Long-acting oral medicine containing hypoxia-inducible factor-proline hydroxylase inhibitor and application of long-acting oral medicine

Abstract

The invention relates to a long-acting oral medicine containing a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) and application of the long-acting oral medicine. Specifically, the present application discloses a long-acting oral pharmaceutical preparation containing a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, adjuvants or excipients, the long-acting oral pharmaceutical preparation being suitable for administration at an administration interval of one week or more, therefore, the composition is suitable for long-term administration in treatment of chronic anemia.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the priority of Chinese invention patent application 202311391445.2, filed on October 24, 2023, entitled “Long-acting oral drugs containing hypoxia-inducible factor-proamide hydroxylase inhibitors and their applications”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present application belongs to the field of medicine, and in particular, the present application relates to the treatment of diseases related to proline hydroxylase (such as anemia, etc.). Background Art

[0004] 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 in the body's blood. Because the main function of hemoglobin is to carry oxygen to various organs for use, low levels of hemoglobin directly lead to insufficient oxygen supply to various organs of the body. Since the normal physiological activities of the body rely on the full utilization of oxygen, different degrees of anemia will cause various clinical symptoms. Common secondary symptoms of anemia include cardiovascular system diseases (heart failure, atrial fibrillation, angina pectoris, etc.), urinary system diseases (renal failure, proteinuria), nervous system diseases (dizziness, headache, tinnitus, blurred vision, lack of energy, fatigue and drowsiness, irritability, and difficulty concentrating. Severe anemia may cause fainting), digestive system diseases (loss of appetite, constipation), reproductive system diseases (loss of libido, irregular menstruation), etc. Anemia can not only seriously affect the patient's physical health and quality of life, but also threaten the patient's life safety if anemia is not corrected in time.

[0005] There are many causes of anemia, usually due to reduced production of erythropoietin (EPO). Chronic Kidney Disease (CKD) leads to reduced synthesis of erythropoietin, so most CKD patients suffer from anemia, namely chronic renal anemia (CKD anemia). There are two main types of drug treatments for chronic renal anemia. The first type is based on EPO or erythropoiesis stimulating agents (ESA) with similar functions, all of which require injection. In recent years, another type of oral drug for the treatment of chronic renal anemia, hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), has gradually been approved by some regulatory agencies. HIF-PHI is a new type of small molecule oral drug for the treatment of renal anemia. It stabilizes the level of HIF in the body by inhibiting hypoxia-inducible factor prolyl hydroxylase, regulates multiple downstream target genes, and thus promotes the production of EPO, which has a similar effect on the treatment of renal anemia as ESA. Some HIF-PHIs are disclosed in documents such as WO2004108681, WO2007070359, WO2007150011, WO2008076425, WO2011007856, WO201206472, WO2013043621, WO2014102818, and WO2018205928.

[0006] Whether it is the injectable ESA mentioned above or the oral HIF-PHI drugs, they basically go through two stages in the treatment of renal anemia. The first stage is the dose fixing period (fixing period), which generally does not exceed two months. The purpose is to increase or adjust the hemoglobin of anemic patients to the range specified by various regulatory agencies; the second stage is the dose adjustment stage (titration period), which is the routine, long-term treatment to maintain the patient's hemoglobin to the range specified by various regulatory agencies. This stage is a long-term stage and patients need to take medication for a long time.

[0007] Studies have shown that for chronic diseases that require long-term treatment (such as diabetes and chronic renal anemia), the treatment effect is highly correlated with the patient's adherence to the drug, which in turn is closely related to the frequency or interval of administration. For example, for drugs that require injections such as subcutaneous injection or intramuscular injection, such as insulin (Diabetes Spectr 2016, 29(3), 166–170) and GLP-1 agonists (Int J Clin Pract. 2021, 75: e14060), it has been proven that the longer the interval, the better the patient's adherence to the drug and the better the long-term efficacy. In the field of chronic kidney disease anemia, research on existing injectable ESA drugs (Cureus 2020, 12(9): e10358) also shows that patients have better adherence to so-called long-acting ESAs with long dosing cycles (long intervals between two consecutive doses) and better long-term efficacy.

[0008] For injectable drugs, there are many ways to extend the time interval between two consecutive dosings in the prior art. However, for oral drugs, extending the time interval between two consecutive dosings is a huge challenge. In the prior art, it is rare to have a dosing interval (cycle) as long as once a week or longer, because the excretion half-life (Elimination half-life, t 1 / 2 ) is often shorter. For the HIF-PHI mentioned above for the treatment of chronic renal anemia, oral drugs that have been approved for marketing or are still in the clinical trial stage are often administered once a day, such as Daprodustat (t 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), Enarodustat (t 1 / 2 :8.2–8.7h; see Drugs2021,81,169-174), Molidustat(t 1 / 2 :4–10h; see AdvChronic Kidney Dis. 2019, 26(4), 253-266); or three times a week, such as roxadustat (t 1 / 2 :12–15h; see Adv Chronic Kidney Dis. 2019, 26(4), 253-266), Desidustat, 1 / 2:6–15h, Drugs 2022, 82(11), 1207–1212).

[0009] The dosing schedules of these existing HIF-PHI oral drugs are all much shorter than one week (seven days) without exception. For a disease such as chronic renal anemia that requires long-term medication, a once-a-week oral dosing schedule will make patients more sticky to the drug than a once-a-day or three-times-a-week oral dosing schedule, making it easier to manage the disease; on the other hand, most patients with chronic renal anemia have complications such as hypertension, diabetes, hyperphosphatemia, hyperkalemia, hypercholesterolemia, hyperlipidemia, etc. They need to take multiple other drugs at the same time every day. A once-a-week dosing schedule also makes it easier to avoid the interaction between drugs for treating anemia and drugs for treating hypertension, diabetes, hyperphosphatemia, hyperkalemia, hypercholesterolemia or hyperlipidemia that the patient is taking, such as staggering the time of taking HIF-PHI and other drugs (if it is taken once a day or three times a week, it will greatly increase the difficulty of staggering the patients' medication).

[0010] Therefore, there is a great need for a long-acting oral drug that can be used to treat chronic anemia (such as chronic renal anemia, etc.). Summary of the invention

[0011] The existing technology lacks long-acting oral drugs for chronic renal anemia. This is because traditional pharmacological theory believes that after a patient takes a drug for 5 t 1 / 2 After that, it is generally believed that the drug has been almost completely excreted from the patient's blood. Therefore, the time interval between two consecutive doses of a drug for treating chronic diseases (dosing cycle) usually cannot exceed five excretion half-lives. In actual operation, in order to ensure the efficacy, it is rare for the dosing interval (dosing cycle) to exceed 3 excretion half-lives. According to pharmacological theory, if you want the dosing interval of oral drugs to be no less than once a week, that is, the dosing cycle is not less than one week, then the excretion half-life of the drug cannot be shorter than 24h x 7 / 5, that is, t 1 / 2 It cannot be less than 33.6 hours. For example, Trelagliptin, an oral DPP-4 inhibitor for the treatment of diabetes mellitus approved in Japan, has a drug excretion half-life of t 1 / 2 It is 38.44–54.26h (J Diabetes Investig 2018, 9, 354-359).

[0012] However, unexpectedly, the inventors of the present application have proved through animal experiments and human clinical trials that for hypoxia-inducible factor-proline hydroxylase inhibitors (HIF-PHI) drugs, even if the excretion half-life of the drug is t 1 / 2Far shorter than 33.6 hours, it is still possible to maintain hemoglobin in the expected range by taking oral medication once a week or longer during the titration period of chronic anemia. This unexpected discovery allows the use of a new drug delivery method to improve the adherence of chronic renal anemia patients to drug therapy, improve treatment outcomes, and thus make it easier to manage chronic diseases in the long term.

[0013] Therefore, the first aspect of the present application provides a long-acting oral pharmaceutical preparation, which contains a hypoxia-inducible factor-proline 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 preparation is suitable for administration at a dosing interval of once a week or longer. In particular, the present application surprisingly found that a dosing frequency of once a week during the titration period can reduce the patient's side effects compared to a dosing frequency of three times a week.

[0014] The second aspect of the present application provides a pharmaceutical product, comprising a packaging container, a drug instruction sheet, and a pharmaceutical preparation contained in the packaging container, wherein the pharmaceutical preparation contains 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 instruction sheet contains instructions indicating that the pharmaceutical preparation is suitable for oral administration at a dosing interval of once a week or longer.

[0015] The third aspect of the present application provides the use of a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof in the preparation of a long-acting oral drug for treating chronic anemia, wherein the long-acting oral drug is suitable for administration at an interval of once a week or longer.

[0016] The fourth aspect of the present application provides a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof for oral treatment of chronic anemia, wherein the oral treatment is carried out at a dosing interval of once a week or longer.

[0017] The fifth aspect of the present application provides the use of a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof for treating chronic anemia, wherein the HIF-PHI or a pharmaceutically acceptable salt thereof is orally administered at a dosing interval of once a week or longer.

[0018] The sixth aspect of the present application provides a method for treating chronic anemia, comprising: orally administering a therapeutically effective amount of a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof to a patient in need of treatment at a dosing interval of once a week or longer. DETAILED DESCRIPTION

[0019] 1. Hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) or its pharmaceutically acceptable salt

[0020] In various aspects of the present application and various embodiments of various aspects, the hypoxia-inducible factor-proline hydroxylase inhibitor can be various hypoxia-inducible factor-proline hydroxylase inhibitor compounds known in the art, or in the form of their pharmaceutically acceptable salts. In some embodiments, the HIF-PHI or its pharmaceutically acceptable salt is t 1 / 2 Those of less than 33.6 hours, less than 24 hours, less than 16 hours, or less than 10 hours.

[0021] In some preferred embodiments of the present application, the hypoxia-inducible factor-proline hydroxylase inhibitor can be a HIF-PHI compound or a pharmaceutically acceptable salt thereof that has been approved for clinical use or is undergoing 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-proline hydroxylase inhibitor (HIF-PHI) is roxadustat or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

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

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

[0033] In the present application, unless otherwise specified, when any compound or its pharmaceutically acceptable salt is mentioned or referred to by structural formula, name or code, for example, "compound of Formula I" (synonymous with "compound represented by general formula I"), "rosuvastatin", or "(6'-hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indolizine]-7'-carbonyl)glycine", etc., various forms of these compounds are included, such as their tautomers, optical isomers, geometric isomers, or isomer mixtures (such as racemic mixtures), isotope-modified compounds thereof, and solvates or hydrates of these compounds, as well as their various solid forms (such as various crystalline forms or amorphous forms).

[0034] The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center may exist in the R configuration or the S configuration, and the various isomers thus constituted are optical isomers. Optical isomers include all diastereomers, enantiomers, mesomers, racemates or mixtures thereof. For example, optical isomers can be separated by chiral chromatography or by chiral synthesis.

[0035] The term "geometric isomer" means that when a double bond exists in a compound, the compound may exist as cis isomers, trans isomers, E isomers and Z isomers. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers or a mixture thereof.

[0036] The term "tautomer" refers to an isomer that is produced by the rapid movement of an atom in a molecule between two positions. Those skilled in the art will appreciate that tautomers can be mutually converted and may reach an equilibrium state and coexist under a certain state. For example, the "compound of formula I" described herein also encompasses any tautomer of the compound of formula I. Specifically, the inventors have discovered that the compound of formula I may exist in the following tautomers Ia, Ib, Ic, or Id:

[0037]

[0038] An "isotopically modified compound" refers to a compound in which any atom in the compound is replaced by an isotope atom thereof. The "isotopically modified compound" in the present application includes all pharmaceutically acceptable isotopically modified compounds of a compound, in which one or more atoms are replaced by atoms having the same atomic number as the atoms usually found in nature but a different atomic mass or mass number.

[0039] Examples of isotopes suitable for inclusion in the compounds of the present application include isotopes of hydrogen such as 2 H(D) and 3 H(T), isotopes of carbon, such as 11 C. 13 C and 14 C, isotopes of chlorine, such as 36 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O. 17 O and 18 O, and isotopes of sulfur such as 35 S.

[0040] Certain isotopically modified compounds (e.g., those containing radioactive isotopes) are useful in drug and / or substrate tissue distribution studies. Deuterium (i.e., the isotope) is preferred because of its ease of incorporation and convenient means of detection. 2 H), tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) is particularly useful for this purpose.

[0041] Using deuterium (i.e. 2 H) or tritium (i.e. 3Substitution with heavier isotopes of H) may afford certain therapeutic advantages resulting from greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.

[0042] Using positron emitting isotopes such as 11 C. 18 F. 15 O and 13 N) substitution can be used in positron emission topography (PET) research to detect the substrate receptor occupancy state.

[0043] Isotopically modified compounds can generally be prepared by conventional techniques known to those skilled in the art or by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used in an analogous manner to those described in the Examples and Preparations appended herein.

[0044] Certain compounds of the present application can exist in unsolvated forms as well as solvated forms, including hydrated forms.

[0045] Certain compounds of the present application may exist in different crystalline or amorphous forms, and any form thereof is included within the scope of the present application.

[0046] In the present application, "pharmaceutically acceptable salt" refers to the inorganic or organic acid addition salt or organic or inorganic base addition salt of the compound suitable for use in mammals (i.e., having safety and effectiveness when used). These salts can be prepared in situ during the final separation and purification of the compound, or by reacting the pure compound in free form with a suitable organic or inorganic acid or base, and separating the formed salt to prepare. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, glucoheptonate, lactobionate, lauryl sulfonate, etc. These salts can include salts based on alkali and alkaline earth metals (e.g., sodium, lithium, potassium, calcium, magnesium, etc.) cations, as well as non-toxic ammonium, quaternary ammonium, and amine cations (including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like).

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

[0048]

[0049] In some embodiments, in the compound represented by formula I:

[0050] R 1 and R 2 independently selected from cyano, alkyl, heterocyclic, alkenyl, alkynyl, aryl, heteroaryl and acyl; wherein the above alkyl, heterocyclic, alkenyl, alkynyl, aryl, heteroaryl, acyl are optionally substituted by one or more substituents, wherein the substituents are independently selected from halogen, cyano, hydroxyl, amino, carboxyl, acyl, alkyl, heterocyclic, alkenyl, alkynyl, aryl, heteroaryl, =O, =S, -SH, R 10 O-、R 10 S-, R 10 (O=)S- and R 10 (O=)2S-, where R 10 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; or R 1 and R 2 Put together to form a ring;

[0051] R 3 is selected from the group consisting of alkyl, heterocyclyl, alkenyl, alkynyl, aryl and heteroaryl;

[0052] R 4 and R 5 is hydrogen;

[0053] R 6 and R 6’ is hydrogen;

[0054] R 7 is hydrogen;

[0055] R 8 is selected from hydrogen and alkyl;

[0056] X is an oxygen atom.

[0057] In some embodiments, in the compound represented by formula I:

[0058] R 1 and R 2independently selected from cyano, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl containing 3 to 8 ring atoms, heterocycloalkenyl containing 3 to 8 ring atoms, heteroaryl containing 5 to 14 ring atoms, C1-C12 alkyl-C(=O)- and C2-C12 alkenyl-C(=O)-; wherein the above-mentioned C1-C12 alkyl, C2-C12 alkenyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl containing 3 to 8 ring atoms, heterocycloalkenyl containing 3 to 8 ring atoms, heteroaryl containing 5 to 14 ring atoms, C1-C12 alkyl-C(=O)- and C2-C12 alkenyl-C(=O)- C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl containing 3 to 8 ring atoms, heterocycloalkenyl containing 3 to 8 ring atoms, heteroaryl containing 5 to 14 ring atoms, C1-C12 alkyl-C(=O)-, C2-C12 alkenyl-C(=O)- are optionally substituted with 1 to 3 substituents, wherein the substituents are independently selected from hydroxy, halogen, cyano, amino, carboxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl-, C2-C6 alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl containing 5 to 14 ring atoms, C1-C6 alkyl-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyl-O-, C2-C6 alkynyl-O-, C3-C8 cycloalkenyl-O-, C6-C14 aryl-O-, heteroaryl containing 5 to 14 ring atoms, C1-C6 alkyl-S-, C3-C8 cycloalkyl -S-, C2-C6 alkenyl-S-, C2-C6 alkynyl-S-, C3-C8 cycloalkenyl-S-, C6-C14 aryl-S-, heteroaryl-S- containing 5 to 14 ring atoms, heterocycloalkyl containing 3 to 8 ring atoms, heterocycloalkenyl containing 3 to 8 ring atoms, =O, =S, -SH, -CF3, -CO2, C1-C6 alkyl, C1-C6 alkyl-S-, C1-C6 alkyl(O=)S- and C1-C6 alkyl(O=)2S-; or

[0059] R 1 and R 2 Taken together, they form an optionally substituted cycloalkane ring, cycloalkene ring, heterocycloalkane ring, or heterocycloalkene ring containing 3 to 8 ring atoms;

[0060] R 3is selected from the group consisting of C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl containing 3 to 8 ring atoms, heterocycloalkenyl containing 3 to 8 ring atoms and heteroaryl containing 5 to 14 ring atoms; wherein the above-mentioned C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl containing 3 to 8 ring atoms, heterocycloalkenyl containing 3 to 8 ring atoms and heteroaryl containing 5 to 14 ring atoms The cycloalkyl group is a C-C8 cycloalkyl, a C3-C8 cycloalkenyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a C3-C8 cyclo ... C6-C14 aryl, heteroaryl containing 5 to 14 ring atoms, C1-C6 alkyl-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyl-O-, C2-C6 alkynyl-O-, C3-C8 cycloalkenyl-O-, C6-C14 aryl-O-, heteroaryl containing 5 to 14 ring atoms, C1-C6 alkyl-S-, C3-C8 cycloalkyl-S-, C2-C6 alkenyl-S-, C 2-C6 alkynyl-S-, C3-C8 cycloalkenyl-S-, C6-C14 aryl-S-, heteroaryl-S- containing 5 to 14 ring atoms, heterocycloalkyl containing 3 to 8 ring atoms, heterocycloalkenyl containing 3 to 8 ring atoms, =O, =S, -SH, -CF3, -CO2, C1-C6 alkyl, C1-C6 alkyl-S-, C1-C6 alkyl(O=)S- and C1-C6 alkyl(O=)2S-;

[0061] R 4 and R 5 is hydrogen;

[0062] R 6 and R 6’ is hydrogen;

[0063] R 7 is hydrogen;

[0064] R 8is selected from hydrogen, C1-C12 alkyl and C3-C8 cycloalkyl; wherein C1-C12 alkyl and C3-C8 cycloalkyl are optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxy, halogen, cyano, amino, carboxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl-, C2-C6 alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl containing 5 to 14 ring atoms, C1-C6 alkyl-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyl-O-, C2-C6 alkynyl-O-, C3-C8 cycloalkenyl-O-, C6-C14 aryl-O- and heteroaryl containing 5 to 14 ring atoms;

[0065] X is an oxygen atom.

[0066] In some preferred embodiments of the present application, in the compound represented by general formula I, R 1 and R 2 are independently selected from cyano and unsubstituted C1-C6 alkyl; or R 1 and R 2 Taken together they form an optionally substituted cycloalkane or heterocycloalkane ring containing 3 to 8 ring atoms.

[0067] In some preferred embodiments of the present application, in the compound represented by general formula I, R 1 and R 2 are independently selected from methyl and ethyl; or R 1 and R 2 They are combined to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a methylcyclohexane ring, a cycloheptane ring, a tetrahydrofuran ring or a tetrahydropyran ring.

[0068] In some preferred embodiments of the present application, in the compound represented by general formula I, R 1 and R 2 Independently selected from cyano and unsubstituted C1-C6 alkyl.

[0069] In some preferred embodiments of the present application, in the compound represented by general formula I, R 1 and R 2 Independently selected from methyl and ethyl.

[0070] In some preferred embodiments of the present application, in the compound represented by general formula I, R 1 and R 2 Taken together they form an optionally substituted heterocycloalkane ring containing 3 to 8 ring atoms.

[0071] In some preferred embodiments of the present application, in the compound represented by general formula I, R 1and R 2 Together they form a tetrahydrofuran ring or a tetrahydropyran ring.

[0072] In some preferred embodiments of the present application, in the compound represented by general formula I, R 1 and R 2 Taken together they form an optionally substituted cycloalkane ring containing 3 to 8 ring atoms.

[0073] In some preferred embodiments of the present application, in the compound represented by general formula I, R 1 and R 2 Together they form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a methylcyclohexane ring or a cycloheptane ring.

[0074] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 Selected from C1-C6 alkyl, C6-C14 aryl, C3-C8 cycloalkyl and heteroaryl containing 5 to 14 ring atoms; wherein the above-mentioned C1-C6 alkyl, C6-C14 aryl, C3-C8 cycloalkyl are optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxyl, halogen, cyano, amino, carboxyl, C6-C14 aryl and C1-C6 alkyl.

[0075] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 Selected from methyl, ethyl, propyl, butyl, phenyl, benzyl, tolyl, methoxyphenyl, chlorophenyl, fluorophenyl, bromophenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and pyridyl.

[0076] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 Selected from C1-C6 alkyl; wherein the above C1-C6 alkyl is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxyl, halogen, cyano, amino, carboxyl, C6-C14 aryl and C1-C6 alkyl.

[0077] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 Selected from methyl, ethyl, propyl and butyl.

[0078] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 Selected from C6-C14 aryl; wherein the above C6-C14 aryl is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxyl, halogen, cyano, amino, carboxyl, C6-C14 aryl and C1-C6 alkyl.

[0079] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 It is selected from phenyl, benzyl, tolyl, methoxyphenyl, chlorophenyl, fluorophenyl and bromophenyl, preferably selected from phenyl.

[0080] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 Selected from C3-C8 cycloalkyl; wherein the above C3-C8 cycloalkyl is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxyl, halogen, cyano, amino, carboxyl, C6-C14 aryl and C1-C6 chain alkyl.

[0081] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 Selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0082] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 is selected from heteroaryl groups containing 5 to 14 ring atoms.

[0083] In some preferred embodiments of the present application, in the compound represented by general formula I, R 3 Selected from pyridyl.

[0084] In some preferred embodiments of the present application, in the compound represented by general formula I, R 8 is selected from hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxy, halogen, cyano, amino, carboxyl, C1-C6 alkyl and C1-C6 alkyl-O-.

[0085] In some preferred embodiments of the present application, in the compound represented by general formula I, R 8 Selected from hydrogen, methyl, ethyl, propyl, butyl and pentyl.

[0086] In some preferred embodiments of the present application, in the compound represented by general formula I, R 8 Selected from hydrogen.

[0087] In some preferred embodiments of the present application, in the compound represented by general formula I, R 8 Selected from C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxy, halogen, cyano, amino, carboxyl, C1-C6 alkyl and C1-C6 alkyl-O-.

[0088] In some preferred embodiments of the present application, in the compound represented by general formula I, R 8 Selected from methyl, ethyl, propyl, butyl and pentyl.

[0089] In some preferred embodiments of the present application, in the compound represented by general formula I, R 1 and R 2 taken together to form an optionally substituted cycloalkane ring containing 3 to 8 ring atoms; R 3 is selected from C6-C14 aryl; wherein the above C6-C14 aryl is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxyl, halogen, cyano, amino, carboxyl, C6-C14 aryl and C1-C6 alkyl; and R 8 is selected from hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxy, halogen, cyano, amino, carboxyl, C1-C6 alkyl and C1-C6 alkyl-O-.

[0090] In some preferred embodiments of the present application, in the compound represented by general formula I, R 1 and R 2 Each is independently selected from C1-C6 alkyl, wherein the above C1-C6 alkyl is optionally substituted by 1 to 3 C1-C6 alkyl substituents; or R 1 and R 2 Taken together, they form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a methylcyclohexane ring, a cycloheptane ring or a tetrahydropyran ring; R 3 is selected from C6-C14 aryl; wherein the above C6-C14 aryl is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxyl, halogen, cyano, amino, carboxyl, C6-C14 aryl and C1-C6 alkyl; and R 8 is selected from hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxy, halogen, cyano, amino, carboxyl, C1-C6 alkyl and C1-C6 alkyl-O-.

[0091] In some preferred embodiments of the present application, in the compound represented by general formula I, R 1 and R 2 Taken together, they form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a methylcyclohexane ring or a cycloheptane ring; R 3is selected from C6-C14 aryl; wherein the above C6-C14 aryl is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxyl, halogen, cyano, amino, carboxyl, C6-C14 aryl and C1-C6 alkyl; and R 8 Selected from hydrogen.

[0092] In some particularly preferred embodiments of the present application, the compound represented by general formula I is a compound (6'-hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indolizine]-7'-carbonyl)glycine, wherein R 1 and R 2 Together with the C atoms to which they are attached, they form a cyclopentane ring (i.e., R 1 and R 2 is -CH2CH2CH2CH2-), R 3 is phenyl, R 4 and R 5 Hydrogen, R 6 and R 6’ is hydrogen, R 7 is hydrogen, R 8 is a compound of formula I wherein R is hydrogen and X is an oxygen atom.

[0093] In the above different preferred embodiments, the preferred options of each substituent can be combined with each other, and various combinations thereof are within the scope of the present application.

[0094] To avoid ambiguity, the following definitions are given for various terms used in this article. Unless otherwise specified, the meanings of the terms used in this article are as follows.

[0095] The term "hydroxy" refers to -OH.

[0096] The term "halogen" or "halo" refers to -F, -Cl, -Br, or -I.

[0097] The term "amino" refers to -NH2.

[0098] The term "cyano" refers to -CN.

[0099] The term "carboxy" refers to -C(=O)OH.

[0100] The term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in the group are independently replaced by a corresponding number of substituents.

[0101] The term "independently" means that when there are more than one substituent, these substituents may be the same or different.

[0102] The term "optional" or "optionally" means that the event it describes can occur or not occur. For example, a group "optionally substituted" means that the group can be unsubstituted or substituted.

[0103] The term "heteroatom" as used herein refers to oxygen (O), nitrogen (N), or S (O) m (wherein m can be 0, 1 or 2, i.e. a sulfur atom S, or a sulfoxide group SO, or a sulfonyl group S(O)2).

[0104] The term "alkyl" refers to a group formed when a saturated hydrocarbon composed of only two elements, C and H, loses a hydrogen atom from any carbon atom. The "alkyl" described herein includes chain alkyl groups such as straight chain alkyl groups and branched chain alkyl groups; it also includes cycloalkyl groups such as monocyclic alkyl groups, spirocyclic alkyl groups, condensed cycloalkyl groups and bridged cycloalkyl groups. Preferably, the "alkyl" in this application refers to chain alkyl groups. Alkyl groups may be unsubstituted or substituted.

[0105] The "alkyl" described herein includes optionally substituted chain alkyl groups, which preferably have 1 to 20 carbon atoms, more preferably 1 to 12 carbon atoms, and most preferably 1 to 6 carbon atoms; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, chloromethyl, fluoroethyl, trifluoromethyl or 1,1,1-trifluoroethyl, etc.

[0106] The "alkyl" described herein also includes optionally substituted cycloalkyl (e.g., C3-C20 cycloalkyl or C3-C12 cycloalkyl or C3-C8 cycloalkyl), for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalinyl, norpinyl, adamantyl, fluorocyclopropyl, 2-iodocyclobutyl, 2,3-dimethylcyclopentyl, 2,2-dimethoxycyclohexyl and 3-phenylcyclopentyl, etc.

[0107] "C1-C6 chain alkyl" is also called "lower chain alkyl", which refers to a subset of alkyl, which refers to straight chain alkyl and branched chain alkyl having 1 to 6 carbon atoms, including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0108] The "alkyl" described herein is optionally substituted by one or more substituents, wherein the substituents are independently selected from halogen, cyano, nitro (-NO2), hydroxyl, amino, carboxyl, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, =O, =S, -SH, R 16 O-、R 16 S-, R 16 (O=)S- and R 16 (O=)2S-, where R 16is an alkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an aryl group, or a heteroaryl group.

[0109] Preferably, the "alkyl" described herein is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxy, halogen, nitro, cyano, amino, carboxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl-, C2-C6 alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl containing 5 to 14 ring atoms, C1-C6 alkyl-O-, C3-C8 cycloalkyl-O-, C2-C6 alkenyl-O-, C2-C6 alkynyl-O-, C3-C8 cycloalkenyl-O-, C6-C14 aryl- O-, heteroaryl-O- containing 5 to 14 ring atoms, C1-C6 alkyl-S-, C3-C8 cycloalkyl-S-, C2-C6 alkenyl-S-, C2-C6 alkynyl-S-, C3-C8 cycloalkenyl-S-, C6-C14 aryl-S-, heteroaryl-S- containing 5 to 14 ring atoms, heterocycloalkyl containing 3 to 8 ring atoms, heterocycloalkenyl containing 3 to 8 ring atoms, =O, =S, -SH, -CF3, -CO2, C1-C6 alkyl, C1-C6 alkyl-S-, C1-C6 alkyl(O=)S- and C1-C6 alkyl(O=)2S-

[0110] The term "alkenyl" refers to any hydrocarbon compound consisting of only two elements, C and H, and containing one or more carbon-carbon double bonds but no carbon-carbon triple bonds or aromatic bonds, formed after any carbon atom loses a hydrogen atom. The "alkenyl" described herein includes alkenyls such as straight-chain alkenyls and branched-chain alkenyls; and also includes cycloalkenyls such as monocyclic alkenyls, spirocyclic alkenyls, fused-cyclic alkenyls and bridged-cyclic alkenyls. Alkenyls may be unsubstituted or substituted.

[0111] The “alkenyl” described herein includes optionally substituted alkenyl groups, preferably having 2 to 20 carbon atoms, more preferably having 2 to 12 carbon atoms, and most preferably having 2 to 6 carbon atoms; for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, isohexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl, and the like.

[0112] The term "alkenyl" described herein also includes optionally substituted cycloalkenyl groups (e.g., C3-C20 cycloalkenyl or C3-C12 cycloalkenyl or C3-C8 cycloalkenyl), for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cycloheptatrienyl, and the like.

[0113] The "alkenyl" described herein is optionally substituted by one or more (eg, 1 to 3) substituents, wherein the selection and preferred range of the substituents are the same as those of the "alkyl" substituents.

[0114] The term "alkynyl" refers to a group formed when a hydrocarbon consisting of only two elements, C and H, and containing one or more carbon-carbon triple bonds but no aromatic bonds, loses a hydrogen atom from any carbon atom. The "alkynyl" described herein includes chain alkynyls such as straight chain alkynyls and branched chain alkynyls; and also includes cycloalkynyls such as monocyclic alkynyls, spirocyclic alkynyls, fused cyclic alkynyls and bridged cyclic alkynyls. The alkynyl group may optionally contain one or more carbon-carbon double bonds. The alkynyl group may be unsubstituted or substituted.

[0115] The “alkynyl” described herein includes optionally substituted alkynyl groups, preferably having 2 to 20 carbon atoms, more preferably having 2 to 12 carbon atoms, and most preferably having 2 to 6 carbon atoms; for example, ethynyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, 1-pentynyl, 2-pentynyl, isopentenyl, 3-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 3-heptynyl, 1-octynyl, 1-nonynyl, 1-decynyl, 1-undecanynyl, 1-dodecynyl, and the like.

[0116] The term "alkynyl" described herein also includes optionally substituted cycloalkynyl (eg, C8-C18 cycloalkynyl), for example, cyclooctynyl and the like.

[0117] The "alkynyl" described herein is optionally substituted by one or more (eg, 1 to 3) substituents, wherein the selection and preferred range of the substituents are the same as those of the "alkyl" substituents.

[0118] The term "heterocyclyl" refers to a monocyclic or polycyclic compound substituent that is saturated or contains a carbon-carbon double bond or a carbon-carbon triple bond; it contains 3 to 20 ring atoms (preferably 3 to 12 ring atoms, more preferably 3 to 8 ring atoms), wherein one or more ring atoms are selected from heteroatoms, and the remaining ring atoms are carbon; any of the rings are non-aromatic. The "heterocyclyl" described herein also includes spiro heterocyclyl, fused heterocyclyl and bridged heterocyclyl. The heterocyclyl group may be unsubstituted or substituted. The heterocyclyl group may be a heterocycloalkyl, heterocycloalkenyl or heterocycloalkynyl. Examples of suitable monocyclic heterocycles include, but are not limited to, piperidinyl, pyrrolidinyl, piperazinyl, azetidinyl, aziridine, morpholinyl, thietidinyl, oxolanyl (tetrahydrofuranyl), oxahexyl (tetrahydropyranyl), etc.

[0119] It should be understood that the "heterocyclyl" described herein is optionally substituted by one or more (eg, 1-3) substituents, wherein the selection and preferred range of the substituents are the same as those of the "alkyl" substituents.

[0120] The term "aryl" 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 a heteroaromatic ring, a heterocyclic ring, a cycloalkane, a spirocycloalkane, a fused cycloalkane, a bridged cycloalkane, a cycloalkene, a spirocycloalkene, a fused cycloalkene, a bridged cycloalkene, a cycloalkyne, a spirocycloalkyne, a fused cycloalkyne or a bridged cycloalkyne. The aryl group may be unsubstituted or substituted. Examples include, but are not limited to, phenyl, naphthyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, methoxyphenyl (e.g., 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl), chlorophenyl (e.g., 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl), fluorophenyl (e.g., 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl), bromophenyl (e.g., 2-bromophenyl, 3-bromophenyl, 4-bromophenyl), 2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 3-chloro-2-methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-2-methylphenyl, 4-chloro-3-methylphenyl, 5-chloro-2-methylphenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, and the like.

[0121] The "aryl" described herein is optionally substituted by 1 to 4 or 1 to 3 substituents, wherein the selection and preferred range of the substituents are the same as those of the "alkyl" substituents.

[0122] The term "heteroaryl" refers to an aromatic system containing 5 to 18 ring atoms (preferably 5 to 14 ring atoms) and wherein 1 to 4 ring atoms are heteroatoms selected from oxygen, nitrogen and sulfur. The heteroaryl itself can be fused with an aromatic ring, a heterocycle, a cycloalkane, a spirocycloalkane, a condensed cycloalkane, a bridged cycloalkane, a cycloalkene, a spirocycloalkene, a condensed cycloalkene, a bridged cycloalkene, a cycloalkyne, a spirocycloalkyne, a condensed cycloalkyne or a bridged cycloalkyne. It can be unsubstituted or substituted. Examples of heteroaryl include, but are not limited to, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, pyrazinyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzimidazolyl, indolyl, quinolyl, isoquinolyl and quinazolinyl etc.

[0123] The "heteroaryl" described herein is optionally substituted by 1-4 or 1-3 substituents, wherein the selection and preferred range of the substituents are the same as those of the "alkyl" substituents.

[0124] The term "acyl" as used herein refers to RC(=O)-, wherein R is C1-C18 (preferably C1-C12, more preferably C1-C6) alkyl. Examples of "acyl" include, but are not limited to, formyl, acetyl, benzoyl, nicotinoyl, propionyl, isobutyryl, oxalyl, and the like.

[0125] The acyl group RC(=O)- is optionally substituted by one or more (eg, 1 to 3) substituents, wherein the selection and preferred range of the substituents are the same as those of the "alkyl" group.

[0126] The term "cyclization" as used herein refers to the formation of a cyclic structure such as a cycloalkane ring, a cycloalkene ring, a cycloalkyne ring, an aromatic ring, a heterocycloalkane ring, a heterocycloalkene ring, a heterocycloalkyne ring, a heteroaromatic ring, etc., wherein the cyclic structure may be a monocyclic, bicyclic or polycyclic structure, including fused rings, bridged rings, and spirocyclic structures thereof. In particular, the substituent R herein 1 and R 2 The formed ring is preferably a 3- to 12-membered ring, particularly preferably a 3- to 12-membered cycloalkane ring, cycloalkene ring, heterocycloalkane ring, heterocycloalkene ring, and most preferably a 3- to 8-membered cycloalkane ring, cycloalkene ring, heterocycloalkane ring, and heterocycloalkene ring, such as a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a tetrahydrofuran ring, a tetrahydropyran ring, etc. The ring structure is optionally substituted with one or more (e.g., 1-3) substituents, wherein the selection and preferred range of the substituents are the same as those of the substituents of "alkyl".

[0127] In this article, the numerical ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms represent a list of all integers within the range, and the range is only used as a simplified representation. For example:

[0128] "1 to 4 substituents" means 1, 2, 3 or 4 substituents;

[0129] "1 to 3 substituents" means 1, 2 or 3 substituents;

[0130] "3 to 12 membered ring" means a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring;

[0131] "3 to 8 membered ring" means a 3, 4, 5, 6, 7 or 8 membered ring;

[0132] “1-12 carbon atoms” or “C1-C12” means 1 (C1), 2 (C2), 3 (C3), 4 (C4), 5 (C5), 6 (C6), 7 (C7), 8 (C8), 9 (C9), 10 (C10), 11 (C11) or 12 carbon atoms (C12);

[0133] “1-6 carbon atoms” or “C1-C6” means 1 (C1), 2 (C2), 3 (C3), 4 (C4), 5 (C5) or 6 carbon atoms (C6);

[0134] “2-6 carbon atoms” or “C2-C6” means 2 (C2), 3 (C3), 4 (C4), 5 (C5) or 6 carbon atoms (C6);

[0135] "C3-C8" means 3 (C3), 4 (C4), 5 (C5), 6 (C6), 7 (C7) or 8 carbon atoms (C8);

[0136] "3 to 8 ring atoms" means 3, 4, 5, 6, 7 or 8 ring atoms.

[0137] Therefore, numerical ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms also include any subranges thereof, and each subrange is also deemed to be disclosed herein.

[0138] In some particularly preferred embodiments of the present application, the hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) is a compound disclosed in WO2018205928 (6'-hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indolizine]-7'-carbonyl)glycine or a pharmaceutically acceptable salt thereof. The compound (6'-hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indolizine]-7'-carbonyl)glycine is wherein R 1 and R 2 Together with the C atoms to which they are attached, they form a cyclopentane ring (i.e., -CH2CH2CH2CH2-), R 3 is phenyl, R 4 and R 5 Hydrogen, R 6 and R 6’ is hydrogen, R 7 is hydrogen, R 8 is a compound of formula I wherein R is hydrogen and X is an oxygen atom.

[0139] 2. Pharmaceutical Preparations

[0140] The first aspect of the present application provides a long-acting oral pharmaceutical preparation, which contains a hypoxia-inducible factor-proline 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 preparation is suitable for administration at a dosing interval of once a week or longer. In the context of the present application, a long-acting oral pharmaceutical preparation refers to an oral pharmaceutical preparation that allows administration at a dosing interval of once a week or longer in terms of therapeutic effect.

[0141] For therapeutic use, HIF-PHI is usually administered to a patient in the form of a pharmaceutical composition comprising at least one of the above compounds as an active ingredient, optionally together with a pharmaceutically acceptable adjuvant and / or excipient and a pharmaceutically acceptable solid or liquid carrier.

[0142] The pharmaceutical composition of the present application can be formulated into various pharmaceutical dosage forms suitable for oral administration as required. Therefore, if a solid carrier is used, the preparation can be tableted, placed in a hard gel capsule in the form of powder or particles, or in the form of lozenges or lozenges. Solid carriers can include conventional excipients, such as adhesives, fillers, tableting lubricants, disintegrants, wetting agents, etc. If necessary, the tablet can be coated with conventional technology films. If a liquid carrier is used, the preparation can be in the form of syrup, emulsion, soft gel capsule, aqueous or non-aqueous liquid suspension, or can be a dry product reconstituted with water or other suitable carriers before use. Liquid preparations can include conventional additives, such as suspending agents, emulsifiers, wetting agents, non-aqueous carriers (including edible oils), preservatives, and flavoring agents and / or coloring agents.

[0143] These pharmaceutical compositions (or pharmaceutical preparations) may also include various excipients, such as preservatives, wetting agents, emulsifiers and dispersants. The inhibition of the effects of microorganisms may be ensured by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.). Isotonic agents may also be included, such as sugar, sodium chloride, etc. The absorption of injectable pharmaceutical dosage forms may be extended by using delayed absorption agents (e.g., aluminum monostearate and gel).

[0144] Solid dosage forms for oral administration include capsules, tablets, pills, 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), which may also include: (a) fillers or admixtures (e.g., starch, lactose, sucrose, glucose, mannitol and silicic acid); (b) binders (e.g., carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic); (c) humectants (e.g., glycerol); (d) disintegrants (e.g., agar); The invention can be prepared by mixing (a) agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solution retarder (e.g., paraffin); (f) absorption promoter (e.g., quaternary ammonium compounds); (g) wetting agents (e.g., cetyl alcohol and glycerol monostearate); (h) adsorbents (e.g., kaolin and bentonite) and (i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate) or mixtures thereof.

[0145] Solid pharmaceutical compositions (or pharmaceutical formulations) of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols.

[0146] Solid dosage forms (e.g., tablets, dragees, capsules, pills and granules) can be prepared with coatings and shells (e.g., enteric coatings and others known in the art). They may contain opacifiers, and they may also be pharmaceutical compositions (or pharmaceutical preparations) that release the active compound or compounds in a delayed manner in a certain part of the intestinal tract. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0147] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents (e.g., water or other solvents), solubilizers and emulsifiers (e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide ammonium), oils (specifically, cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol and fatty acid esters of sorbitan or mixtures of these substances, etc., commonly used in the art.

[0148] Besides these inert diluents, the pharmaceutical composition (or pharmaceutical preparation) may also include, for example, wetting agents, emulsifying and suspending agents, perfuming agents, flavoring agents and perfuming agents.

[0149] In addition to the active compounds, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

[0150] The amount of the HIF-PHI compound in the pharmaceutical composition (or pharmaceutical preparation) can be appropriately determined by those skilled in the art according to needs.

[0151] In some embodiments, the amount of HIF-PHI or a pharmaceutically acceptable salt thereof contained in each unit of the pharmaceutical preparation is about 1-1000 mg, about 1-10 mg, about 10 mg, about 5 mg, about 4.5 mg, about 1-3 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg, about 6-8 mg, about 7-9 mg, about 8-10 mg, about 9-11 mg, about 10-12 mg, about 4.5-5 mg, 20 mg, 30 mg, 30 -100 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 10-30 mg, about 30-50 mg, about 50-70 mg, about 10-90 mg, about 10-800 mg, about 10-700 mg, about 10-600 mg, about 10-500 mg, about 10-400 mg, about 10-300 mg, or about 10-200 mg, or an amount within any range defined by any of these values.

[0152] In some embodiments, the amount of HIF-PHI or a pharmaceutically acceptable salt thereof contained in each unit of the pharmaceutical preparation is about 0.01-0.2 mg, about 0.2-0.4 mg, about 0.4-0.6 mg, about 0.6-0.8 mg, about 0.8-1 mg, about 1-1.2 mg, about 1.2-1.4 mg, about 1.4-1.6 mg, about 1.6-1.8 mg, about 1.8-2 mg, about 2-2.2 mg, about 2.2-2.4 mg, about 2.4-2.6 mg, about 2.6-2.8 mg, about 2.8-3 mg, about 3-3.2 mg, about 3.2-3.4 mg, about 3.4-3.6 mg, about 3.6-3.8 mg, about 3.8-4 mg, about 3.4-3.6 mg, about 3.8-3.8 mg, about 3.8-4 mg. 9-4.1mg, about 4-4.2mg, about 0.2-0.4mg, about 0.2-0.6mg, about 0.2-0.8mg, about 0.2-1mg, about 0.2-1.2mg, about 0.2-1.4mg, about 0.2-1.6mg, about 0.2-1.8mg, about 0.2-2.0mg, 0.2-2.5mg, about 0.2-3.0mg, about 0.2-3.5mg, about 0.2-4.0mg, 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, about 70-80mg, about 80- 90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-150mg, about 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, about 1-10mg, about 10-200mg, about 10-150mg, about 10-100mg, about 10-180mg, about 10-160mg, about 10-140mg, about 10-120mg, about 10-100mg, about 10-20mg, about 20-30mg, about 3 In some embodiments, the present invention relates to an amount of at least one embodiment of the present invention, wherein the amount of the at least one embodiment of the present invention is at least one embodiment of the present invention. The amount of the at least one embodiment of the present invention can be 0.0 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg, about 70 to 80 mg, about 80 to 90 mg, about 90 to 100 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 220 mg, about 220 to 240, about 240 to 250 mg, about 250 to 260 mg, about 260 to 280 mg, about 280 to 300 mg, about 300 to 350 mg, about 350 to 400 mg, about 25 mg, about 50 mg, about 100 mg, about 250 mg, or an amount within any range defined by any of these values.

[0153] In some embodiments, the amount of HIF-PHI or a pharmaceutically acceptable salt thereof contained in each unit of the pharmaceutical preparation is about 0.1% (w / w) to about 10% (w / w), about 0.05% (w / w) to about 5% (w / w), about 0.2% (w / w) to about 15% (w / w), about 0.5% (w / w) to about 30% (w / w), about 1% (w / w) to about 25% (w / w), about 2% (w / w), about 3% (w / w), about 4% (w / w), about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / w), at least about 70% (w / w). % (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 a ratio within any range defined by any of these ratios.

[0154] The preparation of the pharmaceutical composition (or pharmaceutical preparation) can adopt methods known or commonly used in the art, which generally include the process of mixing the active ingredient HIF-PHI with a pharmaceutically acceptable carrier, adjuvant or excipient, and optional post-treatment or processing steps (such as drying, granulation, encapsulation, etc.).

[0155] 3. Pharmaceutical products

[0156] The second aspect of the present application provides a pharmaceutical product, comprising a packaging container, a drug instruction sheet, and a drug preparation contained in the packaging container, wherein the drug preparation is the drug preparation according to the first aspect of the present application, and the drug instruction sheet contains instructions indicating that the drug preparation is suitable for oral administration at a dosing interval of once a week or longer.

[0157] The pharmaceutical product in this application refers to a pharmaceutical product that can be sold in a pharmacy and directly selected or purchased by a doctor or patient and meets the requirements of the relevant regulatory agency. It usually has an independent package or packaging container, including a pharmaceutical preparation contained in a packaging container, and is accompanied by a drug instruction sheet, wherein the drug instruction sheet records the specified content required by the relevant regulatory agency (such as active ingredients, auxiliary ingredients, indications, contraindications, possible side effects, methods of use, precautions, etc.). The drug instruction sheet can be an independent paper, note, brochure contained in the packaging container, or it can be an explanatory text directly printed on the packaging container. The drug instruction sheet can also be an attached electronic drug instruction sheet, such as a separate CD (CD-ROM, etc.) or a URL or QR code with a network address information of the instruction sheet.

[0158] Since the pharmaceutical preparation in the present application is a long-acting oral pharmaceutical preparation, the drug instructions should contain a description indicating that the pharmaceutical preparation allows or is suitable for oral administration at a dosing interval of once a week or longer.

[0159] IV. Drug Use or Treatment Method

[0160] The third aspect of the present application provides the use of a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof in the preparation of a long-acting oral drug for treating chronic anemia, wherein the long-acting oral drug is suitable for administration at an interval of once a week or longer.

[0161] The fourth aspect of the present application provides a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof for oral treatment of chronic anemia, wherein the oral treatment is carried out at a dosing interval of once a week or longer.

[0162] The fifth aspect of the present application provides the use of a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof for treating chronic anemia, wherein the HIF-PHI or a pharmaceutically acceptable salt thereof is orally administered at a dosing interval of once a week or longer.

[0163] The sixth aspect of the present application provides a method for treating chronic anemia, comprising: orally administering a therapeutically effective amount of a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof to a patient in need of treatment at a dosing interval of once a week or longer.

[0164] Herein, the term "patient" means all mammals, and includes humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, mice, pigs and rabbits.

[0165] Herein, chronic anemia can be selected from: idiopathic anemia, chronic renal anemia, anemia induced by tumor chemotherapy, anemia caused by blood loss, anemia caused by menorrhagia in women, iron deficiency anemia, vitamin deficiency anemia, cell reduction and aplastic anemia, hemolytic anemia, iron loss anemia and anemia caused by hypothyroidism, preferably chronic renal anemia.

[0166] The pharmaceutical preparation of the present application can also be used to treat anemia complications or ischemic diseases, such as ischemic cerebrovascular disease (ischemic cerebrovascular disease), ischemic renal disease (ischemic renal disease, IRD), ischemic cardiomyopathy (ischemic cardiomyopathy, ICM), etc.

[0167] When using the pharmaceutical preparation of the present application to treat chronic anemia, it is usually necessary to give the patient a therapeutically effective amount of the active ingredient (i.e. HIF-PHI). Herein, the term "therapeutically effective amount" is the amount that can effectively delay or eliminate the patient's symptoms or improve the patient's health status when the active ingredient mentioned in the present application is given to the patient. The specific application dosage can be determined by the doctor according to the patient's specific circumstances. The precise dosage to be used depends not only 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, but can also be determined according to the judgment of the health care practitioner. In vitro or in vivo tests can be used to help determine the optimal dosage range.

[0168] For example, the compound of formula I of the present application can be administered to a patient at a dosage of about 0.01-4000 mg, or 0.05-2000 mg, or 0.1-1000 mg, or 0.1-500 mg, or 9-30 mg, or 9-18 mg, or 18-30 mg per week. However, the specific dosage used can vary. Those skilled in the art know how to determine the optimal dosage for a particular patient.

[0169] In some embodiments, the dose of HIF-PHI administered each time can be about 0.01-0.2 mg, about 0.2-0.4 mg, about 0.4-0.6 mg, about 0.6-0.8 mg, about 0.8-1 mg, about 1-1.2 mg, about 1.2-1.4 mg, about 1.4-1.6 mg, about 1.6-1.8 mg, about 1.8-2 mg, about 2-2.2 mg, about 2.2-2.4 mg, about 2.4-2.6 mg, about 2.6-2.8 mg, about 2.8-3 mg, about 3-3.2 mg, about 3.2-3.4 mg, about 3.4-3.6 mg, about 3.6-3.8 mg, about 3.8-4 mg, about 3.9-4.1 mg, about 4 -4.2mg, about 0.2-0.4mg, about 0.2-0.6mg, about 0.2-0.8mg, about 0.2-1mg, about 0.2-1.2mg, about 0.2-1.4mg, about 0.2-1.6mg, about 0.2-1.8mg, about 0.2-2.0mg, 0.2-2.5mg, about 0.2-3.0mg, about 0.2-3.5mg, about 0.2-4.0mg, 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, about 70-80mg, about 80-90mg, about 90- 100mg, about 100-120mg, about 120-140mg, about 140-150mg, about 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, about 1-10mg, about 10-200mg, about 10-150mg, about 10-100mg, about 10-180mg, about 10-160mg, about 10-140mg, about 10-120mg, about 10-100mg, about 10-20mg, about 20-30mg, about 30-40mg, about about 250-250 mg, about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-350 mg, about 350-400 mg, about 25 mg, about 50 mg, about 100 mg, about 250 mg, or a dose within any range defined by any value within these doses or dose ranges.

[0170] This application proposes an innovative drug administration method that breaks the limitation of traditional pharmaceutical theory on drug administration cycle. According to the drug administration scheme described in this application, when patients with chronic renal anemia are given long-term treatment, that is, when the drug is administered during the titration period, the patient's drug adhesion can be improved, thereby improving the efficacy and making it easier to manage chronic diseases in the long term.

[0171] The present application is further described below with reference to embodiments and drawings; however, these embodiments do not limit the scope of the present application. BRIEF DESCRIPTION OF THE DRAWINGS

[0172] Figure 1 The hemoglobin bar graphs of the rats in each group in Example 3 on days 0, 7, 14, 21 and 28 are shown.

[0173] Figure 2 The figure shows the comparison of hemoglobin bar graphs of rats in each group on the 28th day in Example 3 and the statistical significance among the groups.

[0174] Example

[0175] The embodiments described below are part of the embodiments of the present invention, rather than all of the embodiments. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention claimed for protection, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without departing from the principles of the present invention and without making creative work are within the scope of protection of the present invention.

[0176] For the sake of simplicity, some materials, equipment and method steps commonly used in the field are not specified in the examples. All process methods and analytical test processes (and related parameters) not specifically specified in the examples are carried out according to those commonly used by those skilled in the art; materials, reagents and equipment without specific sources are conventional laboratory materials and equipment and can be obtained through commercial channels. Example 1: (6'-Hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indolizine]-7'-carbonyl)

[0177] Glycine ( 1 )

[0178]

[0179] The compound was synthesized according to the method of Example 24 in WO2018205928 1 .

[0180] The structures of the compounds were determined by liquid chromatography-mass spectrometry (LCMS) or nuclear magnetic resonance (NMR). NMR chemical shifts (δ) were expressed in 10 -6 The unit of (ppm) is used for NMR measurement. Bruker-500 NMR instrument is used, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-D6), deuterated chloroform (CDCl3), etc., and the internal standard is tetramethylsilane (TMS). LCMS is measured by Shimadzu LCMS-2020 or Thermo UltiMate3000.

[0181] The thin layer chromatography silica gel plate uses Shandong Yantai Huanghai HSGF254 or Shandong Qingdao GF254 silica gel plate. Column chromatography generally uses Shandong Yantai Huanghai silica gel 200 to 300 mesh silica gel as a carrier.

[0182] All starting materials used in this example were purchased from chemical suppliers or synthesized by literature methods.

[0183] The abbreviations that may be used in this embodiment are as follows:

[0184] DMSO-d6: dimethyl sulfoxide with all six hydrogen atoms replaced by deuterium

[0185] CDCl3: deuterated chloroform

[0186] CAS: Chemical Abstracts Registration Number

[0187] NMR: Nuclear Magnetic Resonance

[0188] LCMS: Liquid chromatography-mass spectrometry

[0189] ESI: Electrospray ionization

[0190] ppm: parts per million

[0191] δ: NMR chemical shift

[0192] TMS: Tetramethylsilane

[0193] s: NMR singlet

[0194] d: NMR doublet

[0195] t: NMR triplet

[0196] br: NMR broad peak

[0197] CDI: Carbonyldiimidazole

[0198] DCC: N,N'-dicyclohexylcarbodiimide

[0199] NBS: N-bromocyclosuccinimide

[0200] Compound 1 The main synthetic steps are as follows.

[0201] Step 1: 1-(2-phenyl-1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid ( 1a )

[0202]

[0203] Compound 3-(1,3-dioxacyclohexane-2-yl)-1-phenylpropane-1-one (prepared according to 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. Then, after the reaction was cooled, the acetic acid was dried as much as possible; water and ethyl acetate were added to dilute; the organic phase was collected, and the organic phase was washed several times with a dilute sodium chloride aqueous solution until the aqueous phase was close to neutral; then the ethyl acetate layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the compound 1a 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).

[0204] Step 2: Dimethyl 2-(1-(2-phenyl-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate ( 1b )

[0205]

[0206] The second step compound in Example 15 of WO2018205928 is used 15b The synthetic route is 15a Replace with 1a , you can get 1b LCMS ESI(+):370(M+1) + . 1H NMR (500MHz, DMSO-d6) δ7.28–7.22(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(d d,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).

[0207] Step 3: 6'-Hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indolizine]-7'-carboxylic acid methyl ester ( 1c )

[0208]

[0209] The third step compound in Example 15 of WO2018205928 is used 15c The synthetic route is 15b Replace with 1b , you can get 1c LCMS ESI(+):338(M+1) + . 1 H NMR(500MHz,DMSO-d6)δ13.84(s,1H),7.54-7.43(m,5H),7.09(d,J=4.0Hz,1H),6.35(d,J=4.0H z,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).

[0210] Step 4: (6'-Hydroxy-8'-oxo-3'-phenyl-8'H-spiro[cyclopentane-1,5'-indolizine]-7'-carbonyl)glycine ( 1 )

[0211]

[0212] The fourth step compound in Example 15 of WO2018205928 is used 15 The synthetic route is 15c Replace with 1c , the compound can be obtained 1 LCMS ESI(+):381(M+1) + . 1H NMR (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).

[0213] Example 2: Inhibitory effect of Comp-1 on HIF PHD-2

[0214] In this example and the following examples, the compound prepared in Example 1 was used. 1 Tests are performed and compounds are referred to as "Comp-1" 1 .

[0215] Prepare the following stock solutions: HEPES buffer (pH 7.4, 50 mM), DMSO / HEPES solution of HIF-1α peptide (sequence: DLDLEMLAPYIPMDDDFQL; Genscript) (0.5 mM; preparation method: first prepare a 20 mM DMSO solution of the peptide, and then dilute to 40 times the volume with the aforementioned HEPES buffer), ascorbic acid solution (10 mM), FeSO4 hydrochloric acid solution (0.1 mM, hydrochloric acid concentration 10 μM), 2-oxopentanoic acid solution (2-OG: 1 mM), EDTA solution (pH 8.0; 0.5M), 8 concentrations of Comp-1 / DMSO solution (concentrations were 4000μM, 1333μM, 444.4μM, 148.1μM, 49.4μM, 16.5μM, 5.5μM and 1.82μM). The above concentrations of reagents were added to 9 Eppendorf tubes: 50μL HEPES solution, 10μL ascorbic acid solution, 10μL FeSO4 hydrochloric acid solution, 10μL 2-OG solution, 10μL HIF-1α peptide solution; then 5μL of the above 8 concentrations of Comp-1 / DMSO solution and 5μL DMSO were added respectively; finally, 5μL PHD2 enzyme (Active Motif; concentration: 0.2μg / μL) was added to each tube; the reaction system was incubated at 30℃ in the dark for 2 hours; finally, 10μL EDTA solution was added to each tube to terminate the reaction. The liquid of each reaction system was filtered with a 0.45 μm filter, and then HIF-peptide and hydroxylated HIF-peptide were separated by high performance liquid chromatography, and the concentrations of HIF-peptide and hydroxylated HIF-peptide were quantified by ultraviolet absorption detector to calculate their ratio. IC was calculated by Graph Prism 6.0 software 50 ; IC of Comp-1 to HIF PHD-2 50 It is 2.36μM.

[0216] Example 3: Excretion half-life of compounds in rats

[0217] Preparation of intravenous injection preparation: Weigh 4.0005g HP-β-CD (Shandong Binzhou Zhiyuan Biotechnology Co., Ltd.), dissolve in 16.0mL water for injection, stir for 20 minutes, and dilute to 20mL to obtain a 20% HP-β-CD solution. Weigh 4.93mg Comp-1, dissolve in 0.984mL ethanol, stir for 13 minutes, and ultrasonicate for 5 minutes. Then add 8.0+0.856mL 20% HP-β-CD, followed by stirring for 4 minutes and ultrasonicate for 4 minutes to obtain 9.84mL of Comp-1 clear solution with a final concentration of 0.5mg / mL. Preparation of single-dose oral preparation: Weigh 25.3800g meglumine (Sigma), dissolve in 80mL deionized water, stir for 35 minutes, and dilute to 130mL to obtain a 1M 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 1M meglumine solution were added, respectively. Stir for 31 minutes and ultrasonic 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. 18 SD rats (half male and half female) were randomly divided into 3 groups (3 males and 3 females in each group) and given 1.5, 5.0 and 15.0 mg / kg of Comp-1 by oral gavage. Blood was collected before administration and 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48 and 72 hours after administration. The oral solvent was 1M meglumine deionized water solution, and the administration volume was 10 mgL / kg. All collected plasma samples were stored at -75±15℃ until analysis. Liquid chromatography-mass spectrometry was used to measure the concentration of Comp-1 in SD rat plasma using Tolbutamide as the internal standard compound. The mass spectrometer used an electrospray ion source and monitored the parent ion and daughter ion mass-to-charge ratios of Comp-1 and Tolbutamide in positive ion mode, which were 381.2→306.3 (Comp-1) and 270.9→155.0 (Tolbutamide), respectively. The pharmacokinetic parameters of Comp-1 were calculated by the software Phoenix TMWinNonlin version 6.1 was calculated using a non-compartmental model. Pharmacokinetic data were calculated using the linear logarithmic trapezoidal method with a weight of 1 / Y*Y. Samples with concentrations below the lower limit of quantification were not included in the calculation of pharmacokinetic parameters. Microsoft Excel 2010 was used to calculate the average values ​​of various parameters, and the average values ​​were determined by the pharmacokinetic parameters of each animal. The average excretion half-lives of Comp-1 in male rats at three doses of 1.5, 5.0 and 15.0 mg / kg were 6.72 hours, 15.0 hours and 10.2 hours, respectively; the average excretion half-lives of Comp-1 in female rats at three doses of 1.5, 5.0 and 15.0 mg / kg were 12.9 hours, 5.72 hours and 24.9 hours, respectively. All t 1 / 2 Both are far less than 33.6 hours.

[0218] Example 4: Effect of oral administration of Comp-1 three times a week (tiw) and once a week (qw) on hemoglobin elevation in normal rats

[0219] A total of 70 male SD rats of about 7 weeks old were raised in the experimental environment for 10 days before the experiment began. During the entire experimental period, the animals were raised in ordinary animal cages with 24-hour continuous central air conditioning, temperature set at 24 degrees Celsius, and 12-hour light and dark alternation (5 rats per cage). All rats were free to eat (dry granular food) and drink purified water. The animals were randomly divided into 8 groups, including 5 rats in each of the vehicle (vehicle) tiw group and vehicle qw group; 6 drug groups Comp-1 3mpk tiw, 6mpk tiw, 10mpk tiw, 9mpk qw, 18mpk qw and 30mpk qw, each with 10 rats (mpk means mg / kg). The solvent was 1M meglumine aqueous solution. Each rat was orally gavaged with the solvent or the corresponding weight of Comp-1 solvent solution according to its body weight and group (tiw, qw) for a total of 4 weeks. Blood was drawn from each rat on days 0, 7, 14, 21, and 28 to measure the hemoglobin value (HGB, i.e., Hb). The rats were tail-clipped and blood was collected, and the hemoglobin value was read using a hemoglobin detector (HemoCue Hb 201+, manufactured by Radiometer). The quantitative data results were statistically analyzed using one-way analysis of variance (ANOVA) between groups, followed by Dunnett's multiple comparison method. The statistics were analyzed using a two-tailed analysis, and the statistical significance level was set at P<0.05. The hemoglobin results of rats in each group are shown in the figure. Figure 1 , Figure 2 As shown in Table 1.

[0220] Table 1: Comparison of hemoglobin levels in rats of each group on days 0, 7, 14, 21 and 28

[0221]

[0222] **** P<0.0001vs vehicle tiw. *** P<0.001vs vehicle tiw. ** P<0.01vsvehicle tiw. * P<0.05vs vehicle tiw.

[0223] ####P<0.0001vs vehicle qw.###P<0.001vs vehicle qw.##P<0.01vsvehicle qw.#P<0.05vs vehicle qw.<

[0224] according to Figure 1 , Figure 2 As shown in the results of Table 1, on the 28th day, the hemoglobin of the rats in the three groups that were given once a week (qw) was statistically significantly higher than that of the rats that were given the vehicle orally once a week (qw), and the hemoglobin of the former was able to maintain the increase in hemoglobin. In addition, in the treatment of non-dialysis-dependent renal anemia (NDD CKD), the most critical factor is not effectiveness but cardiovascular safety, that is, it is not the higher the hemoglobin increase, the better, the faster the better, but a certain increase in hemoglobin during the initial fixed period of treatment and a lower rate of increase in hemoglobin is safer than a higher rate. From the comparison of hemoglobin between the groups with the same total weekly dose on the 28th day in Table 1 (Comp-1 6mg / kg, tiw vs. Comp-1, 18mg / kg, qw; Comp-1 10mg / kg, tiw vs. Comp-1, 30mg / kg, qw), it can be found that the absolute value of hemoglobin increase in the qw group is lower and the rate of increase is slower than that in the tiw group.

[0225] Example 5: Effects of oral administration of Comp-1 once a day (QD), three times a week (tiw), and once a week (qw) on hemoglobin elevation in normal mice

[0226] This study evaluated the effects of the same weekly dose but different administration frequencies of the test compound Comp-1 on hemoglobin and various blood routine indexes in male C57BL / 6J mice.

[0227] After feeding, blood was collected from the submandibular vein of 92 male mice aged 6-8 weeks on Day 0 for routine hematological analysis. 80 mice were selected from the Hb (hemoglobin) results of Day 0 as mice for this experiment, namely: Vehicle (solvent group) (QD, 5 mice), Comp-1 (4.5 mg / kg, QD, 5 mice), Comp-1 (10.5 mg / kg, TIW, 5 mice), Comp-1 (31.5 mg / kg, QW, 5 mice), Comp-1 (9 mg / kg, QD, 15 mice), Comp-1 (21 mg / kg, TIW, 15 mice), Comp-1 (63 mg / kg, QW, 15 mice), Comp-1 (15 mg / kg, QD, 5 mice), Comp-1 (35 mg / kg, TIW, 5 mice), Comp-1 (105 mg / kg, QW, 5 mice); on Day 14, Day Blood was collected from the submandibular vein on Day 28 for routine hematological analysis. The quantitative data were analyzed statistically using one-way analysis of variance (ANOVA) between groups, followed by Dunnett's multiple comparison method. Two-tailed analysis was used for statistics, and the statistical significance level was set at P<0.05. The hemoglobin results of mice in each group are shown in Table 2; on Day 14 and Day 28, the average hemoglobin values ​​of all mice taking Comp-1 were significantly different from those in the Vehicle control group, P<0.001.

[0228] Table 2: Comparison of hemoglobin levels in mice of each group on days 0, 14 and 28

[0229]

[0230] According to the results in Table 2 above, under the same total weekly dose, similar to mice with a dosing frequency of once a day or three times a week, mice dosed once a week (qw) can also significantly increase hemoglobin and maintain the increase in hemoglobin for a long time, which is statistically significant compared with the control group. Moreover, compared with mice dosed once a day or three times a week, the absolute increase in hemoglobin with a once a week dosing frequency is smaller and the rate of increase is slower, which is more helpful for improving the safety of the treatment of anemia in chronic kidney disease.

[0231] Example 6: Excretion half-life of Comp-1 in humans after single and multiple oral administrations

[0232] In a phase I, randomized, double-blind, placebo-controlled, single-dose and multiple-dose clinical study, a total of 46 healthy volunteers were assigned to one of the six dose groups of 1mg, 4mg, 10mg, 20mg, 30mg, and 50mg in the single-dose phase. Two volunteers in each dose group received matching placebo, four volunteers in the 1mg 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 were collected from volunteers within 1 hour before administration and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, and 72 hours after administration for pharmacokinetic (PK) analysis. In the multiple-dose phase, a total of 32 healthy volunteers were assigned to one of the four dose groups of 4mg, 10mg, 20mg, and 30mg. Two volunteers in each dose group received matching placebo, and six volunteers received Comp-1 once a day for 10 consecutive days. Blood samples for PK analysis were collected from volunteers within 1 hour before dosing and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after dosing on the first dosing day (i.e., dosing day 1), as well as within 1 hour before dosing and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, and 72 hours after dosing on dosing days 6, 7, 8, and 10.

[0233] In the single-dose phase, volunteers who received a single dose of Comp-1 showed a significant difference in the response rate between 3 and 4.5 hours (T max The median value) reaches the peak drug concentration (C max ); Exposure (C max , AUC 0-t and AUC 0-inf ) increased in a dose-proportional manner; the mean excretion half-life (t 1 / 2 ) was 13.06-19.70 hours, with no obvious dose-related effect; the average clearance rate (C L / F ) There was no dose-related trend.

[0234] In the multi-dose phase, volunteers received Comp-1 on the first day, and each dose group had a 2-3 hour (T max The median value) reaches the peak drug concentration (C max ), there was no significant difference between the dose levels. max , AUC 0-t and AUC 0-inf ) increases with increasing dose; the average half-life is 10.14-19.43 hours, and there is no trend of change with dose. L / FThere was no obvious trend of change with dose. After 10 consecutive days of administration, T max The median duration was 3-4 hours; COMP-1 exposure (C ss,max , AUC 0-τ , AUC 0-t and AUC 0-inf ) increased in a dose-proportional manner; the mean excretion half-life was 12.41-15.75 hours, with no dose-related trend; the mean clearance (C L / F ) There was no dose-related trend. These excretion half-lives were much shorter than 33.6 hours.

[0235] Example 7: Phase II clinical trial results of Comp-1 in patients with chronic renal anemia

[0236] In a phase II, 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 an 8-week dose adjustment period (also known as a titration period). A total of 113 patients with renal anemia were first randomized into the fixed dose period. Patients with renal anemia in the fixed period received Comp-1 8mg, 12mg or 16mg three times a week (TIW), or matched placebo. At the sixth week study visit, a total of 44 eligible patients were randomly entered into the dose adjustment period (titration period) for the second time. The dosing frequency of patients in the Comp-1 group had a 50% chance of switching to once a week (QW) based on the original TIW. The starting dose of this stage continued the dose in the fixed period and could be adjusted according to the weekly hemoglobin value to maintain hemoglobin within the critical range of 10.0-11.0g / dL. To maintain double blindness, patients in the placebo group were pseudo-randomized and maintained with matched placebo. In this study, patients underwent weekly study visits to measure the primary efficacy indicator, hemoglobin levels, and safety was compared among patients who entered the titration period according to dosing frequency (three times a week (TIW) dosing and once a week (QW) dosing).

[0237] The primary efficacy objective of the study was to compare the average hemoglobin increase rate (g / dL / week) of the three Comp-1 dose groups at the end of the fixed period (i.e., 5 weeks after administration) with the placebo group. The results showed that the average hemoglobin increase rate of each dose group of Comp-1 showed a dose-related increase, which was 0.2839 g / dL / week in the 8 mg group, 0.3893 g / dL / week in the 12 mg group, and 0.4817 g / dL / week in the 16 mg main group, all of which were significantly higher than the placebo group of -0.0382 g / dL / week (p values ​​were all <0.0001). In the analysis of hemoglobin during the adjustment period (titration period), at week 14 (i.e., at the end of the titration period or after 13 weeks of administration), the mean hemoglobin levels of the TIW group and the QW group in Comp-1 were 10.74 g / dL and 10.09 g / dL, respectively, both of which were maintained within the study target range of 10.0-11.0 g / dL inclusive of the critical value, while the mean hemoglobin level in the placebo group was 9.57 g / dL. During the late adjustment period (titration period), i.e., weeks 10-14, the mean hemoglobin level was >10.0 g / dL in all dose frequency groups including the placebo group, and was 10.73 g / dL and 10.77 g / dL in the TIW and QW groups summarized in Comp-1, respectively, and 10.26 g / dL in the placebo group. The change in hemoglobin level from baseline was 1.60 g / dL and 1.63 g / dL in the TIW and QW groups summarized in Comp-1, respectively, and was 0.48 g / dL in the placebo group. This indicates that patients in the placebo group who underwent the second random screening could be maintained within the study target range even without relevant treatment and with only a small increase (or fluctuation) in hemoglobin level during the adjustment period, and the performance of increasing and maintaining hemoglobin level was comparable in the TIW and QW groups summarized in Comp-1. In the analysis of hemoglobin over the entire adjustment period (titration period), i.e., weeks 6-14, the mean hemoglobin for the TIW and QW groups in the Comp-1 pool was 10.84 g / dL and 10.91 g / dL, respectively, and for the placebo group was 10.23 g / dL. The change from baseline in hemoglobin was 1.71 g / dL and 1.78 g / dL, respectively, for the TIW and QW groups in the Comp-1 pool, and 0.45 g / dL for the placebo group, again indicating that the TIW and QW groups were comparable in their ability to increase and maintain hemoglobin levels. Throughout the 13-week treatment period, the cumulative percentage of patients whose hemoglobin reached the target range, i.e., 10.0-11.0 g / dL inclusive, and whose hemoglobin increased by ≥1.0 g / dL from baseline was similar between the pooled Comp-1 TIW and QW groups, 100% and 90%, respectively, and 40% for the placebo group. Table 3 below provides a safety comparison of patients entering the titration period according to dosing frequency.

[0238] Table 3: Safety comparison according to dosing frequency during the titration period

[0239]

[0240] TEAE (treatment emergent adverse event) refers to all adverse reactions that occur after the start of treatment; 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 occur; n represents the number of patients with adverse reactions.

[0241] As can be seen from Table 3, after entering the titration period, the QW (once a week) dosing frequency is less than the TIW (three times a week) dosing frequency in terms of the percentage of TEAEs and treatment-related TEAEs, especially in terms of the total number of adverse reactions (NE), the QW (once a week) dosing frequency is less. Considering that the HIF-PHI inhibitors that have been approved for marketing to treat CKD anemia are either administered once a day or three times a week, it is surprising to find that patients with low dosing frequency have fewer adverse reactions.

[0242] According to Example 6, the excretion half-life of Comp-1 is much shorter than one-fifth of a week, i.e., 33.6 hours. However, even if it is taken orally once a week during the dosage adjustment period (titration period) for treating patients with chronic renal anemia, the therapeutic effect can still be achieved, i.e., the patient's hemoglobin is within the expected range, and the side effects of the once-a-week dosing frequency are less than those of the three-a-week dosing frequency. Therefore, this is an innovative dosing regimen and dosing frequency that achieves unexpected therapeutic effects.

[0243] Although the embodiments of the present application have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the present application. More specifically, the words used in this specification are merely descriptive and non-restrictive, and it should be understood that various changes can be made without departing from the spirit and scope of the present application.

Claims

1. A long-acting oral pharmaceutical preparation comprising a hypoxia-inducible factor-proline 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 preparation is suitable for administration at an interval of once a week or longer.

2. A pharmaceutical product comprising a packaging container, a drug instruction sheet, and a pharmaceutical preparation contained in the packaging container, wherein the pharmaceutical preparation contains a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, adjuvants or excipients, and the drug instruction sheet contains an instruction indicating that the pharmaceutical preparation is suitable for oral administration at a dosing interval of once a week or longer.

3. Use of a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof in the preparation of a long-acting oral drug for treating chronic anemia, wherein the long-acting oral drug is suitable for administration at an interval of once a week or longer.

4. A method for treating chronic anemia, comprising: A therapeutically effective amount of a hypoxia-inducible factor-prolamide hydroxylase inhibitor (HIF-PHI) or a pharmaceutically acceptable salt thereof is orally administered to a patient in need of treatment at a dosing interval of once a week or longer.

5. The pharmaceutical preparation 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 or a pharmaceutically acceptable salt thereof has a t 1 / 2 Less than 33.6 hours, less than 24 hours, less than 16 hours, or less than 10 hours.

6. The pharmaceutical preparation 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 chronic anemia is selected from: idiopathic anemia, chronic renal anemia, anemia induced by tumor chemotherapy, anemia caused by blood loss, anemia caused by menorrhagia in women, iron deficiency anemia, vitamin deficiency anemia, cell hypoplasia and aplastic anemia, hemolytic anemia, iron loss anemia and anemia caused by hypothyroidism, preferably chronic renal anemia.

7. The 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 selected from the group consisting of: Roxadustat, Daprodustat, Vadadustat, Molidustat, Enarodustat, Desidustat, HIF117 (SSS17), HEC53856 and DDO-3055.

8. The pharmaceutical formulation of claim 1, the pharmaceutical product of claim 2, the use of claim 3 or the method of claim 4, wherein the HIF-PHI is Comp-1.

9. The pharmaceutical preparation 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 a compound of formula I as follows: in: R 1 and R 2 independently selected from cyano, alkyl, heterocyclic, alkenyl, alkynyl, aryl, heteroaryl and acyl; wherein the above alkyl, heterocyclic, alkenyl, alkynyl, aryl, heteroaryl, acyl are optionally substituted by one or more substituents, wherein the substituents are independently selected from halogen, cyano, hydroxyl, amino, carboxyl, acyl, alkyl, heterocyclic, alkenyl, alkynyl, aryl, heteroaryl, =O, =S, -SH, R 10 O-、R 10 S-, R 10 (O=)S-、R 10 (O=)2S-, where R 10 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl; or R 1 and R 2 Put together to form a ring; R 3 is selected from the group consisting of alkyl, heterocyclyl, alkenyl, alkynyl, aryl and heteroaryl; R 4 and R 5 is hydrogen; R 6 and R 6’ is hydrogen; R 7 is hydrogen; R 8 is selected from hydrogen and alkyl; X is oxygen.

10. The pharmaceutical preparation, pharmaceutical product, use or method according to claim 9, wherein in the compound of formula I, R 1 and R 2 Together with the C atoms to which they are attached, they form a cyclopentane ring (i.e., R 1 and R 2 is -CH2CH2CH2CH2-), R 3 is phenyl, R 4 and R 5 is hydrogen, R 6 and R 6’ is hydrogen, R 7 is hydrogen, R 8 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'-indolizine]-7'-carbonyl)glycine.

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