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US-12617798-B2 - Imidazopyrazne derivatives

US12617798B2US 12617798 B2US12617798 B2US 12617798B2US-12617798-B2

Abstract

The invention provides novel imidazopyrazine derivatives having the general formula (I), and pharmaceutically acceptable salts thereof, wherein X 1 to X 4 , R 1 to R 5 , R 8 to R 10 , A, and L 1 are as described herein: Further provided are pharmaceutical compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds as medicaments, in particular methods of using the compounds as antibiotics for the treatment or prevention of bacterial infections and resulting diseases.

Inventors

  • Christian Lerner
  • Yongqiang Liu
  • Song Yang
  • Chengang Zhou

Assignees

  • HOFFMANN-LA ROCHE INC.

Dates

Publication Date
20260505
Application Date
20221129
Priority Date
20200601

Claims (20)

  1. 1 . A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 1 is N or C—R 6 ; X 2 is N or C—R 7 ; X 3 is N or C—R 11 ; X 4 is N or C—R 12 ; provided that at most one of X 1 to X 4 is N; R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, hydroxy, amino, halogen, cyano, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, cyano-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, carbamoyl-C 1 -C 6 -alkyl, carboxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, and a group R 4 is hydrogen or C 1 -C 6 -alkyl; R 5 is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkoxy; R 6 , R 7 , R 11 , and R 12 are each independently selected from the group consisting of hydrogen, hydroxy, amino, halogen, cyano, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, cyano-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and halo-C 1 -C 6 -alkoxy; R 8 , R 9 , and R 10 are each independently selected from the group consisting of hydrogen, halogen, cyano, amino, hydroxy, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, cyano-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, and C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl; R 13 , R 14 , and R 15 are each independently selected from the group consisting of hydrogen, halogen, cyano, amino, hydroxy, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, cyano-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and halo-C 1 -C 6 -alkoxy; A and C are each independently a 3- to 14-membered heterocycle; B is a 5- to 14-membered heteroaryl; and L 1 and L 2 are each independently selected from the group consisting of a covalent bond, carbonyl, and C 1 -C 6 -alkyldiyl.
  2. 2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: X 1 is C—R 6 .
  3. 3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: X 2 is N or C—R 7 .
  4. 4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: X 3 is C—R 11 .
  5. 5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: X 4 is C—R 12 .
  6. 6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from hydrogen, C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, carbamoyl-C 1 -C 6 -alkyl, carboxy-C 1 -C 6 -alkyl, and
  7. 7 . The compound of formula (I) according to any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, and carboxy-C 1 -C 6 -alkyl.
  8. 8 . The compound of formula (I) according to any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, wherein: R 8 is C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl.
  9. 9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: L 1 is C 1 -C 6 -alkyldiyl.
  10. 10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: L 2 is C 1 -C 6 -alkyldiyl.
  11. 11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: A is piperidyl.
  12. 12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: B is pyrazolyl.
  13. 13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: C is azetidinyl.
  14. 14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: X 1 is C—R 6 ; X 2 is N or C—R 7 ; X 3 is C—R 11 ; X 4 is C—R 12 ; R 1 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, carbamoyl-C 1 -C 6 -alkyl, carboxy-C 1 -C 6 -alkyl, and R 2 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, and carboxy-C 1 -C 6 -alkyl; R 3 , R 4 , R 13 , R 14 , and R 15 are hydrogen; R 5 is C 1 -C 6 -alkyl; R 6 , R 7 , and R 11 are each independently hydrogen or halogen; R 8 is selected from the group consisting of C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, cyano-C 1 -C 6 -alkyl, and C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl; R 9 , R 10 , and R 12 are each independently hydrogen or C 1 -C 6 -alkyl; A and C are each independently a 3- to 14-membered heterocycle; B is a 5- to 14-membered heteroaryl; and L 1 and L 2 are each independently C 1 -C 6 -alkyldiyl.
  15. 15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: X 1 is C—R 6 ; X 2 is N or C—R 7 ; X 3 is C—R 11 ; X 4 is C—R 12 ; R 1 is R 2 is C 1 -C 6 -alkyl or carboxy-C 1 -C 6 -alkyl; R 3 , R 4 , R 11 , R 12 , R 13 , R 14 , and R 15 are hydrogen; R 5 is C 1 -C 6 -alkyl; R 6 and R 7 are halogen; R 8 is C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl; R 9 and R 10 are each independently hydrogen or C 1 -C 6 -alkyl; A and C are each independently a 3- to 14-membered heterocycle; B is a 5- to 14-membered heteroaryl; and L 1 and L 2 are each independently C 1 -C 6 -alkyldiyl.
  16. 16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: X 1 is C—R 6 ; X 2 is N or C—R 7 ; X 3 is C—R 11 ; X 4 is C—R 12 ; R 1 is R 2 is methyl or carboxymethyl; R 3 , R 4 , R 11 , R 12 , R 13 , R 14 , and R 15 are hydrogen; R 5 is ethyl; R 6 and R 7 are fluoro; R 8 is methyl or 2-methoxyethyl; R 9 and R 10 are each independently hydrogen or methyl; A is piperidyl; B is pyrazolyl; C is azetidinyl; and L 1 and L 2 are —CH 2 —.
  17. 17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: N-[[1-(azetidin-3-ylmethyl)-4-piperidyl]methyl]-4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; 2-[1-(azetidin-3-ylmethyl)-4-[4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]piperidin-1-ium-1-yl]acetic acid; 2-[4-[[[4-[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-piperidyl]acetic acid; 2-[4-[[[4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-methyl-piperidin-1-ium-1-yl]acetic acid; N-[1-(azetidin-3-ylmethyl)-4-piperidyl]methyl]-4-[3-[2,3-difluoro-4-[3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-[3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; N-[[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[3-[4-[1-(cyanomethyl)-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; N-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; 2-[1-(2-amino-2-oxo-ethyl)-4-[[4-[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(carboxymethyl)-4-[4-[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]piperidin-1-ium-1-yl]acetic acid; N-[[1-(azetidin-3-ylmethyl)-4-piperidyl]methyl]-2-ethyl-4-[3-[2-fluoro-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide; N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-2-ethyl-4-[[3-[2-fluoro-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide; N-[1-(azetidin-3-ylmethyl)-4-piperidyl]methyl]-4-[[3-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-fluoro-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; N-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[3-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-fluoro-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-2-ethyl-4-[[3-[5-fluoro-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide; N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-2-ethyl-4-[[3-[4-methyl-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide; N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-2-ethyl-4-[[3-[4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide; 4-[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-(4-piperidylmethyl) benzamide; N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; N-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; 4-[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-[1-(2-hydroxyethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]benzamide; 4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[(1,1-dimethylpiperidin-1-ium-4-yl)methyl]-2-ethyl-benzamide; N-[[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; 4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-[[1-(2-hydroxyethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]benzamide; and N-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide.
  18. 18 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.
  19. 19 . A process of manufacturing the compounds of formula (I) according to claim 1 , or pharmaceutically acceptable salts thereof, the process comprising: (i) Suzuki coupling of a heteroaryl halide C1, wherein R 1 to R 5 , A, and L 1 are as defined herein and “Hal” is a halogen, preferably iodine, with a boronic acid (ester) B1, wherein X 1 to X 4 , R 8 to R 10 and ring B are as defined herein, and each R is independently hydrogen or alkyl, wherein the two R groups, taken together with the oxygen and boron atoms to which they are attached, may form a cyclic boronic acid ester; in the presence of a transition metal catalyst, such as 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex or Tris(dibenzylideneacetone)dipalladium(0), to afford said compound of formula (I); or (ii) Suzuki coupling of an aryl/heteroaryl halide E1, wherein R 1 to R 5 , A, L 1 , and X 1 to X 4 are as defined herein and “Hal” is a halogen, preferably chlorine, with a boronic acid (ester) I1, wherein R 8 to R 10 and ring B are as defined herein, and each R is independently hydrogen or alkyl, wherein the two R groups, taken together with the oxygen and boron atoms to which they are attached, may form a cyclic boronic acid ester; in the presence of a transition metal catalyst, such as 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex or Tris(dibenzylideneacetone)dipalladium(0), to afford said compound of formula (I).
  20. 20 . A method for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli , or a combination thereof, the method comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a mammal in need thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Continuation Application of International Patent Application No. PCT/EP2021/064473, filed on May 31, 2021, which claims benefit of priority to International Patent Application No. PCT/CN2020/093723, filed on Jun. 1, 2020, each of which is incorporated herein by reference in its entirety. BACKGROUND The present invention relates to novel imidazopyrazine derivatives which exhibit antibacterial properties. The invention also relates to methods of using the compounds for the treatment or prevention of bacterial infections and resulting diseases, in particular for the treatment or prevention of infections with Acinetobacter baumannii and/or Pseudomonas aeruginosa and resulting diseases. Acinetobacter baumannii and Pseudomonas aeruginosa are Gram-negative, aerobic, nonfermenting bacteria recognized over the last decades as emergining pathogens with very limited treatment options. Carbapenem-resistant A. baumannii and Multi-Drug Resistant (MDR) P. aeruginosa are considered to be urgent and serious threats, respectively, by the US Centers for Disease Control and Prevention and belongs to the so called ‘ESKAPE’ pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species & E. coli) that currently cause the majority of nosocomial infections and effectively “escape” the activity of antimicrobial agents. A. baumannii and P. aeruginosa are often encountered in intensive care units and surgical wards, where extensive antibiotic use has enabled selection for resistance against all known antimicrobials and where it causes infections that include bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection. A. baumannii has an exceptional ability to upregulate and acquire resistance determinants and shows an environmental persistance that allows its survival and spread in the nosocomial setting, making this organism a frequent cause of outbreaks of infection and an endemic, health care-associated pathogen. P. aeruginosa infections also usually occur in the nosocomial setting or in patients with a weakened immune system. It is particularly dangerous for patients with chronic lung diseases. P. aeruginosa has intrinsic resistance to many different types of chemotherapeutic agents and antibiotics, making it a very difficult pathogen to eliminate. Due to increasing antibiotic resistance to most if not all available therapeutic options, MDR A. baumannii infections, especially those caused by Carbapenem resistant A. baumannii, are extremely difficult or even impossible to treat with high mortality rate as well as increased morbidity and length of stay in intensive care unit. Similarly, some types of MDR P. aeruginosa are resistant to nearly all antibiotics, including carbapenems. The threat remains high. The 2019 report by the CDC reported 32,600 cases and 2,700 deaths in US hospitals. Acinetobacter baumannii has been defined and still remains “a prime example of a mismatch between unmet medical needs and the current antimicrobial research and development pipeline” according to the Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA). Thus, there is a high demand and need to identify compounds suitable for the treatment of diseases and infections caused by Acinetobacter baumannii. The present invention provides novel compounds which exhibit activity against drug-susceptible as well as drug-resistant strains of Acinetobacter baumannii and/or Pseudomonas aeruginosa. SUMMARY OF THE DISCLOSURE In a first aspect, the present invention provides compounds of formula (I) or a pharmaceutically acceptable salts thereof, wherein X1 to X4, R1 to R5, R8 to R10, A, and L1 are as described herein. In one aspect, the present invention provides a process of manufacturing the compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, comprising: (i) Suzuki coupling of a heteroaryl halide C1, wherein R1 to R5, A, and L1 are as defined herein and “Hal” is a halogen, preferably iodine, with a boronic acid (ester) B1, wherein X1 to X4, R8 to R10 and ring B are as defined herein, and each R is independently hydrogen or alkyl, wherein the two R groups, taken together with the oxygen and boron atoms to which they are attached, may form a cyclic boronic acid ester; in the presence of a transition metal catalyst, such as 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex or Tris(dibenzylideneacetone)dipalladium(0), to afford said compound of formula (I); or(ii) Suzuki coupling of an aryl/heteroaryl halide E1, wherein R1 to R5, A, L1, and X1 to X4 are as defined herein and “Hal” is a halogen, preferably chlorine, with a boronic acid (ester) I1, wherein R8 to R10 and ring B are as defined herein, and each R is independently hydrogen or alkyl, wherein the two R groups, taken together