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CN-121991093-A - Pyridone derivative and application thereof

CN121991093ACN 121991093 ACN121991093 ACN 121991093ACN-121991093-A

Abstract

The invention relates to pyridone derivatives shown in a formula (I) or stereoisomers thereof, prodrugs and pharmaceutically acceptable salts of the pyridone derivatives, a pharmaceutical composition containing the pyridone derivatives shown in the formula (I), and application of the pyridone derivatives in preparation of medicines for preventing and/or treating HIV infection. The compound has remarkable anti-HIV virus activity, low solubility and low clearance rate, is suitable for developing a long-acting injection prevention and treatment scheme, and is used for preparing medicines of HIV virus integrase inhibitors or medicine compositions containing the medicines and is beneficial to patients suffering from HIV virus infection.

Inventors

  • CAO QIN
  • XU SHIJIE

Assignees

  • 博远医药(苏州)有限公司

Dates

Publication Date
20260508
Application Date
20241106

Claims (20)

  1. 1. A pyridone derivative or a stereoisomer thereof, a prodrug of a pyridone derivative, a pharmaceutically acceptable salt thereof, the pyridone derivative having a structure represented by formula (I): Wherein: (1) R 1 is selected from the group consisting of unsubstituted or substituted C 1-20 alkyl, deuterated C 1-20 alkyl, C 3-6 cycloalkyl, Deuterated C 3-6 cycloalkyl, alkynyl-substituted C 1-20 alkyl, alkynyl-substituted C 3-6 cycloalkyl, alkynyl-substituted C 3-6 heterocycloalkyl, C 3-10 cycloalkyl C 1-10 alkyl, C 2-8 heterocycle C 1-10 alkyl, and substituent used for substitution is one or more selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, Halogenated C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 6-10 aryl, C 3-10 heteroaryl, C 1-6 alkylthio, c 1-6 Alkylmercapto, cyano or hydroxy; (2) Each R 2 is independently selected from halogen, cyano, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl or C 2-6 alkynyl, n is 1, 2, 3 or 4, (3) R 3a 、R 3b is independently selected from H, D, C 1-6 alkyl, deuterated C 1-6 alkyl; (4) Q is selected from amide, unsubstituted or substituted 4-6 membered heterocycle, and the substituent used for substitution is one or more selected from halogen, C 1-2 alkyl, halogenated C 1-2 alkyl, C 1-6 alkoxy, cyano or oxo; (5) X, Y is independently selected from CH or N; (6) A is absent or A is selected from unsubstituted or substituted 5-10 membered heterocyclyl or 5-10 membered carbocyclyl, and the substituents employed for substitution are one or more selected from halogen, cyano, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkynyl, hydroxy, oxo, exocyclic double bond, halogenated exocyclic double bond, C 1-6 alkoxy or C 1-6 alkoxy C 1-3 alkyl, wherein when two substituents are present, the two substituents are joined and together with A form a spiro, fused or bridged ring; When A is absent, R 1 is linked to Y and taken together with the N to which R 1 is linked forms a 3-20 membered heterocyclic ring; (7) The heteroatoms in the C 3-6 heterocycloalkyl, C 2-8 heterocycle, C 3-10 heteroaryl, 4-6 membered heterocycle, 5-10 membered heterocyclyl, 3-20 membered heterocycle are independently selected from one or more of O, S, N, -SO 2 -, se, and oxo.
  2. 2. The pyridone derivative or the stereoisomer thereof, the prodrug of the pyridone derivative, the pharmaceutically acceptable salt of the pyridone derivative according to claim 1, wherein X is N and Y is CH.
  3. 3. The pyridone derivative or a stereoisomer thereof, a prodrug of the pyridone derivative, a pharmaceutically acceptable salt of the pyridone derivative according to claim 1, wherein X, Y are each CH when a is absent.
  4. 4. The pyridone derivative or the stereoisomer thereof, the prodrug or the pharmaceutically acceptable salt of the pyridone derivative according to claim 1, wherein the chirality of the carbon atom to which the a ring is attached to Y is selected from the group consisting of the S configuration, the R configuration and the R/S configuration, wherein the R/S configuration is as shown in formula (I), and wherein the S configuration and the R configuration are as shown in formula (Ia) and formula (Ib), respectively:
  5. 5. The pyridone derivative or the stereoisomer thereof, the prodrug of the pyridone derivative, or the pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of unsubstituted and substituted 5-to 10-membered heterocycles, and the substituent employed for substitution is one or more selected from the group consisting of F, cl, br, methyl, deuterated methyl, ethyl, deuterated ethyl, trifluoromethyl, difluoromethyl, cyclopropyl, methoxy, ethoxy, propoxy, butoxy, halogenated methoxy, halogenated ethoxy, halogenated propoxy, halogenated butoxy, ethynyl, propynyl, oxo, exocyclic double bond, halogenated exocyclic double bond, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl.
  6. 6. The pyridone derivative or a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt of the pyridone derivative according to claim 1, wherein the pyridone derivative has a structure of formula (I-a): In the formula (I-A), R 1 、R 2 、n、R 3a 、R 3b is defined as O, CH 2 , oxo, exocyclic double bond and halogenated exocyclic double bond respectively as in claim 1;W, R 4 is absent or selected from C 1-3 alkyl and deuterated C 1-3 alkyl, R 5 、R 6 is independently selected from H, methyl, deuterated methyl, ethyl, deuterated ethyl, ethynyl, propynyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl and propoxypropyl, or R 5 、R 6 is connected with a ring where W is located to form a bridged ring.
  7. 7. The pyridone derivative or the stereoisomer thereof, the prodrug of the pyridone derivative, the pharmaceutically acceptable salt according to claim 6, wherein in the formula (I-A), Selected from the group consisting of unsubstituted and substituted:
  8. 8. The pyridone derivative or the stereoisomer thereof, the prodrug, the pharmaceutically acceptable salt of the pyridone derivative according to any of claims 1 to 7, wherein R 1 is selected from the group consisting of unsubstituted or substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-6 cycloalkyl, deuterated C 3-6 cycloalkyl, C 2-4 alkynyl C 1-6 alkyl, C 2-4 alkynyl halogenated C 1-6 alkyl, C 2-4 alkynyl C 3-6 cycloalkyl, C 2-4 alkynyl halogenated C 3-6 cycloalkyl, C 2-4 alkynyl C 3-6 heterocycloalkyl.
  9. 9. The pyridone derivative or the stereoisomer thereof, the prodrug of the pyridone derivative, or the pharmaceutically acceptable salt thereof according to claim 8, wherein R 1 is selected from the group consisting of unsubstituted or substituted methyl, ethyl, propyl, butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated n-butyl, deuterated isobutyl, cyclopropyl, deuterated cyclopropyl, ethynylmethyl, ethynylethyl, ethynylpropyl, ethynylhalomethyl, ethynylhaloethyl, ethynylhalopropyl, ethynylC 3-6 cycloalkyl, ethynylhaloC 3-6 cycloalkyl, ethynyl C 3-6 heterocycloalkyl, and wherein the substituent employed for substitution is one or more selected from the group consisting of F, cl, br, methyl, ethyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, cyclopropyl, hydroxy.
  10. 10. The pyridone derivative or stereoisomer thereof, the prodrug, the pharmaceutically acceptable salt of the pyridone derivative according to claim 9, wherein R 1 is selected from
  11. 11. The pyridone derivative or a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt of the pyridone derivative according to claim 1, wherein the pyridone derivative has a structure of formula (I-B): In the formula (I-B), R 2 、n、R 3a 、R 3b is defined as in claim 1, E is CH or N, R 7 、R 8 is independently selected from H, halogen, cyano, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl or C 2-6 alkynyl, and m and p are independently 1, 2 or 3.
  12. 12. A pyridone derivative or a stereoisomer thereof, a prodrug of a pyridone derivative, a pharmaceutically acceptable salt according to any of claims 1 to 7, 11, wherein Q is selected from an amide or from an unsubstituted or substituted five membered heterocycle.
  13. 13. A pyridone derivative or a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt of the pyridone derivative according to claim 12, wherein Q is selected from the group consisting of an amide wherein the carbonyl carbon of the amide is attached to a carbon on the pyridone, or Q is selected from the group consisting of
  14. 14. The pyridone derivative or a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt of a pyridone derivative according to any of claims 1 to 7, 11, wherein R 2 is selected from F, cl, br, hydroxy, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, fluoroethyl, ethynyl, n is 1,2 or 3, and/or R 3a 、R 3b is independently selected from H or D.
  15. 15. The pyridone derivative or the stereoisomer thereof, the prodrug or the pharmaceutically acceptable salt of the pyridone derivative according to claim 1, wherein the prodrug is a compound which metabolizes a hydroxyl-shielding group to a prodrug by chemical means or by in vivo enzyme, and further wherein the hydroxyl-shielding group comprises the structure H, C 6-20 OC(＝O)-、C 6-20 C(＝O)-、C 6-20 C(＝O)-、C 6-20 C(＝O)-、C 6-20 OCH 2 O-,
  16. 16. The pyridone derivative or a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt of the pyridone derivative according to claim 1, wherein the pyridone derivative is selected from the group consisting of:
  17. 17. A pharmaceutical composition comprising a pyridone derivative or a stereoisomer thereof, a prodrug of a pyridone derivative, or a pharmaceutically acceptable salt thereof according to any of claims 1 to 16, further wherein the pharmaceutical composition is an antiviral pharmaceutical composition further comprising one or more therapeutic agents selected from the group consisting of nucleoside or nucleotide reverse transcriptase inhibitors, non-nucleoside or nucleotide reverse transcriptase inhibitors, HIV protease inhibitors, HIV capsid inhibitors, CXCR4 inhibitors, GP41 inhibitors, GP120 inhibitors, CCR5 inhibitors, HIV latency reversal agents, capsid polymerization inhibitors, HIV bNAbs, TLR 7, 8 or 9 agonists, and PK enhancers or other anti-HIV agents.
  18. 18. Use of a pyridone derivative or a stereoisomer thereof, a prodrug of a pyridone derivative, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 17 for the preparation of a medicament for the prevention and/or treatment of a viral infection disease.
  19. 19. Use of a pyridone derivative or a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt of a pyridone derivative according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 17 for the manufacture of a medicament for the prophylaxis and/or treatment of HIV viral infection diseases, further wherein the pharmaceutical composition has a long-acting effect, and the pharmaceutical composition comprises an oral formulation, an injectable formulation or an external formulation.
  20. 20. An intermediate for the preparation of a pyridone derivative or a stereoisomer thereof, a prodrug of a pyridone derivative, or a pharmaceutically acceptable salt thereof according to any of claims 1 to 16, wherein the intermediate has a structure of formula (VI), formula (VII) or formula (VIII): In the formula (VI), R 1 、R 2 、n、R 3a 、R 3b and X, Y, A are defined as the previous, R 9 is a hydroxyl protecting group; In the formula (VII), R 1 、R 2 、n、R 3a 、R 3b is defined as above, R 9 is a hydroxyl protecting group, R 10 is H, R 4 、R 5 、W、R 6 is as defined above; In the formula (VIII), R 2 、n、R 3a 、R 3b is defined as above, and R 11 is hydrogen or a hydroxyl protecting group.

Description

Pyridone derivative and application thereof Technical Field The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a pyridone derivative or a stereoisomer thereof, various prodrugs of the pyridone derivative, pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the pyridone derivative and application of the pyridone derivative and the pharmaceutical composition as antiviral drugs, in particular to the application of the pyridone derivative or the stereoisomer thereof and the various prodrugs of the pyridone derivative and the pharmaceutical composition containing the pyridone derivative as antiviral drugs, and particularly to the application of the pyridone derivative or the pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating HIV virus infection. Background The HIV virus is a lethal infectious disease virus that, under its direct or indirect action, causes the destruction of a large number of cd4+ T lymphocytes, resulting in a cellular immune deficiency, causing serious infection and tumorigenesis, and eventually progressing to acquired immunodeficiency syndrome (acquire immunodeficiency syndrome, AIDS), also known as AIDS. Reverse transcriptase, protease and integrase are important drug action targets in the development strategy of antiviral therapeutic drugs. The combination of these drugs has been validated as an effective antiviral drug in approved aids drugs, achieving a sustained compression of viral titres in most infected individuals. However, due to the mutation of the virus itself and the long-term use of the existing medicines, the medicines of the virus aiming at the combination therapy still generate drug resistance and finally cause treatment failure, and in addition, the combined use of multiple medicines puts higher demands on the research on drug interaction and safety evaluation in the body of a patient to be treated. Compared with the daily medication treatment scheme, the long-acting therapeutic agent can remarkably improve the compliance of patients, and meanwhile, the low-frequency medication can also improve the convenience for the treatment of patients in partial underdeveloped areas or special people. Thus, there is an urgent need to develop new drugs to address the resistance, safety and patient compliance issues of current drugs. Among antiviral therapeutic drugs commonly adopted at present, integrase chain transfer Inhibitors (INTEGRASE STRAND TRANSFER Inhibitors, INSTIs) have the advantages of good safety and tolerance, rapid inhibition of virus replication, strong antiviral activity, high genetic drug resistance barrier and the like, and are drugs with better antiviral efficacy at present. INSTIs is an antiviral drug which has been put into practical use in recent years and has been used in a wide range of fields worldwide, however, HIV-infected persons need to take a drug for a long period of time and the problem of drug resistance has been developed with the increase of the treatment time. In order to effectively limit the occurrence of drug resistance in the treatment process, overcome the resistance of the existing drug-resistant strain and improve the convenience of drug use and patient compliance, the invention provides a compound shown as a formula (I), which has high antiviral activity and good long-acting drug properties, comprises the pharmacokinetic characteristics of low clearance rate, low solubility, good permeability and the like, and can ensure that the drug can keep effective exposure dose and stable antiviral level in vivo for a long time in combination with the development of a long-acting preparation process. Disclosure of Invention The invention aims to provide a pyridone derivative or a stereoisomer thereof, a prodrug of the pyridone derivative, a pharmaceutically acceptable salt and a pharmaceutical composition containing the same as shown in formula (I), or a deuterated pyridone derivative or a stereoisomer thereof, various prodrugs of the deuterated pyridone derivative, a pharmaceutically acceptable salt and a pharmaceutical composition containing the same as shown in formula (I), which have broad-spectrum anti-HIV activity, can highly inhibit clinical resistant strains generated by existing anti-HIV drugs with different and same mechanisms, and also show good inhibition activity on clinical resistant strains with crossed drug resistance, on the other hand, the compound of the invention has very high drug resistance barrier and other anti-HIV drugs for combined use, and even if patients are treated for a long time, the combined therapy can nearly completely suppress escape and mutation of viruses. The substitution of hydrogen atoms with deuterium atoms in the drug molecules of the present invention, although with little structural change, results in deuterated compounds that significantly improve the pharmacokinetic profile of the drug compoun