Novel Tricyclic Compounds for Treating Bacterial Infection

Important Compound Classes

Title

Tricyclic Compounds for the Treatment and Prophylaxis of Bacterial Infection

Patent Publication Number

WO 2020/109190 A1

Publication Date

June 4, 2020

Priority Application

CN PCT/CN2018/117718

Priority Date

November 27, 2018

Inventors

Dey, F.; Hu, Y.; Liu, Y.; Shen, H.; Shi, H.; Tan, X.; Yan, S.; Zhang, W.; Zhang, Z.; Zhou, C.; Zhou, M.; Zhu, W.

Assignee Company

F. Hoffmann-La Roche AG, Switzerland, and Hoffmann-La Roche Inc., USA

Disease Area

Bacterial infection

Biological Target

DNA gyrase and topoisomerase IV

Summary

Bacterial infections pose a continuing medical problem because antibacterial drugs eventually engender resistance in the bacteria on which they are used. Bacterial resistance against virtually all current antibiotic drugs is increasing. Many forms of antibiotic resistance can even cross international boundaries and spread with remarkable speed.

One target for development of antibacterial drugs has been DNA gyrase and topoisomerase IV (bacterial type IIA topoisomerases), which are essential to cell life and solve DNA topological problems resulting from the replication, transcription, and recombination of DNA. DNA gyrase controls DNA supercoiling and relieves topological stress that occurs when the DNA strands are untwisted, such as during replication. Topoisomerase IV primarily resolves linked chromosome dimers at the conclusion of DNA replication. Both enzymes can introduce double stranded DNA breaks, pass a second DNA strand through the break, and rejoin the broken strands. The activity of both enzymes is driven by the binding and hydrolysis of ATP.

Inhibition of DNA gyrase and topoisomerase IV has potential for the development of broad-spectrum antibiotics. The enzymes are highly conserved across a broad range of Gram-positive and Gram-negative pathogens. Recently, strong inhibition of DNA gyrase and topoisomerase IV has been recognized to be important for low resistance development in bacterial strains treated by inhibitors of the enzymes.

The present application describes a series of novel tricyclic compounds as inhibitors of DNA gyrase and topoisomerase IV and is useful for treatment and/or prophylaxis of bacterial infection. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁ = oxopyridinyl; pyrazolo[1,5-a]pyrimidinyl; pyridinyl substituted by cyano, C_1–6alkoxycarbonyl, or C_1–6alkylaminocarbonylC_1–6alkyl; pyrimidinyl substituted by C_1–6alkoxy or carboxyC_3–7cycloalkyl;

R₂ = (aminoC_1–6alkyl)C_3–7cycloalkyl; (C_1–6alkyl)₂amino; 2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrolyl substituted by C_1–6alkyl; 3,6-diazabicyclo[3.1.1]heptanyl; azabicyclo[3.1.0]hexanyl substituted by aminoC_1–6alkyl; azaspiro[2.4]heptanyl substituted by amino; azaspiro[3.3]heptanyl substituted by amino; azaspiro[3.4]octanyl substituted by amino; diazabicyclo[3.1.1]heptanyl; morpholinyl substituted by aminoC_1–6alkyl; piperidinyl substituted once or twice by substituents independently selected from amino, aminoC_1–6alkyl, C_1–6alkyl, and halogen; or pyrrolidinyl substituted once, twice, or three times by substituents independently selected from amino, aminoC_1–6alkyl, C_1–6alkyl, and halogen;

R₃ = H, C_1–6alkyl or halogen;

R₄ = halogen or haloC_1–6alkyl;

R₅ = H or halogen;

R₆ = C_1–6alkyl.

Key Structures

Biological Assay

The bacterial growth inhibition assay was performed. The compounds described in this application were tested in vitro for antibacterial activity against Staphylococcus aureus (ATCC29213), Klebsiella pneumoniae (ATCC10031), and Acinetobacter baumannii (9ATCC17978). The data of IC₅₀ (μM) over S. Aureus (ATCC29213), K. pneumoniae (ATCC10031), and A. baumannii (ATCC17978) are shown in the following table.

Biological Data

The table below shows representative compounds that were tested for bacterial growth inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 20

Compound claims: 12

Use of compound claims: 4

Process for preparing compound claims: 1

Pharmaceutical composition claims: 1

Method of treatment claims: 1

Invention claims: 1

Recent Review Articles

• 1.Dighe S. N.; Collet T. A.. Eur. J. Med. Chem. 2020, 199, 112326.
• 2.Dehshahri A.; Ashrafizadeh M.; Afshar E. G.; Pardakhty A.; Mandegary A.; Mohammadinejad R.; Sethi G.. Pharmacol. Res. 2020, 151, 104551.
• 3.Jaswal S.; Nehra B.; Kumar S.; Monga V.. Bioorg. Chem. 2020, 104, 104266.
• 4.Bax B. D.; Murshudov G.; Maxwell A.; Germe T.. J. Mol. Biol. 2019, 431, 3427.

The author declares no competing financial interest.