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CN-121991051-A - Antibiotic compound containing five-membered aromatic heterocycle

CN121991051ACN 121991051 ACN121991051 ACN 121991051ACN-121991051-A

Abstract

The present invention relates to the field of biomedical technology, a compound of formula (1), or a pharmaceutically acceptable salt, derivative, hydrate, solvate, complex, isomer, tautomer, bioisostere, N-oxide, ester, prodrug, isotope or protected form thereof: The novel antibiotic compounds, compositions comprising these compounds, and the use of these compounds in the treatment of bacterial diseases and infections, are useful in the treatment of gram positive bacterial infections and diseases caused by gram positive bacterial infections.

Inventors

  • LV HAINING
  • LIU LIBIN
  • HUO TAO
  • ZHANG BING
  • MA XIAOPING

Assignees

  • 北京杰玺医药科技有限公司

Dates

Publication Date
20260508
Application Date
20241102

Claims (17)

  1. 1. A compound of formula (1), or a pharmaceutically acceptable salt, derivative, hydrate, solvate, complex, isomer, tautomer, bioisostere, N-oxide, ester, prodrug, isotope, or protected form thereof: Wherein X, Y, Z are each independently selected from N, O, S; v, W are each independently selected from N-R 1 , carbonyl, amido; When V is selected from N-R 1 , R 1 is selected from H, methine, when R 1 is selected from methine, the methine may be simultaneously linked to Ar 2 to form a ring, wherein Ar 1 is selected from substituted or unsubstituted ethynyl, cyano, carbamoyl, a 6 membered ring system, if Ar 1 is selected from a 6 membered ring system, having formula (A1): A1 represents a 6-membered benzene ring, an aromatic heterocyclic ring, or a substituted 6-membered saturated ring; A is selected from carbon atoms and hetero atoms; R 2 is one or more optional substituents, each independently selected from H, halogen, cyano, nitro, amino, C 1-4 alkoxy, C 3-4 cycloalkyl, halogenated C 1-4 alkyl, 1-3 halomethyl, wherein the substitution positions of the substituents are each independently ortho, meta, para to the 6-membered ring connection position; Wherein Ar 2 is selected from a substituted or unsubstituted 6-membered benzene ring, aromatic heterocycle, or a substituted or unsubstituted 1,2,3, 4-tetrahydroisoquinolin-N-yl group at the 6-position, or an aza 1,2,3, 4-tetrahydroisoquinolin-N-yl group at the 6-position; If selected from a substituted or unsubstituted 6 membered benzene ring, aromatic heterocycle, having formula (A2): B. C, D are each independently selected from C, N; R 3 is one or more optional substituents, each independently selected from H, halogen, hydroxy, C 1-4 alkyl, C 1-4 straight or branched alkoxy, C 3-7 cycloalkyloxy, 4-tetrahydropyranyloxy, 4-R 4A -piperidin-1-yl, morpholin-N-yl, N' -R 4B -piperazin-N-yl, 3-R 4C -azetidin-N-yl, tetrahydropyr-l-1-yl, imidazolyl, wherein: R 4A is one or more optional substituents, each independently selected from H, C 1-4 alkyl, amino; R 4B is selected from C 1-4 alkyl, C 1-4 alkanoyl; R 4C is selected from hydroxy, C 1-4 straight or branched alkoxy, C 3-5 alkyl and forms a spiro ring with azetidine, C 2-4 alkoxyalkyl and an oxaspiro ring with azetidine; If Ar 2 is selected from 6-R 5 -1,2,3, 4-tetrahydroisoquinolin-N-yl, R 5 is one or more optional substituents, each of which is independently selected from H, C 1-4 straight or branched alkoxy, piperidin-1-yl, halogen.
  2. 2. The compound of claim 1, wherein Ar1 is:
  3. 3. The compound of claim 1 or 2, R 2 is one or more optional substituents each independently selected from H, halogen, cyano, nitro, amino, C 1-4 alkoxy, C 3-4 cycloalkyl, halo C 1-4 alkyl, 1-3 halomethyl, wherein the substitution positions of the substituents are each independently ortho, meta, para to the 6-membered ring connection position.
  4. 4. A compound according to any one of claims 1 to 3, ar 1 being independently selected from one of the following groups:
  5. 5. a compound according to any one of claims 1 to 3, X, Y, Z each independently selected from N, O, S.
  6. 6. A compound according to any one of claims 1 to 3, X, Y, Z being part of a constitutive 5-membered ring system independently selected from one of the following ring systems:
  7. 7. A compound according to any one of claims 1 to 3 wherein V, W is independently selected from N-R 1 , carbonyl, and amido, R 1 is selected from H and methine when V is selected from N-R 1 , and methine is simultaneously linked to Ar 2 to form a ring when R 1 is selected from methine.
  8. 8. A compound according to any one of claims 1 to 3, ar 2 is selected from a substituted or unsubstituted 6-membered benzene ring, aromatic heterocycle, or 1,2,3, 4-tetrahydroisoquinolin-N-yl substituted or unsubstituted in the 6-position, or aza 1,2,3, 4-tetrahydroisoquinolin-N-yl in the 6-position.
  9. 9. A compound according to any one of claims 1 to 3, ar 2 being independently selected from one of the following ring systems:
  10. 10. A compound according to any one of claims 1 to 3, R 3 is one or more optional substituents, each independently selected from H, halogen, hydroxy, C 1-4 alkyl, C 1-4 straight or branched alkoxy, C 3-7 cycloalkyloxy, 4-tetrahydropyranyl oxy, 4-R 4A -piperidin-1-yl, morpholin-N-yl, N' -R 4B -piperazin-N-yl, 3-R 4C -azetidin-N-yl, tetrahydropyrl-1-yl, imidazolyl, wherein: R 4A is one or more optional substituents, each independently selected from H, C 1-4 alkyl, amino; R 4B is selected from C 1-4 alkyl, C 1-4 alkanoyl; R 4C is selected from hydroxy, C 1-4 straight or branched alkoxy, C 3-5 alkyl and forms a spiro ring with azetidine, C 2-4 alkoxyalkyl and an oxaspiro ring with azetidine; R 5 is one or more optional substituents, each independently selected from H, C 1-4 straight or branched alkoxy, piperidin-1-yl, halogen.
  11. 11. A compound according to any one of claims 1 to 3, wherein the moiety-V-W-Ar 2 is a structurally independent moiety selected from the group consisting of:
  12. 12. A compound according to any one of claims 1 to 3, which is one of the following examples and pharmaceutically acceptable salts thereof, for example: And pharmaceutically acceptable salts thereof.
  13. 13. A pharmaceutical composition comprising a compound of any one of claims 1 to 12 and a pharmaceutically acceptable excipient or carrier.
  14. 14. Use of a compound according to any one of claims 1 to 12 in the manufacture of a medicament for the treatment of a bacterial infection and/or a disease caused by a bacterial infection, or for the manufacture of a medicament for the treatment of a bacterial infection and/or a disease caused by a bacterial infection.
  15. 15. A method of treating a bacterial infection and/or a disease caused by a bacterial infection comprising administering to a mammal suffering from such an infection or disease an effective amount of a compound as claimed in any one of claims 1 to 12.
  16. 16. The compound of claim 14, or the method of claim 15, wherein the bacterial infection is caused by a gram positive bacterium.
  17. 17. The compounds and methods according to claim 16, wherein the bacterial infection is caused by Staphylococcus aureus (Staphylococcus aureus), staphylococcus epidermidis (Staphylococcus epidermidis), staphylococcus hemolyticus (Staphylococcus haemalyticus), staphylococcus intermedia (Staphylococcus intermedia), streptococcus pneumoniae (Streptococcus pneumoniae), streptococcus pyogenes (Streptococcus agalactiae), streptococcus agalactiae (Streptococcus agalactiae), listeria monocytogenes (Listeria monocytogenes), enterococcus faecium (Enterococcus faecium), bacillus anthracis (Clostridium perfringens), clostridium difficile (Clostridium perfringens), clostridium perfringens (Clostridium perfringens).

Description

Antibiotic compound containing five-membered aromatic heterocycle Technical Field The present invention relates to the field of biotechnology, an antibiotic compound containing a five membered aromatic heterocycle as defined herein, compositions comprising these compounds and methods of using these compounds in the treatment of bacterial diseases and infections. The compounds are useful in the treatment of gram positive bacterial infections and diseases caused by gram positive bacterial infections. Background Gram-positive bacteria are the main pathogenic bacteria causing community or hospital infectious diseases, historically these infectious diseases have been successfully controlled and cured clinically through the use of various antibiotics, but long-term antibiotic application has led to the generation of various drug-resistant gram-positive bacteria, especially the generation of multi-resistant gram-positive bacteria such as methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE), vancomycin-resistant enterococci (VRE) and penicillin-resistant streptococcus pneumoniae (PRSP), and part of the bacteria have become superbacteria, and have caused wide public health problems worldwide, and although the clinical application of various iterative antibiotics such as vancomycin-derived novel antibiotics such as new generation oxazolidinone antibiotics has been solved, the corresponding drug-resistant strains have appeared in a large number, and cause serious infectious diseases which are difficult to cure by means of the existing antibiotics, regardless of the community or the hospital, so the novel antibiotics are required to be clinically solved. Disclosure of Invention In one aspect, the invention provides a compound of formula (1), or a pharmaceutically acceptable salt, derivative, hydrate, solvate, complex, isomer, tautomer, bioisostere, N-oxide, ester, prodrug, isotope or protected form thereof. In another aspect, there is provided a compound as defined above, or a pharmaceutically acceptable salt, derivative, hydrate, solvate, complex, isomer, tautomer, bioisostere, N-oxide, ester, prodrug, isotope or protected form thereof, for use in therapy and prophylaxis. In another aspect, there is provided a compound as defined above, or a pharmaceutically acceptable salt, derivative, hydrate, solvate, complex, isomer, tautomer, bioisostere, N-oxide, ester, prodrug, isotope or protected form thereof, for use in a method of treatment of a bacterial infection or a disease caused by a bacterium. In another aspect, there is provided a compound as defined above, or a pharmaceutically acceptable salt, derivative, hydrate, solvate, complex, isomer, tautomer, bioisostere, N-oxide, ester, prodrug, isotope or protected form thereof, and a pharmaceutically acceptable excipient or carrier. In a further aspect, there is provided a compound as defined above, or a pharmaceutically acceptable salt, derivative, hydrate, solvate, complex, isomer, tautomer, bioisostere, N-oxide, ester, prodrug, isotope or protected form thereof, for use in the manufacture of a medicament for the treatment of a bacterial infection or a disease caused by a bacterium. In another aspect, there is provided a method of treating a bacterial infection or a disease caused by bacteria in a subject in need of such treatment, comprising administering to said subject an effective amount of a compound as defined above, or a pharmaceutically acceptable salt, derivative, hydrate, solvate, complex, isomer, tautomer, bioisostere, N-oxide, ester, prodrug, isotope or protected form thereof. In a further aspect there is provided a bactericidal or bacteriostatic composition comprising a compound or composition as defined above. In certain embodiments, the compounds of the invention have bacteriostatic and/or bactericidal activity against drug-resistant staphylococcus aureus and are useful for treating or preventing drug-resistant staphylococcus aureus infections or diseases caused by drug-resistant staphylococcus aureus. Other aspects and embodiments of the invention are defined in the claims. The specific technical scheme is as follows: definition and general preferences The term "bacterial disease" as used herein refers to any disease involving the presence and/or replication of bacteria in a subject and/or within cells. The term thus includes diseases caused or exacerbated by bacterial toxins. The term "bacterial infection" as used herein is used to define a condition in which a subject is infected with bacteria. Infection may be symptomatic or asymptomatic. In the former case, the subject may be identified as an infected person according to established diagnostic criteria. In the latter case, the subject may be identified as an infected person based on various assays, including, for example, biochemical experiments, serological experiments, microbiological culture, and/or microscopy. Thus, the invention is useful f