C4), 5 (C5), 6 (C6), 7 (C7), or 8 (C8) carbon atoms. "3 to 8 ring atoms" means 3, 4, 5, 6, 7, or 8 ring atoms.

[0113] Accordingly, the range of numbers related to the number of substituents, the number of carbon atoms, and the number of ring atoms also covers any one of its subranges, and each subrange is also considered to be disclosed herein.

[0114] In some particularly preferred embodiments of this application, the hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is the compound (6'-hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indridine]-7'-carbonyl)glycine disclosed in WO2018205928 or a pharmaceutically acceptable salt thereof. The compound (6'-hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indridine]-7'-carbonyl)glycine is R 1 and R 2 These, together with the C atoms bonded to them, form a cyclopentane ring (i.e., -CH2CH2CH2CH2-), R 3 is a phenyl group, R 4 and R 5 is hydrogen, R 6 and R 6’ is hydrogen, R 7 is hydrogen, R 8 It is a compound of formula I, where is hydrogen and X is an oxygen atom.

[0115] (2) Pharmaceutical preparations A first aspect of this application provides a long-acting oral pharmaceutical formulation comprising a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, adjuvants, or excipients, wherein the long-acting oral pharmaceutical formulation is suitable for administration at intervals of one week or more. In the context of this application, a long-acting oral pharmaceutical formulation means an oral pharmaceutical formulation that is therapeutically effective when administered at intervals of one week or more.

[0116] For therapeutic use, HIF-PHI is typically administered to patients in the form of a pharmaceutical composition, which comprises at least one of the above compounds as an active ingredient, and optionally includes pharmaceutically acceptable adjuvants and / or excipients, as well as a pharmaceutically acceptable solid or liquid carrier.

[0117] The pharmaceutical compositions of the present invention can be prepared in various pharmaceutical dosage forms suitable for oral administration, as needed. Therefore, when using a solid carrier, the formulation may be encapsulated in a hard gel capsule in the form of a powder or particles, or prepared in the form of a sugar-coated tablet or granule. The solid carrier may contain conventional excipients such as binders, fillers, lubricant lumps, disintegrants, and wetting agents. If necessary, the tablets may be coated with a conventional film. When using a liquid carrier, the formulation may be in the form of a syrup, emulsion, softgel capsule, aqueous or non-aqueous liquid suspension, or a dry product restored with water or other suitable carrier before use. The liquid formulation may contain conventional additives such as suspending agents, emulsifiers, wetting agents, non-aqueous carriers (including edible oils), preservatives, flavoring agents, and / or coloring agents.

[0118] These pharmaceutical compositions (or pharmaceutical preparations) may further contain various excipients, such as preservatives, humectants, emulsifiers, and dispersants. Inhibition of microbial activity can be ensured by various antimicrobial and antifungal agents (e.g., parahydroxybenzoate, chlorobutanol, phenol, sorbic acid, etc.). They may also contain isotonic agents, such as sugars and sodium chloride. The absorption of injectable pharmaceutical dosage forms can be extended by using delayed absorption reagents (e.g., aluminum monostearate and gel).

[0119] Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate), and further comprising: (a) fillers or mixtures (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid); (b) binders (e.g., carboxymethylcellulose, alginate esters, gels, polyvinylpyrrolidone, sucrose, and gum arabic); (c) humectants (e.g., glycerin); and (d) disintegrants (e.g., agar - agar, calcium carbonate, potato). Alternatively, it may contain (e) tapioca starch, alginic acid, synthetic silicate esters, sodium carbonate), (f) a solution retarder (e.g., paraffin), (g) an absorption enhancer (e.g., quaternary ammonium compounds), (g) a wetting agent (e.g., hexadecane alcohol and glyceryl monostearate), (h) an adsorbent (e.g., kaolin and bentonite), and (i) a lubricant (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate) or a mixture thereof.

[0120] Similar types of solid pharmaceutical compositions (or pharmaceutical preparations) can also be used as fillers in soft capsules and hard capsules that use lactose and high molecular weight polyethylene glycol as excipients.

[0121] Solid dosage forms (e.g., tablets, sugar-coated pills, capsules, pills, and granules) can be prepared using a coating layer and a shell (e.g., an intestinal coating layer and others known in the art). These may contain light-shielding agents and may be pharmaceutical compositions (or pharmaceutical preparations) that release the active compound or various active compounds to a portion of the intestinal tract in a delayed manner. The active ingredient may be microencapsulated and may contain one or more of the above excipients, if appropriate.

[0122] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may also contain inert diluents commonly used in this art (e.g., water or other solvents), solubilizers and emulsifiers (e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethylbenzylammonium), oils (specifically, cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil), glycerin, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan or mixtures thereof.

[0123] In addition to these inert diluents, the pharmaceutical composition (or pharmaceutical preparation) may further include, for example, humectants, emulsifiers and suspending agents, fragrances, flavorings, and fragrance enhancers.

[0124] In addition to the active compound, the suspension may also contain suspending agents such as ethoxylated isooctadecanol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline fibers, boehmite, bentonite, agar-agar and tragacanth gum, or mixtures thereof.

[0125] The amount of HIF-PHI compound in a pharmaceutical composition (or pharmaceutical preparation) can be appropriately determined by a person skilled in the art as needed.

[0126] In some embodiments, the amount of HIF-PHI or a pharmaceutically acceptable salt contained in each unit of the pharmaceutical preparation is approximately 1-1000 mg, approximately 1-10 mg, approximately 10 mg, approximately 5 mg, approximately 4.5 mg, approximately 1-3 mg, approximately 2-4 mg, approximately 3-5 mg, approximately 4-6 mg, approximately 5-7 mg, approximately 6-8 mg, approximately 7-9 mg, approximately 8-10 mg, approximately 9-11 mg, approximately 10-12 mg, approximately 4.5-5 mg, 20 mg, 30 mg, 30-10 mg The amount is 0 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 10-30 mg, approximately 30-50 mg, approximately 50-70 mg, approximately 10-90 mg, approximately 10-800 mg, approximately 10-700 mg, approximately 10-600 mg, approximately 10-500 mg, approximately 10-400 mg, approximately 10-300 mg, or approximately 10-200 mg, or any amount within any range defined by any of these values.

[0127] In some embodiments, the amount of HIF-PHI or a pharmaceutically acceptable salt contained in each unit of the pharmaceutical preparation is approximately 0.01-0.2 mg, approximately 0.2-0.4 mg, approximately 0.4-0.6 mg, approximately 0.6-0.8 mg, approximately 0.8-1 mg, approximately 1-1.2 mg, approximately 1.2-1.4 mg, approximately 1.4-1.6 mg, approximately 1.6-1.8 mg, approximately 1.8-2 mg, approximately 2-2.2 mg, approximately 2.2-2.4 mg, approximately 2.4-2.6 mg, approximately 2.6-2.8 mg, and approximately 2.8-3 mg. Approximately 3-3.2 mg, approximately 3.2-3.4 mg, approximately 3.4-3.6 mg, approximately 3.6-3.8 mg, approximately 3.8-4 mg, approximately 3.9-4.1 mg, approximately 4-4.2 mg, approximately 0.2-0.4 mg, approximately 0.2-0.6 mg, approximately 0.2-0.8 mg, approximately 0.2-1 mg, approximately 0.2-1.2 mg, approximately 0.2-1.4 mg, approximately 0.2-1.6 mg, approximately 0.2-1.8 mg, approximately 0.2-2.0 mg, 0.2-2.5 mg, approximately 0.2-3.0 mg, approximately 0.2-3.5 mg, approximately 0.2-4 mg.0mg, about 5-10mg, about 10-15mg, about 15-20mg, about 20-25mg, about 25-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60~70mg, approx. 70~80mg, approx. 80~90mg, approx. 90~100mg, approx. 100~120mg, approx. 120~140mg, approx. 140~150mg, approx. 150~16 0mg, about 160-180mg, about 180-200mg, about 200-220mg, about 220-240, about 10-500mg, about 50-400mg, about 50-300mg, Approx. 100~250mg, approx. 1~10mg, approx. 10~200mg, approx. 10~150mg, approx. 10~100mg, approx. 10~180mg, approx. 10~160mg, approx. 10~140m g, about 10-120 mg, about 10-100 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, Approx. 70~80mg, approx. 80~90mg, approx. 90~100mg, approx. 100~120mg, approx. 120~140mg, approx. 140~160mg, approx. 160~180mg, approx. 180 This refers to amounts within any range defined by any value among these, such as ~200 mg, approximately 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-350 mg, approximately 350-400 mg, approximately 25 mg, approximately 50 mg, approximately 100 mg, approximately 250 mg, or any of these values.

[0128] In some embodiments, the amount of HIF-PHI or a pharmaceutically acceptable salt contained in each unit of the pharmaceutical preparation is approximately 0.1% (w / w) to 10% (w / w), approximately 0.05% (w / w) to 5% (w / w), approximately 0.2% (w / w) to 15% (w / w), approximately 0.5% (w / w) to 30% (w / w), approximately 1% (w / w) to 25% (w / w), approximately 2% (w / w), approximately 3% (w / w), approximately 4% (w / w), approximately 5% (w / w), at least approximately 10% (w / w), at least approximately 20% (w / w), at least approximately 50% (w / w), and at least approximately 7% (w / w). 0%(w / w), at least about 80%, about 10%(w / w) to about 30%(w / w), about 10%(w / w) to about 20%(w / w), about 20%(w / w) to about 30%(w / w), about 30%(w / w) to about 50%(w / w), about 30%(w / w) to about 40%(w / w), about 40%(w / w) to about 50%(w / w), about 50%(w / w) to about 80%(w / w), about 50%(w / w) to about 60%(w / w), about 70%(w / w) to about 80%(w / w), or about 80%(w / w) to about 90%(w / w), or any ratio within any range defined by any value among these ratios.

[0129] The preparation of a pharmaceutical composition (or pharmaceutical formulation) may be carried out using methods well known or commonly used in the art, and typically includes the steps of mixing the active ingredient HIF-PHI with a pharmaceutically acceptable carrier, adjuvant, or excipient, and optional post-treatment or processing steps (e.g., drying, granulation, encapsulation, etc.).

[0130] (3) Pharmaceutical products A second aspect of this application provides a pharmaceutical product comprising a packaging container, a drug information sheet, and a pharmaceutical product contained in the packaging container, wherein the pharmaceutical product is a pharmaceutical product according to the first aspect of this application, and the drug information sheet includes a description indicating that the pharmaceutical product is suitable for oral administration at intervals of one week or more.

[0131] In this application, a pharmaceutical product means a pharmaceutical product that meets the requirements of the relevant regulatory body, is sold in a pharmacy, and can be directly selected or purchased by a physician or patient. It typically has separate packaging or a packaging container, contains a pharmaceutical preparation housed in the packaging container, and is accompanied by a pharmaceutical information sheet that contains the specifications required by the relevant regulatory body (e.g., active ingredients, auxiliary ingredients, indications, contraindications, possible side effects, method of use, precautions, etc.). The pharmaceutical information sheet may be a separate sheet of paper, a sticky note, or a pamphlet housed in the packaging container, or it may be an explanatory text printed directly on the packaging container. The pharmaceutical information sheet may also be an accompanying electronic pharmaceutical information sheet, such as a standalone optical disc (CD-ROM, etc.) or a URL or QR code with information about the information sheet network address.

[0132] Since the pharmaceutical formulation in this application is a long-acting oral pharmaceutical formulation, the drug information sheet should include a description indicating that the pharmaceutical formulation can or is suitable to be administered orally at intervals of one week or more.

[0133] (4) Medical use or treatment method A third aspect of this application proposes the use of a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof in the manufacture of a long-acting oral pharmaceutical for the treatment of chronic anemia, wherein the long-acting oral pharmaceutical is suitable for administration at intervals of one week or more.

[0134] A fourth aspect of this application provides a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof for the oral treatment of chronic anemia, wherein the oral treatment is administered at intervals of at least one week.

[0135] A fifth aspect of this application provides the use of a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof for the treatment of chronic anemia, wherein the HIF-PHI or a pharmaceutically acceptable salt thereof is administered orally at intervals of at least one week.

[0136] A sixth aspect of this application provides a method for treating chronic anemia, comprising orally administering to a patient in need of treatment a therapeutically effective dose of a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof at intervals of at least one week.

[0137] In this specification, the term “patient” means all mammals, including humans. Patients include humans, cattle, dogs, cats, goats, sheep, mice, pigs, rabbits, and others.

[0138] In this specification, chronic anemia can be selected from idiopathic aplastic anemia, chronic renal anemia, anemia induced by chemotherapy for tumors, anemia due to blood loss, anemia due to menorrhagia in women, iron deficiency anemia, vitamin deficiency anemia, cytoplasmic and aplastic anemia, hemolytic anemia, iron utilization disorder anemia, and anemia due to hypothyroidism, and is preferably chronic renal anemia.

[0139] The pharmaceutical formulations described in this application can also be used to treat anemia complications or ischemic diseases, such as ischemic cerebrovascular disease, ischemic nephropathy (IRD), and ischemic cardiomyopathy (ICM).

[0140] When treating chronic anemia with the pharmaceutical formulation of this application, it is usually necessary to administer a therapeutically effective dose of the active ingredient (i.e., HIF-PHI) to the patient. In this specification, the term "therapeutic dose" refers to the amount of the active ingredient described in this application that, when administered to a patient, effectively delays the progression of the patient's symptoms or improves the patient's health. The specific dose may be determined by a physician based on the patient's specific circumstances. The exact dose used may depend on the route of administration, the disease, the severity of the disease to be treated, and various physical factors related to the individual being treated, as well as the judgment of the healthcare provider. In vitro or in vivo studies may be used to determine the optimal dose range.

[0141] For example, the compound of general formula I of this application can be administered to a patient in doses of approximately 0.01 to 4000 mg, 0.05 to 2000 mg, 0.1 to 1000 mg, 0.1 to 500 mg, 9 to 30 mg, 9 to 18 mg, or 18 to 30 mg per week. However, the specific dose is variable. Those skilled in the art will know how to determine the optimal dose for a particular patient.

[0142] In some embodiments, the dose of HIF-PHI administered each time is approximately 0.01-0.2 mg, approximately 0.2-0.4 mg, approximately 0.4-0.6 mg, approximately 0.6-0.8 mg, approximately 0.8-1 mg, approximately 1-1.2 mg, approximately 1.2-1.4 mg, approximately 1.4-1.6 mg, approximately 1.6-1.8 mg, approximately 1.8-2 mg, approximately 2-2.2 mg, approximately 2.2-2.4 mg, approximately 2.4-2.6 mg, approximately 2.6-2.8 mg, approximately 2.8-3 mg, approximately 3-3.2 mg. Approximately 3.2-3.4 mg, approximately 3.4-3.6 mg, approximately 3.6-3.8 mg, approximately 3.8-4 mg, approximately 3.9-4.1 mg, approximately 4-4.2 mg, approximately 0.2-0.4 mg, approximately 0.2-0.6 mg, approximately 0.2-0.8 mg, approximately 0.2-1 mg, approximately 0.2-1.2 mg, approximately 0.2-1.4 mg, approximately 0.2-1.6 mg, approximately 0.2-1.8 mg, approximately 0.2-2.0 mg, 0.2-2.5 mg, approximately 0.2-3.0 mg, approximately 0.2-3.5 mg, approximately 0.2-4 mg.0mg, about 5-10mg, about 10-15mg, about 15-20mg, about 20-25mg, about 25-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 6 0~70mg, approx. 70~80mg, approx. 80~90mg, approx. 90~100mg, approx. 100~120mg, approx. 120~140mg, approx. 140~150mg, approx. 150~160mg , about 160-180mg, about 180-200mg, about 200-220mg, about 220-240, about 10-500mg, about 50-400mg, about 50-300mg, about 100 ~250mg, approx. 1~10mg, approx. 10~200mg, approx. 10~150mg, approx. 10~100mg, approx. 10~180mg, approx. 10~160mg, approx. 10~140mg, approx. 10 ~120mg, approx. 10~100mg, approx. 10~20mg, approx. 20~30mg, approx. 30~40mg, approx. 40~50mg, approx. 50~60mg, approx. 60~70mg, approx. 70~80 mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about The dosage may be 200-220 mg, approximately 220-240 mg, approximately 240-250 mg, approximately 250-260 mg, approximately 260-280 mg, approximately 280-300 mg, approximately 300-350 mg, approximately 350-400 mg, approximately 25 mg, approximately 50 mg, approximately 100 mg, or approximately 250 mg, or any dosage within these ranges or any value within the specified range.

[0143] This application provides an innovative administration method that breaks the limitations on the administration cycle of traditional pharmaceutical theory. According to the administration method described in this application, when treating patients with chronic renal anemia over a long period, i.e., during the dose adjustment phase (titration period), patient adherence to the medication can be improved, therapeutic effects can be enhanced, and chronic diseases can be managed more easily over a longer period.

[0144] The present application will be further described below with reference to examples and drawings, but these examples are not intended to limit the scope of the present application.

[0145] Examples The embodiments described below are not all embodiments of the present invention, but rather some embodiments. The detailed description of embodiments of the present invention is not intended to limit the scope of the invention for which protection is sought, but rather to show only selective embodiments of the present invention. All other embodiments that a person skilled in the art could obtain based on the embodiments of the present invention without departing from the principles of the present invention and without performing any creative work are all within the scope of the present invention.

[0146] For the sake of brevity, the steps of materials, apparatus, and methods commonly used in the art are not explicitly stated in the examples. Process methods and analytical test procedures (and related parameters) not specifically stated in the examples are all based on those commonly used by those skilled in the art, and materials, reagents, and equipment whose specific origins are not specified are all common laboratory materials and equipment that are commercially available.

[0147] Example 1: (6'-hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indolidine]-7'-carbonyl)glycine ( 1 ) synthesis

[0148] [ka]

[0149] Compound according to the method of Example 24 of WO2018205928 1 They were synthesized.

[0150] The structure of the compound is determined by liquid-phase chromatography-mass spectrometry (LCMS) or nuclear magnetic resonance (NMR). The NMR chemical shift (δ) is 10 -6The values ​​are expressed in units of ppm. A Bruker-500 nuclear magnetic resonance spectrometer was used for nuclear magnetic resonance measurements, with dehydrogenated dimethyl sulfoxide (dmso-d6) and dehydrogenated chloroform (CDCl3) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard. LCMS measurements were performed using a Shimadzu LCMS-2020 or Thermo UltiMate3000.

[0151] Thin-layer chromatography silica gel plates used were either Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates from Shandong Province, China. Column chromatography generally uses 200-300 mesh silica gel from Yantai Huanghai, Shandong Province, China as the support.

[0152] All starting materials used in this embodiment are purchased from chemical suppliers or synthesized by literature methods.

[0153] The following abbreviations can be used in this example: DMSO-d6: Dimethyl sulfoxide in which 6 hydrogen atoms are replaced by deuterium atoms. CDCl3: Deuterated chloroform CAS: CAS registration number NMR: nuclear magnetic resonance LCMS: Liquid-phase chromatography-mass spectrometry ESI: Electrospray Ionization ppm: one part per million δ: Nuclear magnetic resonance chemical shift TMS: Tetramethylsilane s: Nuclear magnetic resonance single peak d: Nuclear magnetic double peak t: Nuclear magnetic resonance triple peak br: Nuclear magnetic broad peak CDI: Carbonyldiimidazole DCC:N,N'-Dicyclohexylcarbodiimide NBS: N-bromocyclosuccinimide

[0154] compound1 The main synthesis steps are as follows:

[0155] Step 1: 1-(2-phenyl-1H-pyrrole-1-yl)cyclopentan-1-carboxylic acid 1a )

[0156] [ka]

[0157] Compound 3-(1,3-dioxan-2-yl)-1-phenylpropan-1-one (prepared by the method described in Patent Document WO / 2011 / 042477) (500 mg) and 1-amino-cyclopentane-1-carboxylic acid (421 mg) were refluxed in 8 mL of acetic acid for 16 hours. After cooling the reaction, the acetic acid was rotated dry as much as possible, diluted with water and ethyl acetate, and the organic phase was collected. The organic phase was washed several times with dilute sodium chloride aqueous solution until the aqueous phase was nearly neutral, the ethyl acetate layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the compound. 1a The result obtained was: LCMS ESI(+):256(M+1) + . 1 H NMR(500MHz,DMSO-d6)δ(ppm):12.95(br,s,1H),7.35-7.33(m,3H),7.25-7.22(m,2H),7.00-6 .99(m,1H),6.04(m,1H),5.95(m,1H),2.14-2.11(m,2H),2.01-1.97(m,2H),1.60-1.57(m,4H).

[0158] Step 2: 2-(1-(2-phenyl-1H-pyrrole-1-yl)cyclopentan-1-carbonyl) dimethyl malonate 1b )

[0159] [ka]

[0160] Second step compound in Example 15 of WO2018205928 15b Using the synthesis route, the raw materials 15a of 1a If you replace it with, 1b This can be obtained. LCMS ESI(+):370(M+1) + . 1 H NMR(500MHz,DMSO-d6)δ 7.28-7.22(m,3H),7.20-7.15(m,2H),7.11(dd,J=3.2,1.8Hz,1H),6.15(t,J=3.3Hz,1H),5.93(dd,J=3.5,1. 7Hz,1H), 5.13(s,1H),3.56(s,6H),2.06(d,J=8.0Hz,2H),1.59(t,J=12.2Hz,2H),1.33(s,2H),1.16(s,2H).

[0161] Step 3: 6'-Hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indolidine]-7'-methyl formate 1c )

[0162] [ka]

[0163] Third step compound in Example 15 of WO2018205928 15c Using the synthesis route, the raw materials 15b of 1b If you replace it with, 1c This can be obtained. LCMS ESI(+):338(M+1) + . 1 H NMR(500MHz,DMSO-d6)δ 13.84(s,1H),7.54-7.43(m,5H),7.09(d,J=4.0Hz,1H),6.35(d,J=4.0Hz,1H),3.81 (s,3H),2.30-2.21(m,2H),2.10-2.01(m,2H),1.48-1.38(m,2H),1.00-0.89(m,2H).

[0164] Step 4: (6'-Hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indolidine]-7'-carbonyl)glycine ( 1 )

[0165] [ka]

[0166] The fourth step compound in Example 15 of WO2018205928 15 Using the synthesis route, the raw materials 15c of 1c If you replace it with, the compound 1 This can be obtained. LCMS ESI(+):381(M+1) + . 1 HNMR(500MHz,DMSO-d6)δ(ppm)17.96(s,1H),12.97(s,1H),9.89-9.87(d,J=5.5Hz,1H),7.53-7.46(m,5H),7.08-7.07(d,1H) ,6.37-6.36(d,1H),4.08-4.07(d,J=5.5Hz,2H),2.35-2.20(m,2H),2.18-2.10(m,2H),1.60-1.46(m,2H),0.98-0.85(m,2H).

[0167] Example 2: Inhibitory effect of Comp-1 on HIF PHD-2

[0168] In this example and the examples described later, the compound prepared in Example 1 1 The test was conducted using the compound 1 This is represented as "Comp-1".

[0169] Preparation of stock solutions for the following reagents: HEPES buffer (pH 7.4, 50 mM), DMSO / HEPES solution of HIF-1α polypeptide (sequence: DLDLEMLAPYIPMDDDFQL, Genscript) (0.5 mM, preparation method: first prepare a 20 mM DMSO solution of the peptide, then dilute it 40 times by volume with the HEPES buffer), ascorbic acid solution (10 mM), hydrochloric acid solution of FeSO4 (0.1 mM, hydrochloric acid concentration 10 μm), 2-oxovaleric acid The following are prepared: a solution of 2-OG (1 mM), EDTA solution (pH 8.0, 0.5 M), and eight concentrations of Comp-1 / DMSO solution (concentrations of 4000 μm, 1333 μm, 444.4 μm, 148.1 μm, 49.4 μm, 16.5 μm, 5.5 μm, and 1.82 μm, respectively). The reagents of the above concentrations (50 μL of HEPES solution, 10 μL of ascorbic acid solution, 10 μL of FeSO4 hydrochloric acid solution, 10 μL of 2-OG solution, and 10 μL of HIF-1α polypeptide solution) were added to nine Eppendorf tubes. Then, 5 μL of the eight concentrations of Comp-1 / DMSO solution and 5 μL of DMSO were added to each tube. Finally, 5 μL of PHD2 enzyme (Active) was added to each tube. Motif (concentration: 0.2 μg / μL) was added, and the reaction system was incubated at 30°C in the dark for 2 hours. Finally, 10 μL of EDTA solution was added to each tube to stop the reaction. After filtering the liquid from each reaction system through a 0.45 μm filter, the HIF-polypeptide and hydroxylated HIF-polypeptide were separated by high-performance liquid-phase chromatography. The ratios of the HIF-polypeptide and hydroxylated polypeptide were calculated by quantifying their concentrations using an ultraviolet absorption detector. IC was performed using Graph Prism 6.0 software. 50 Calculate the IC of Comp-1 compared to HIF PHD-2. 50 Its thickness is 2.36 μm.

[0170] Example 3: Half-life of compound excretion in rats

[0171] Preparation of intravenous injection formulation: 4.0005 g of HP-β-CD (manufactured by Binzhou Zhiyuan Biotechnology Co., Ltd., Shandong, China) was weighed, dissolved in 16.0 mL of sterile water for injection, stirred for 20 minutes, and then diluted to 20 mL to obtain a 20% HP-β-CD solution. 4.93 mg of Comp-1 was weighed, dissolved in 0.984 mL of ethanol, stirred for 13 minutes, and then sonicated for 5 minutes. Subsequently, 8.0 + 0.856 mL of 20% HP-β-CD was added, followed by stirring for 4 minutes and sonication for 4 minutes to obtain 9.84 mL of a clear Comp-1 solution with a final concentration of 0.5 mg / mL. Preparation of single-dose oral formulation: 25.3800 g of meglumine (Sigma) was weighed, dissolved in 80 mL of deionized water, stirred for 35 minutes, and then diluted to 130 mL to obtain a 1 M meglumine solution. 4.31 mg, 13.54 mg, and 40.59 mg of Comp-1 were weighed, and 28.676 mL, 27 mL, and 27 mL of 1 M meglumine solution were added to each. The mixture was stirred for 31 minutes and sonicated for 5 minutes to obtain colorless, transparent solutions with Comp-1 concentrations of 0.15 mg / mL, 0.5 mg / mL, and 1.5 mg / mL, respectively. Eighteen SD rats (half male and half female) were randomly divided into three groups (three males and three females in each group). Comp-1 was administered orally to the stomach at doses of 1.5, 5.0, and 15.0 mg / kg, and blood samples were collected before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 hours after administration. The oral solvent was 1 M deionized meglumine aqueous solution, and the administration volume was 10 mg / kg in all cases. All collected plasma samples were stored at -75±15°C until analysis. The concentration of Comp-1 in SD rat plasma was measured using liquid-phase mass spectrometry with tolbutamide as the internal standard. The mass spectrometer employed an electrospray ion source, and the mass-to-charge ratios of the parention and daughter ions of Comp-1 and Tolbutamide were monitored in positive ion mode scanning, with values ​​of 381.2→306.3 (Comp-1) and 270.9→155.0 (Tolbutamide), respectively. Pharmacokinetic parameters of Comp-1 were analyzed using Phoenix software. TMCalculations were performed using a non-compartmental model with WinNonlin version 6.1. Pharmacokinetic data were calculated using the linear logarithmic trapezoidal method, with weights of 1 / Y*Y. Samples with concentrations below the limit of quantification were not included in the calculation of pharmacokinetic parameters. The mean values ​​of each parameter were calculated using Microsoft Excel 2010, and these mean values ​​were determined by the pharmacokinetic parameters of each animal. In male Comp-1 rats, the mean excretion half-lives for three doses of Comp-1 (1.5, 5.0, and 15.0 mg / kg) were 6.72 hours, 15.0 hours, and 10.2 hours, respectively. In female rats, the mean excretion half-lives for three doses of Comp-1 (1.5, 5.0, and 15.0 mg / kg) were 12.9 hours, 5.72 hours, and 24.9 hours, respectively. 1 / 2 That's also much less than 33.6 hours.

[0172] Example 4: Oral administration of Comp-1 three times a week (tiw) and once a week (qw) has an effect on hemoglobin elevation in normal rats.

[0173] Seventy male SD rats, approximately seven weeks old, were reared in an experimental environment for 10 days before the experiment began. Throughout the experimental phase, the animals were kept in cages for normal animals (5 rats per cage) with 24-hour continuous central air conditioning, a temperature set to 24°C, and alternating light and dark periods for 12 hours. All rats were allowed to eat freely (dry granular food) and drink purified water freely. The animals were randomly divided into eight groups: the solvent (vehicle) tiw group and the vehicle qw group, each consisting of 5 rats; and the six drug groups, Comp-1 (3mpk tiw, 6mpk tiw, 10mpk tiw, 9mpk qw, 18mpk qw, and 30mpk qw), each consisting of 10 rats (mpk is mg / kg). The solvent was a 1M meglumine aqueous solution. Each rat was orally administered a solvent or an equivalent weight of Comp-1 solvent solution to its body weight and location group (tiw, qw) for a total of 4 weeks. Blood was collected from each rat on days 0, 7, 14, 21, and 28, and hemoglobin levels (HGB, i.e., Hb) were measured. After collecting blood from the rat's tail, hemoglobin levels were detected and read using a hemoglobin detector (HemoCue Hb 201+, Radiometer). Quantitative data were analyzed using single-factor analysis of variance (ANOVA) for each group, followed by statistical analysis using Dunnett's multiple comparison method. Double-tail analysis was used for statistics, with a statistical significance level of P<0.05. The hemoglobin results for each group of rats are shown in Figures 1, 2, and Table 1.

[0174] Table 1: Comparison of hemoglobin levels in rats from each group at days 0, 7, 14, 21, and 28. [Table 1]

[0175] The results from Figures 1 and 2 and Table 1 show that the hemoglobin levels of the three groups of rats administered once weekly (qw) on day 28 were statistically significantly higher than those of rats orally administered the solvent once weekly (qw), indicating that this increase in hemoglobin could be maintained. Furthermore, in the treatment of non-dialysis-dependent renal anemia (NDD CKD), the most important factor is not efficacy but cardiovascular safety; that is, it is not the case that the higher the hemoglobin increase, the better, or that the faster the increase, the better. Rather, it is safer to have a certain increase within the initial period of treatment, and for the rate of increase to be slower than for a higher increase. As can be seen from the comparison of hemoglobin levels by group with the same total weekly dose on day 28 in Table 1 (Comp-1 6 mg / kg, tiw control Comp-1 18 mg / kg, qw; Comp-1 10 mg / kg, tiw control Comp-1 30 mg / kg, qw), the qw group showed a lower absolute value increase in hemoglobin and a slower rate of increase than the tiw group.

[0176] Example 5: Oral administration of Comp-1 once daily (QD), three times a week (tiw), and once a week (qw) has an effect on increasing hemoglobin in normal mice.

[0177] This study evaluated the effects of the same weekly dose of the test compound Comp-1 at different administration frequencies on hemoglobin and normal blood indicators in male C57BL / 6J mice.

[0178] After adaptive rearing, on Day 0, standard hematological analysis was performed on submandibular vein blood samples from 92 male mice aged 6-8 weeks. Based on the Hb (hemoglobin) results on Day 0, 80 mice were selected as the mice for this study. These were then divided into the following groups: Vehicle (solvent group) (QD, 5 mice), Comp-1 (4.5 mg / kg, QD, 5 mice), Comp-1 (10.5 mg / kg, TIW, 5 mice), and Comp-1 (31.5 mg / kg). The sample sizes were: g, QW, 5 animals; Comp-1 (9 mg / kg, QD, 15 animals); Comp-1 (21 mg / kg, TIW, 15 animals); Comp-1 (63 mg / kg, QW, 15 animals); Comp-1 (15 mg / kg, QD, 5 animals); Comp-1 (35 mg / kg, TIW, 5 animals); and Comp-1 (105 mg / kg, QW, 5 animals). Standard hematological analysis was performed on submandibular vein blood samples collected on Day 14 and Day 28. Quantitative data were analyzed using single-factor analysis of variance (ANOVA) by group, followed by statistical analysis using Dunnett's multiple comparison method. Double-tail analysis was used for statistical analysis, with a statistical significance level of P < 0.05. Table 2 shows the hemoglobin results for each group of mice. On Day 14 and Day 28, the mean hemoglobin levels of all mice that took the Comp-1 group were significantly different from those of the Vehicle control group, with P<0.001.

[0179] Table 2: Comparison of hemoglobin lists for mice in each group at day 0, day 14, and day 28. [Table 2]

[0180] The results in Table 2 above show that, under similar total weekly dose conditions, mice administered once a week (qw) could significantly increase hemoglobin levels, similar to mice administered once daily or three times a week, and could maintain this increase for a long period, demonstrating statistically significant improvement compared to the control group. Furthermore, the smaller absolute increase in hemoglobin and slower rate of increase with once-weekly administration compared to mice administered once daily or three times a week contribute to improving the safety of treatment for chronic renal anemia.

[0181] Example 6: Half-life of Comp-1 in the human body after single oral administration and multiple consecutive oral administrations.

[0182] In a one-phase, randomized, double-blind, placebo-controlled clinical study involving single-dose and multi-dose administration, a total of 46 healthy volunteers were divided into six dose groups (1 mg, 4 mg, 10 mg, 20 mg, 30 mg, and 50 mg) at the single-dose stage. Two volunteers in each dose group received a matched placebo, four volunteers in the 1 mg dose group received a single dose of Comp-1, and six volunteers in the remaining dose groups received a single dose of Comp-1. Blood samples for pharmacokinetic (PK) analysis were collected from volunteers within one hour before administration and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, and 72 hours after administration. In the high-dose phase, a total of 32 healthy volunteers were assigned to one of four dose groups: 4 mg, 10 mg, 20 mg, and 30 mg. In each dose group, two volunteers received a matched placebo, and six volunteers received Comp-1 once daily for 10 consecutive days. Blood samples were collected from volunteers for PK analysis within one hour before administration and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after administration on the first day of administration (i.e., day 1), and within one hour before administration and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, and 72 hours after administration on days 6, 7, 8, and 10.

[0183] In a single-dose phase, in volunteers who received a single dose of Comp-1, each dose group showed an average response time of 3–4.5 hours (T max Median) and peak drug concentration (C max ) reached, exposure level (C max AUC 0-t and AUC 0-inf ) increases in proportion to the dose, and the mean excretion half-life (t 1 / 2 The time interval was 13.06 to 19.70 hours, with no significant dose-related correlation, and the mean clearance (C) was 13.06 to 19.70 hours. L / F There was no dose-related trend in )

[0184] In the high-dose phase, volunteers received Comp-1 on day 1, and then each dose group received the medication 2-3 hours later (T max Median) drug concentration peak (C max ) was reached, and there was no significant difference between dose levels. Comp-1 exposure after the first dose (C max AUC 0-t and AUC 0-inf The ) increased with increasing dose, and the average half-life was 10.14 to 19.43 hours, showing no tendency to change with dose. L / F There was no clear tendency for the T value to change depending on the dose. After 10 consecutive days of administration, the T value for each dose group was measured. max The median time was 3-4 hours, and the exposure amount for COMP-1 (C ss,max AUC 0-τ AUC 0-t and AUC 0-inf ) increased proportionally with dose, the mean excretion half-life was 12.41-15.75 hours, and did not show a dose-related trend, and the mean clearance (C) L / F There was no dose-related trend in these substances. All of their elimination half-lives were significantly shorter than 33.6 hours.

[0185] Example 7: Test results of Comp-1 in the second phase of clinical treatment for patients with chronic renal anemia.

[0186] In a two-phase, randomized, double-blind, placebo-controlled clinical study of Comp-1 in patients with chronic renal anemia, the study included a total of 13 weeks of treatment, divided into a 5-week fixed-dose period and a 8-week dose-adjustment period (also known as a titration period). A total of 113 patients with renal anemia were randomly entered into the fixed-dose period for the first time, and during the fixed-dose period, patients with renal anemia received either 8 mg, 12 mg, or 16 mg of Comp-1 three times a week (TIW), or a control placebo. In the 6-week study, 44 eligible patients were randomly entered into a second dose adjustment period (titration period) upon visit. Patients in the Comp-1 group received their medication once a week (QW) at a frequency of 50% based on their original TIW. The starting dose at this stage continued the dose from the fixed period and could be adjusted based on weekly hemoglobin levels, maintaining hemoglobin within the critical range of 10.0–11.0 g / dL. To maintain double-blindness, patients in the placebo group underwent sham randomization and maintained placebo-matched dosage. In this study, patients underwent weekly studies to detect hemoglobin levels, the primary efficacy indicator, and safety comparisons were performed for patients entering the titration period using different dosage frequencies (three times a week (TIW) and once a week (QW)).

[0187] The primary efficacy objective of this study was to determine the mean hemoglobin increase rate (g / dL / week) in the three Comp-1 dose groups at the end of the fixed period (i.e., 5 weeks after administration) compared to the placebo group. The results showed that the mean hemoglobin increase rate in each Comp-1 dose group increased in dose correlation, with the 8 mg group at 0.2839 g / dL / week, the 12 mg group at 0.3893 g / dL / week, and the 16 mg main group at 0.4817 g / dL / week. All of these were higher than the placebo group's -0.0382 g / dL / week and were statistically significant (p-value <0.0001 in all cases). In the analysis of hemoglobin during the adjustment period (titration period), at week 14 (i.e., at the end of the titration period or 13 weeks after administration), the mean hemoglobin levels aggregated by Comp-1 for the TIW and QW groups were 10.74 g / dL and 10.09 g / dL, respectively. Both included the cutoff value within the study target range of 10.0-11.0 g / dL, while the mean hemoglobin level of the placebo group remained at 9.57 g / dL. During the later stages of the adjustment period (titration period), weeks 10–14, the mean hemoglobin level was >10.0 g / dL in all dose-frequency groups, including the placebo group. In the TIW and QW groups aggregated by Comp-1, the levels were 10.73 g / dL and 10.77 g / dL, respectively, while the placebo group had a level of 10.26 g / dL. The change from baseline in hemoglobin levels was 1.60 g / dL and 1.63 g / dL in the TIW and QW groups aggregated by Comp-1, respectively, while the placebo group had a change of 0.48 g / dL. This indicates that patients in the placebo group who underwent a second random selection were able to maintain their hemoglobin levels within the study target range even if they increased (or fluctuated) slightly with uncorrelated treatment during the adjustment period, and that the increase and maintenance of hemoglobin levels corresponded to this in the TIW and QW groups aggregated by Comp-1.In hemoglobin analysis during the entire adjustment period (titration period) from weeks 6 to 14, the mean hemoglobin levels aggregated by Comp-1 for the TIW and QW groups were 10.84 g / dL and 10.91 g / dL, respectively, while the placebo group was 10.23 g / dL. The change from baseline in hemoglobin was 1.71 g / dL and 1.78 g / dL for the TIW and QW groups, respectively, while the placebo group was 0.45 g / dL, again indicating an increase and maintenance of hemoglobin level capacity in the TIW and QW groups. Throughout the entire 13-week treatment course, the cumulative percentage of patients whose hemoglobin level included the cutoff value within the target range of 10.0–11.0 g / dL and increased by ≥1.0 g / dL above baseline was similar in the TIW and QW groups aggregated in Comp-1, at 100% and 90%, respectively, compared to 40% in the placebo group. Table 3 below compares safety based on the frequency of administration to patients between dose periods.

[0188] Table 3: Comparison of safety levels based on administration frequency during titration period [Table 3]

[0189] TEAE (treatment emergent adverse event) refers to all adverse reactions that occur after the start of treatment, while treatment-related TEAT (treatment-related TEAE) refers to all treatment-related adverse reactions that occur after the start of treatment. N represents the number of patients, NE represents the total number of adverse reactions that occurred, and n represents the number of patients in whom the adverse reaction occurred.

[0190] As can be seen from Table 3, after entering the infusion period, the frequency of QW (once a week) administration was lower than that of TIW (three times a week) administration, regardless of whether a TEAE occurred or was treatment-related. In particular, the total number of adverse reactions (NE) was lower with QW (once a week) administration. Considering that currently available HIF-PHI inhibitors used to treat CKD anemia are administered once a day or three times a week, the results in Table 3 show that patients with lower administration frequencies experience fewer adverse reactions, which is a surprising finding.

[0191] According to Example 6, although the excretion half-life of Comp-1 is much shorter than 33.6 hours (one-fifth of a week), therapeutic effects can be achieved even with oral administration once a week during the dose adjustment period (titration period) for treating patients with chronic renal anemia. That is, the patient's hemoglobin remains within the desired range, and the adverse reactions with once-weekly administration are fewer than those with three-times-weekly administration. Therefore, this is an innovative dosage plan and frequency for obtaining unexpected therapeutic effects.

[0192] Although embodiments of the present invention have been described above, these embodiments do not describe all possible forms of the invention. More precisely, the terms used herein are merely descriptive, and it should be understood that various modifications are possible without departing from the spirit and scope of this application.

Claims

1. A long-acting oral pharmaceutical preparation, Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI) or pharmaceutically acceptable salts thereof, A compound comprising one or more pharmaceutically acceptable carriers, adjuvants, or excipients, The aforementioned long-acting oral pharmaceutical preparation is a long-acting oral pharmaceutical preparation suitable for administration at intervals of one week or more.

2. A pharmaceutical product comprising a packaging container, a drug information sheet, and a pharmaceutical preparation contained in the packaging container, The pharmaceutical preparation comprises a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, adjuvants, or excipients. A pharmaceutical product wherein the drug information sheet includes a statement indicating that the pharmaceutical preparation is suitable for oral administration at intervals of one week or more.

3. The use of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI) or pharmaceutically acceptable salts thereof in the manufacture of long-acting oral medications for the treatment of chronic anemia, The aforementioned long-acting oral medication is suitable for administration at intervals of one week or more.

4. A method for treating chronic anemia, A method comprising orally administering a therapeutically effective dose of a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof to a patient in need of treatment, at intervals of at least one week.

5. The t of the HIF-PHI or a pharmaceutically acceptable salt thereof １／２ The long-acting oral pharmaceutical formulation according to claim 1, the pharmaceutical product according to claim 2, the use according to claim 3, or the method according to claim 4, wherein the duration is less than 33.6 hours, less than 24 hours, less than 16 hours, or less than 10 hours.

6. The chronic anemia is selected from idiopathic aplastic anemia, chronic renal anemia, anemia induced by chemotherapy for tumors, anemia due to blood loss, anemia due to menorrhagia in women, iron deficiency anemia, vitamin deficiency anemia, cytoplasmic and aplastic anemia, hemolytic anemia, iron utilization disorder anemia, and anemia due to hypothyroidism, and is preferably chronic renal anemia, according to the long-acting oral pharmaceutical formulation according to claim 1, the pharmaceutical product according to claim 2, the use according to claim 3, or the method according to claim 4.

7. The HIF-PHI is selected from roxadustat, daprodustat, vadadustat, molidustat, enarodustat, desidustat, HIF117 (SSS17), HEC53856, and DDO-3055, as described in claim 1, the pharmaceutical product as described in claim 2, the use as described in claim 3, or the method as described in claim 4.

8. The long-acting oral pharmaceutical formulation according to claim 1, the pharmaceutical product according to claim 2, the use according to claim 3, or the method according to claim 4, wherein the HIF-PHI is Comp-1.

9. A long-acting oral pharmaceutical formulation according to claim 1, a pharmaceutical product according to claim 2, a use according to claim 3, or a method according to claim 4, The HIF-PHI is a compound of the following formula I, comprising a long-acting oral pharmaceutical formulation, pharmaceutical product, use, or method. 【Chemistry 1】 (In the formula, R １ and R ２ are each independently selected from a cyano group, an alkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group and an acyl group, and the above alkyl group, heterocyclic group, alkenyl group, alkynyl group, aryl group, heteroaryl group and acyl group are optionally substituted with one or more substituents, wherein the substituents are halogen, cyano group, hydroxy group, amino group, carboxyl group, acyl group, alkyl group, heterocyclic group, alkenyl group, alkynyl group, aryl group, heteroaryl group, =O, =S, -SH, R １０ O-, R １０ S-, R １０ (O=)S-, R １０ (O=) ２ S-, and R １０ is an alkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an aryl group or a heteroaryl group, or R １ and R ２ together form a ring, R ３ This is selected from alkyl groups, heterocyclic groups, alkenyl groups, alkynyl groups, aryl groups, and heteroaryl groups. R ４ and R ５ It is hydrogen, R ６ and R ６’ It is hydrogen, R ７ It is hydrogen, R ８ It is selected from hydrogen and alkyl groups, X is oxygen.

10. In the compound of formula I, R １ and R ２ These, together with the C atoms bonded to them, form a cyclopentane ring, i.e., R １ and R ２ ha-CH ２ CH ２ CH ２ CH ２ - and R ３ R is a phenyl group, ４ and R ５ is hydrogen, R ６ and R ６’ is hydrogen, R ７ is hydrogen, R ８ The long-acting oral pharmaceutical formulation, pharmaceutical product, use, or method according to claim 9, wherein is hydrogen and X is an oxygen atom, that is, the compound of formula I is (6'-hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indolidine]-7'-carbonyl)glycine.

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