Novel imidazopyrazine derivatives

Abstract

The present invention provides novel imidazopyrazine derivatives having the general formula (I), and pharmaceutically acceptable salts thereof, wherein X 1 From X 4 , R 1 From R 5 , R 8 From R 10 , A, and L 1 is as described herein. Pharmaceutical compositions comprising the TIFF2023527479000060.tif6887 compounds, methods of making the compounds, and methods of using the compounds as medicines, particularly methods of using the compounds as antibiotics for the treatment or prevention of bacterial infections and diseases resulting therefrom, are further provided.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to novel imidazopyrazine derivatives that exhibit antibacterial properties. The present invention also relates to methods of using the compounds for the treatment or prevention of bacterial infections and resulting diseases, particularly infections caused by Acinetobacter baumannii and / or Pseudomonas aeruginosa and resulting diseases. [Background technology]

[0002] Background of the Invention Acinetobacter baumannii and Pseudomonas aeruginosa are Gram-negative, aerobic, non-fermenting bacteria that have been recognized over the past few decades as emerging pathogens with very limited therapeutic options.

[0003] Carbapenem-resistant Acinetobacter baumannii and multidrug-resistant (MDR) Pseudomonas aeruginosa are considered urgent and serious threats by the US Centers for Disease Control and Prevention, respectively, and currently cause the majority of hospital-acquired infections, belonging to the so-called ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species, as well as Escherichia coli pathogens) that effectively "escape" the activity of antimicrobial agents.

[0004] Acinetobacter baumannii and Pseudomonas aeruginosa occur most frequently in intensive care units and surgical wards, where widespread antibiotic use allows selection for resistance to all known antimicrobial agents and can cause infections such as bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0005] Acinetobacter baumannii has a remarkable ability to upregulate and acquire resistance determinants, demonstrating environmental persistence that allows its survival and spread in hospital environments, making the organism a frequent cause of infectious disease outbreaks and an endemic healthcare-associated pathogen in those environments. Pseudomonas aeruginosa infections also typically occur in hospital settings or in patients with weakened immune systems. They are particularly dangerous for patients with chronic lung disease. Pseudomonas aeruginosa has inherent resistance to many different types of chemotherapeutic agents and antibiotics, making it a pathogen that is extremely difficult to eliminate.

[0006] Due to increasing antibiotic resistance to most, if not all, available therapeutic options, MDR Acinetobacter baumannii infections, particularly those caused by carbapenem-resistant Acinetobacter baumannii, are extremely difficult or even impossible to treat, resulting in increased morbidity and length of stay in intensive care units (ICUs), as well as high mortality rates. Similarly, several strains of MDR Pseudomonas aeruginosa are resistant to nearly all antibiotics, including carbapenems. The risk remains high. A 2019 report by the CDC reported 32,600 cases and 2,700 deaths in U.S. hospitals. According to the Infectious Diseases Society of America (IDSA) Antimicrobial Availability Task Force (AATF), Acinetobacter baumannii has been and remains considered "a prime example of the mismatch that exists between unmet medical need and the current antibiotic research and development pipeline." Therefore, there is a strong demand and need for identifying compounds suitable for treating diseases and infections caused by Acinetobacter baumannii. The present invention provides novel compounds that exhibit activity against drug-susceptible as well as drug-resistant strains of Acinetobacter baumannii and / or Pseudomonas aeruginosa. Summary of the Invention

[0007] Summary of the Invention In a first aspect, the present invention provides a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof (wherein X 1 From X 4 , R 1 From R 5 , R 8 From R 10 , A and L 1 is as described herein). In one aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (i) Heteroaryl halide C1 (wherein R 1 From R 5 , A and L 1 is as defined herein, and "Hal" is a halogen, preferably iodine; [ka] Boronic acid (ester) B1 (wherein X 1 From X 4 , R 8 From R 10 and Ring B is as defined herein, and each R is independently hydrogen or alkyl, and two R groups together with the oxygen and boron atoms to which they are attached may form a cyclic boronic ester; [ka] Suzuki coupling 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 give said compound of formula (I), or (ii) Aryl / heteroaryl halide E1 (wherein R 1 From R 5 , A, L 1 and X 1 From X 4 is as defined herein and "Hal" is a halogen, preferably chlorine; [ka] Boronic acid (ester) I1 (wherein R 8From R 10 and Ring B is as defined herein, and each R is independently hydrogen or alkyl, and two R groups together with the oxygen and boron atoms to which they are attached may form a cyclic boronic ester; [ka] Suzuki coupling 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 give the compound of formula (I), Provided is a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein.

[0008] In a further aspect, the present invention provides a compound of formula (I) as described herein when prepared according to the process described herein.

[0009] In a further aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0010] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

[0011] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as an antibiotic.

[0012] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of hospital-acquired infections and diseases resulting therefrom.

[0013] In a further aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections caused by Gram-negative bacteria and diseases resulting therefrom.

[0014] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections and diseases resulting therefrom caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description of the Invention definition It should be understood that any feature, integer, characteristic, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, except where inconsistent therewith. All features disclosed herein (including any accompanying claims, abstract, and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel or any novel combination of features disclosed herein (including any accompanying claims, abstract, and drawings), or any novel or any novel combination of steps of any method or process so disclosed.

[0016] The term "alkyl" refers to a monovalent or polyvalent, e.g., monovalent or divalent, straight-chain or branched, saturated hydrocarbon group of 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms ("C1-C6-alkyl"). In some embodiments, an alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred, but non-limiting, example of alkyl is methyl.

[0017] The term "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Unless otherwise specified, an alkoxy group contains 1 to 6 carbon atoms ("C1-C6-alkoxy"). In some preferred embodiments, an alkoxy group contains 1 to 4 carbon atoms. In still other embodiments, an alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred, but non-limiting, example of alkoxy is methoxy.

[0018] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred, but non-limiting, examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0019] The term "aminoalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced by an amino group. Preferably, "aminoalkyl" refers to an alkyl group in which one, two, or three of the alkyl group's hydrogen atoms have been replaced by amino groups. Preferred, but non-limiting, examples of aminoalkyl are aminomethyl and 1-aminoethyl.

[0020] The term "carbamoylalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms is replaced by a carbamoyl group. Preferably, "carbamoylalkyl" refers to an alkyl group in which one, two, or three of the alkyl group's hydrogen atoms are replaced by a carbamoyl group. Preferred, but non-limiting, examples of carbamoylalkyl are carbamoylmethyl, 1-carbamoylethyl, and 2-carbamoylethyl.

[0021] The term "carboxyalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced with a carboxy group. Preferably, "carboxyalkyl" refers to an alkyl group in which one, two, or three of the alkyl group's hydrogen atoms have been replaced with a carboxy group. Preferred, but non-limiting, examples of carboxyalkyl are carboxymethyl, 1-carboxyethyl, and 2-carboxyethyl.

[0022] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, ring system of 3 to 14 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 6 ring atoms, in which 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. More preferably, one of the ring atoms is N, and the remaining ring atoms are carbon. "Bicyclic heterocyclyl" refers to a heterocyclic moiety consisting of two rings having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., the two rings are joined through one common ring atom. Some non-limiting examples of heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, 2-oxopyrrolidin-1-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, 5-oxopyrrolidin-3-yl, 2-oxo-1-piperidyl, 2-oxo-3-piperidyl, 2-oxo-4-piperidyl, 6-oxo-2-piperidyl. , 6-oxo-3-piperidyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, morpholino, morpholin-2-yl, morpholin-3-yl, pyrrolidinyl (e.g., pyrrolidin-3-yl), piperazinyl (e.g., piperazin-1-yl), 3-azabicyclo[3.1.0]hexan-6-yl, or 2,5-diazabicyclo[2.2.1]heptan-2-yl. Particularly preferred, but non-limiting, examples of heterocyclyl include piperidyl and azetidinyl.

[0023] The term "heteroaryl" refers to a monovalent or polyvalent, monocyclic or bicyclic, preferably bicyclic, ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, more preferably 5 to 10 ring members, wherein at least one ring of the system is aromatic and at least one ring of the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5-10 membered heteroaryl containing 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl include 2-pyridyl, 3-pyridyl, 4-pyridyl, indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1,2-benzoxazol-3-yl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl, 1,2-benzoxazol-7-yl, 1H-ind ... Preferred, but non-limiting examples of "heteroaryl" include pyrazolyl, such as 1H-pyrazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-4-yl, and 1,2,4-oxadiazol-3-yl. Preferred, but non-limiting examples of "heteroaryl" include pyrazolyl, such as 1H-pyrazol-4-yl.

[0024] The term "hydroxy" refers to the group --OH.

[0025] The term "amino" refers to the group --NH.sub.2.

[0026] The term "cyano" refers to a -CN (nitrile) group.

[0027] The term "carbamoyl" refers to the group -C(O)NH2.

[0028] The term "carboxy" refers to the group --C(O)OH (ie, a carboxylic acid).

[0029] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by a halogen atom, most preferably fluoro. Particularly preferred, but non-limiting examples of haloalkyl are trifluoromethyl, trifluoroethyl, 2-fluoroethyl, and 2,2-difluoroethyl.

[0030] The term "cyanoalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced with a cyano group. Preferably, "cyanoalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced with a cyano group. Particularly preferred, but non-limiting, examples of cyanoalkyl are cyanomethyl, 1-cyanoethyl, and 2-cyanoethyl.

[0031] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group are replaced by a halogen atom, most preferably fluoro. Particularly preferred, but non-limiting examples of haloalkoxy are difluoromethoxy and trifluoromethoxy.

[0032] The term "alkoxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by an alkoxy group. Preferably, "alkoxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by an alkoxy group. A specific, non-limiting example of an alkoxyalkyl group is 2-methoxyethyl.

[0033] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a hydroxy group. Preferably, "hydroxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms, most preferably one hydrogen atom, of the alkyl group has been replaced by a hydroxy group. Preferred, but non-limiting, examples of hydroxyalkyl are hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), and 3-hydroxy-3-methyl-butyl.

[0034] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, especially hydrochloric acid, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, lactic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc. Particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid), and trifluoroacetate.

[0035] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0036] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom may be of the "R" or "S" configuration.

[0037] The term "treatment," as used herein, includes: (1) suppressing the symptom, disorder, or condition (e.g., in the case of maintenance treatment, arresting, reducing, or delaying the onset or recurrence of at least one clinical symptom or subclinical disease thereof); and / or (2) alleviating the condition (i.e., causing regression of the symptom, disorder, or condition, or at least one of its clinical symptoms or subclinical symptoms). The benefit to the patient to be treated is either statistically significant or at least discernible to the patient or physician. However, it will be understood that when a patient is administered a pharmaceutical agent to treat a disease, the outcome may not necessarily be effective treatment.

[0038] The term "prophylaxis" as used herein includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition that develops in a mammal, particularly in a human suffering from or susceptible to the condition, disorder or condition, but who has not yet experienced or exhibited clinical or asymptomatic symptoms of the condition, disorder or condition.

[0039] The term "mammal," as used herein, includes both humans and non-humans, including, but not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. In particularly preferred embodiments, the term "mammal" refers to humans.

[0040] The term "nosocomial infection" refers to a hospital-acquired infection (HAI), which is an infection acquired in a hospital or other health care facility. To emphasize both hospital and non-hospital settings, it is sometimes called a healthcare-associated infection (HAI or HCAI). Such infections may be acquired in hospitals, nursing homes, rehabilitation facilities, outpatient clinics, or other clinical settings.

[0041] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I) [ka] (In the formula, X 1 But N or CR 6 and X 2 But N or CR 7 and X 3 But N or CR 11 and X 4 But N or CR 12 and However, X 1 From X 4 at most one of is N, R 1 , R 2 and R 3 are each independently hydrogen, hydroxy, amino, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, carboxy-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy and groups [ka] is selected from R 4 is hydrogen or C1-C6-alkyl, R 5 is selected from hydrogen, halogen, cyano, C-C-alkyl, C-C-alkoxy, halo-C-C-alkyl, hydroxy-C-C-alkyl and halo-C-C-alkoxy, R 6 , R 7 , R 11 and R 12 are each independently selected from hydrogen, hydroxy, amino, halogen, cyano, C-C-alkyl, halo-C-C-alkyl, cyano-C-C-alkyl, hydroxy-C-C-alkyl, amino-C-C-alkyl, C-C-alkoxy and halo-C-C-alkoxy; R 8, R 9 and R 10 are each independently selected from hydrogen, halogen, cyano, amino, hydroxy, C-C-alkyl, halo-C-C-alkyl, cyano-C-C-alkyl, hydroxy-C-C-alkyl, amino-C-C-alkyl, C-C-alkoxy, halo-C-C-alkoxy and C-C-alkoxy-C-C-alkyl; R 13 , R 14 and R 15 are each independently selected from hydrogen, halogen, cyano, amino, hydroxy, C-C-alkyl, halo-C-C-alkyl, cyano-C-C-alkyl, hydroxy-C-C-alkyl, amino-C-C-alkyl, C-C-alkoxy and halo-C-C-alkoxy; A and C are each independently a 3- to 14-membered heterocycle; B is a 5- to 14-membered heteroaryl; L 1 and L 2 are each independently selected from a covalent bond, carbonyl, and C1-C6-alkyldiyl. or a pharmaceutically acceptable salt thereof.

[0042] In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the formula (II): [ka] is.

[0043] In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the formula (III): [ka] is.

[0044] In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the formula (IV): [ka] is.

[0045] In one embodiment, the present invention provides X 1 But, CR 6 That is, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0046] In one embodiment, the present invention provides X 2 But N or CR 7 That is, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0047] In one embodiment, the present invention provides X 3 But, CR 11 That is, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0048] In one embodiment, the present invention provides X 4 But, CR 12 That is, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0049] In one embodiment, the present invention provides R 1 is hydrogen, C1-C6-alkyl, hydroxy-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, carboxy-C1-C6-alkyl and groups [ka] Selected from: Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0050] In a preferred embodiment, the present invention comprises: R 1 But, [ka] That is, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0051] In one embodiment, the present invention provides R 2 is selected from hydrogen, C1-C6-alkyl and carboxy-C1-C6-alkyl, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0052] In a preferred embodiment, the present invention comprises: R 2 is selected from C1-C6-alkyl and carboxy-C1-C6-alkyl, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0053] In a particularly preferred embodiment, the present invention comprises: R 2 is selected from methyl and carboxymethyl; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0054] In one embodiment, the present invention provides R 3 is hydrogen, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0055] In one embodiment, the present invention provides R 4 is hydrogen, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0056] In one embodiment, the present invention provides R 5 is alkyl, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0057] In a preferred embodiment, the present invention comprises: R 5 is ethyl, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0058] In one embodiment, the present invention provides R 6 is hydrogen or halogen; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0059] In a preferred embodiment, the present invention comprises: R 6 is a halogen, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0060] In a particularly preferred embodiment, the present invention comprises: R 6 But it is fluoro. Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0061] In one embodiment, the present invention provides R 7 is hydrogen or halogen; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0062] In a preferred embodiment, the present invention comprises: R 7 is a halogen, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0063] In a particularly preferred embodiment, the present invention comprises: R 7 But it is fluoro. Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0064] In one embodiment, the present invention provides R 8 is selected from C1-C6-alkyl, halo-C1-C6-alkyl, cyano-C1-C6-alkyl and C1-C6-alkoxy-C1-C6-alkyl, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0065] In a preferred embodiment, the present invention comprises: R 8 is C1-C6-alkyl or C1-C6-alkoxy-C1-C6-alkyl, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0066] In a particularly preferred embodiment, the present invention comprises: R 8 is methyl or 2-methoxyethyl; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0067] In one embodiment, the present invention provides R 9 is hydrogen or C1-C6-alkyl, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0068] In a preferred embodiment, the present invention comprises: R 9 is hydrogen or methyl; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0069] In one embodiment, the present invention provides R 10 is hydrogen or C1-C6-alkyl, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0070] In a preferred embodiment, the present invention comprises: R 10 is hydrogen or methyl; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0071] In one embodiment, the present invention provides R 11 is hydrogen or halogen; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0072] In a preferred embodiment, the present invention comprises: R 11 is hydrogen, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0073] In one embodiment, the present invention provides R 12 is hydrogen or C1-C6-alkyl, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0074] In a preferred embodiment, the present invention comprises: R 12 is hydrogen, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0075] In one embodiment, the present invention provides R 13 is hydrogen, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0076] In one embodiment, the present invention provides R 14 is hydrogen, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0077] In one embodiment, the present invention provides R 15 is hydrogen, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0078] In one embodiment, the present invention provides L 1 is C1-C6-alkyldiyl, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0079] In a preferred embodiment, the present invention comprises: L 1 is -CH2-, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0080] In one embodiment, the present invention provides L 2 is C1-C6-alkyldiyl, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0081] In a preferred embodiment, the present invention comprises: L 2 is -CH2-, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0082] In one embodiment, the present invention provides A is piperidyl; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0083] In one embodiment, the present invention provides B is pyrazolyl; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0084] In one embodiment, the present invention provides C is azetidinyl; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0085] In one embodiment, the present invention provides X 1 But, CR 6 and X 2 But N or CR 7 and X 3 But, CR 11 and X 4 But, CR 12 and R 6 , R 7 , and R 11 are each independently hydrogen or halogen, and R 12 is hydrogen or C1-C6-alkyl, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0086] In a preferred embodiment, the present invention comprises: X 1 But, CR 6 and X 2 But N or CR 7 and X 3 But, CR 11 and X 4 But, CR 12 and R6 and R 7 is a halogen, and R 11 and R 12 is hydrogen, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0087] In a particularly preferred embodiment, the present invention comprises: X 1 But, CR 6 and X 2 But N or CR 7 and X 3 But, CR 11 and X 4 But, CR 12 and R 6 and R 7 is fluoro, and R 11 and R 12 is hydrogen, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0088] In one embodiment, the present invention provides R 1 is hydrogen, C1-C6-alkyl, hydroxy-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, carboxy-C1-C6-alkyl and groups [ka] is selected from R 2 is selected from hydrogen, C1-C6-alkyl and carboxy-C1-C6-alkyl, R 3 , R 13 , R 14 , and R 15 is hydrogen, L 1 and L 2are each independently C1-C6-alkyldiyl; A and C are each independently a 3- to 14-membered heterocycle; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0089] In a preferred embodiment, the present invention comprises: R 1 But, [ka] and R 2 is hydrogen, C1-C6-alkyl or carboxy-C1-C6-alkyl, R 3 , R 13 , R 14 , and R 15 is hydrogen, L 1 and L 2 are each independently C1-C6-alkyldiyl; A and C are each independently a 3- to 14-membered heterocycle; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0090] In a particularly preferred embodiment, the present invention comprises: R 1 But, [ka] and R 2 is methyl or carboxymethyl, R 3 , R 13 , R 14 , and R 15 is hydrogen, L 1 and L 2 is -CH2-, A is piperidyl, C is azetidinyl; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0091] In one embodiment, the present invention provides X 1 But, CR 6 and X 2 But N or CR 7 and X 3 But, CR 11 and X 4 But, CR 12 and R 1 is hydrogen, C1-C6-alkyl, hydroxy-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, carboxy-C1-C6-alkyl and groups [ka] is selected from R 2 is selected from hydrogen, C1-C6-alkyl and carboxy-C1-C6-alkyl, R 3 , R 4 , R 13 , R 14 and R 15 is hydrogen, R 5 is C1-C6-alkyl, R 6 , R 7 , and R 11 are each independently hydrogen or halogen; R 8 is selected from C-C-alkyl, halo-C-C-alkyl, cyano-C-C-alkyl and C-C-alkoxy-C-C-alkyl, R 9 , R 10 and R 12 are each independently hydrogen or C1-C6-alkyl, A and C are each independently a 3- to 14-membered heterocycle; B is a 5- to 14-membered heteroaryl; L 1 and L 2 are each independently C1-C6-alkyldiyl; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0092] In a preferred embodiment, the present invention comprises: X 1 But, CR 6 and X 2 But N or CR 7 and X 3 But, CR 11 and X 4 But, CR 12 and R 1 But, [ka] and R 2 is C1-C6-alkyl or carboxy-C1-C6-alkyl, R 3 , R 4 , R 11 , R 12 , R 13 , R 14 and R 15 is hydrogen, R 5 is C1-C6-alkyl, R 6 and R 7 is a halogen, R 8 is C1-C6-alkyl or C1-C6-alkoxy-C1-C6-alkyl, R 9 and R 10 are each independently hydrogen or C1-C6-alkyl, A and C are each independently a 3- to 14-membered heterocycle; B is a 5- to 14-membered heteroaryl; L 1 and L 2 are each independently C1-C6-alkyldiyl; Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0093] In a particularly preferred embodiment, the present invention comprises: X 1 But, CR 6 and X 2 But N or CR 7 and X 3 But, CR 11 and X 4 But, CR 12 and R 1 But, [ka] and R 2 is methyl or carboxymethyl, R 3 , R 4 , R 11 , R 12 , R 13 , R 14 and R 15 is hydrogen, R 5 is ethyl, R 6 and R 7 But it is 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; L 1 and L 2is -CH2-, Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0094] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 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

[0095] 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.

[0096] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 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, 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, and

[0097] 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.

[0098] In one embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I) described herein, particularly a pharmaceutically acceptable salt selected from hydrochloride, fumarate, lactate (particularly derived from L-(+)-lactic acid), tartrate (particularly derived from L-(+)-tartaric acid), and trifluoroacetate. In a more particular embodiment, the present invention provides a compound of formula (I) described herein (i.e., as the "free base" or "free acid," respectively).

[0099] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms therein with atoms having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Exemplary isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0100] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may result in greater metabolic stability and may confer certain therapeutic advantages, for example, by increasing in vivo half-life or requiring lower dosages.

[0101] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples set forth below, substituting appropriate isotopically labeled reagents for previously employed non-isotopically labeled reagents.

[0102] Manufacturing Process The preparation of the compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the compounds of the present invention is shown in the following scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following process descriptions have the meanings previously indicated herein, unless otherwise indicated. More specifically, the compounds of formula (I) can be prepared by the methods shown below, the methods shown in the Examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. For literature-described reaction conditions affecting the described reactions, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition, Richard C. Larock, John Wiley & Sons, New York, NY. 2018). The inventors have found it convenient to carry out the reaction in the presence or absence of a solvent. There are no particular limitations on the nature of the solvent used, as long as it does not adversely affect the reaction or the reagents involved and is capable of dissolving the reagents to at least some extent. The reactions described can occur over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. It is convenient to carry out the reactions described at a temperature range between -78°C and reflux. The time required for the reaction can also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days will usually be sufficient to obtain the intermediates and compounds described. The reaction sequence is not limited to that shown in the schemes, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods similar to those shown below, methods described in the references or examples cited herein, or methods known in the art. [ka] In the formula, R 9 and R10 is as defined herein, preferably H or Me; X is halogen or H; R 8 is preferably C as defined herein 1-6 Alkyl, C 1-6 It is an alkoxy or a protecting group such as Boc or MOM.

[0103] Intermediate B compounds can be prepared according to the route in Scheme 1. 8 Alkylation of X with a substituted pyrazole analog (I) gives intermediate A, which can be coupled with building block (II) to give building block III. Boron esters (intermediate B) can then be achieved using a palladium catalyst and phosphine ligands. [ka] In the formula, R 5 is as defined herein, preferably Me, Et or halogen; R 1 is preferably C as defined herein 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Amine or C 1-6 It is an aminocarbonyl or a protecting group such as Boc, MOM, etc.

[0104] Compounds of intermediate C can be prepared according to the route of Scheme 2. 8-Chloro-3-iodo-imidazo[1,2-a]pyrazine (IV) can be reacted with 4-aminobenzoic acid analogue (V) to give building block VI, which can be coupled with amine building block VII with a condensing agent such as HATU / DIPEA in DMSO to give compounds of formula intermediate C1.

[0105] Removal of the protecting group under acidic conditions gives intermediate C2, which can be further reacted with R 1 Alkylation with X can give intermediate C. [ka] In the formula, R 9 and R 10 is as defined herein, preferably H or Me; X is halogen or H; R 8 is preferably C as defined herein 1-6 Alkyl or C 1-6 is alkoxy or a protecting group such as Boc or MOM, R 1 is preferably C as defined herein 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Amine or C 1-6 aminocarbonyl or a protecting group such as Boc or MOM; R 5 is as defined herein, preferably Me, Et or halogen.

[0106] Intermediate D can be prepared according to the route in Scheme 3. The Suziki coupling of intermediate C with a boronic ester (intermediate B) can be achieved using a palladium catalyst and a phosphine ligand to give a compound of formula intermediate D. [ka] In the formula, R 9 and R 10 is as defined herein, preferably H or Me; R 8 is preferably C as defined herein 1-6 Alkyl or C 1-6 is alkoxy or a protecting group such as Boc or MOM, R 1 is preferably C as defined herein 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Amine or C1-6 aminocarbonyl or a protecting group such as Boc or MOM; R 5 is as defined herein, preferably Me, Et or halogen.

[0107] Intermediate F can be prepared according to the route of Scheme 4. Suzuki coupling of intermediate C with aza-arylboronic ester (VIII) can be achieved using a palladium catalyst and a phosphine ligand to give a compound of formula (Intermediate E). Intermediate I can then undergo further Suzuki coupling using a classical palladium catalyst system to give a compound of formula Intermediate F. [ka] In the formula, R 9 and R 10 is as defined herein, preferably H or Me; X is halogen or H; R 8 is preferably C as defined herein 1-6 Alkyl or C 1-6 is alkoxy or a protecting group such as Boc or MOM, R 1 is preferably C as defined herein 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Amine or C 1-6 aminocarbonyl or a protecting group such as Boc or MOM; R 5 is as defined herein, preferably Me, Et or halogen.

[0108] Examples A-D can be prepared according to the route in Scheme 5. Methylation of intermediates D and F can be achieved under mild conditions such as with DIPEA in acetonitrile at room temperature with MeI. Removal of the protecting groups can be performed before or after the methylation step based on different substitutions. In one aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (iii) heteroaryl halide C1 (wherein R 1 From R 5 , A and L 1 is as defined herein, and "Hal" is a halogen, preferably iodine; [ka] Boronic acid (ester) B1 (wherein X 1 From X 4 , R 8 From R 10 and Ring B is as defined herein, and each R is independently hydrogen or alkyl, and two R groups together with the oxygen and boron atoms to which they are attached may form a cyclic boronic ester; [ka] Suzuki coupling 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 give said compound of formula (I), or (iv) Aryl / heteroaryl halide E1 (wherein R 1 From R 5 , A, L 1 and X 1 From X 4 is as defined herein and "Hal" is a halogen, preferably chlorine; [ka] Boronic acid (ester) I1 (wherein R 8 From R 10 and Ring B is as defined herein, and each R is independently hydrogen or alkyl, and two R groups together with the oxygen and boron atoms to which they are attached may form a cyclic boronic ester; [ka] Suzuki coupling 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 give the compound of formula (I), Provided is a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein.

[0109] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when prepared according to the process described herein.

[0110] Uses of the Compounds of the Invention As shown in the experimental section, the compounds of formula (I) and their pharmaceutically acceptable salts possess valuable pharmacological properties for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more particularly Acinetobacter species, and most particularly Acinetobacter baumannii, including bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0111] The compounds of formula (I) and their pharmaceutically acceptable salts exhibit activity as antibiotics, particularly as antibiotics against Acinetobacter species, more particularly as antibiotics against Acinetobacter baumannii, and most particularly as pathogen-specific antibiotics against Acinetobacter baumannii.

[0112] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as antibiotics, i.e., as suitable antibacterial pharmaceutical ingredients in the treatment and prevention of bacterial infections, in particular bacterial infections caused by Acinetobacter species, more particularly bacterial infections caused by Acinetobacter baumannii.

[0113] The compounds of the present invention can be used, alone or in combination with other drugs, for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0114] In one aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0115] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as an antibiotic.

[0116] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of hospital-acquired infections and diseases resulting therefrom.

[0117] In certain embodiments, the nosocomial infections and diseases resulting therefrom are selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, or combinations thereof.

[0118] In a further aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections caused by Gram-negative bacteria and diseases resulting therefrom.

[0119] In certain embodiments, said infections and diseases caused by Gram-negative bacteria are selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, or combinations thereof.

[0120] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections and diseases resulting therefrom caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0121] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infection and resultant disease caused by Acinetobacter baumannii or Pseudomonas aeruginosa, or a combination thereof.

[0122] In a further preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections and resultant diseases caused by Pseudomonas aeruginosa.

[0123] In a further preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infection and resultant disease caused by Acinetobacter baumannii.

[0124] In a further aspect, the present invention provides a method for the treatment or prevention of infections and diseases resulting therefrom caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, comprising administering to a mammal a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0125] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, as an antibiotic.

[0126] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of infections and diseases resulting therefrom caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0127] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment or prevention of infections and diseases resulting therefrom caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0128] In certain embodiments, the infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, or Escherichia coli, or combinations thereof, are selected from bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, or combinations thereof.

[0129] In a further aspect, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections caused by pathogens, in particular bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, and diseases resulting therefrom, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0130] In a further aspect, the present invention provides a method for the treatment or prevention of infections and diseases resulting therefrom caused by pathogens, particularly bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, which method comprises administering to a mammal a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0131] In a further aspect, the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of infections caused by pathogens, in particular bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, and diseases resulting therefrom, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0132] In a further aspect, the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections. Such a medicament comprises a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0133] Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Exemplary pharmaceutical compositions are described in Examples 1-4.

[0134] In a further aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, for the treatment or prevention of infections caused by pathogens, in particular bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, and diseases resulting therefrom, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0135] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatin capsules, liquids, emulsions, or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration can also be carried out parenterally, for example, intramuscularly or intravenously (e.g., in the form of injections or infusions).

[0136] The compound of formula (I) and its pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic additives for the preparation of tablets, coated tablets, dragees, and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such additives for tablets, dragees, and hard gelatin capsules.

[0137] Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances, and liquid polyols.

[0138] Suitable additives for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose etc.

[0139] Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0140] Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0141] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants, and may also contain other therapeutically valuable substances.

[0142] The dosage can vary widely and will of course be adapted to the individual requirements of each particular case.Generally, for oral administration, a daily dosage of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (for example, about 300 mg / person) will be appropriate, preferably divided into 1 to 3 individual dosages, for example, of the same amount.However, it is clear that the upper limit given herein can be exceeded in indicated cases.

[0143] Co-administration of Compounds of Formula (I) with Other Drugs The compound of Formula (I) or its salt, or the compounds disclosed herein or their pharmaceutically acceptable salts, can be used alone or in combination with other drugs for treatment. For example, the second drug in a combined pharmaceutical formulation or administration regimen may have complementary activity to the compound of Formula (I) so that they do not adversely affect each other. The compounds may be administered together in a single pharmaceutical composition or separately. In one embodiment, the compound or its pharmaceutically acceptable salt can be co-administered with an antibiotic, particularly for the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, or Escherichia coli, or a combination thereof.

[0144] The term "co-administering" refers to simultaneous administration or any manner of separate, consecutive administration of the compound of formula (I) or its salt, or the compound disclosed herein or its pharmaceutically acceptable salt, and one or more additional active pharmaceutical ingredients, including antibiotic preparations.If administration is not simultaneous, the compounds are administered close to each other in time.In addition, it is not important whether the compounds are administered in the same dosage form, for example, one compound may be administered intravenously and another compound may be administered orally.

[0145] Typically, drugs with antibacterial activity may be co-administered. Specific examples of such drugs are carbapenems (meropenem), fluoroquinolones (ciprofloxacin), aminoglycosides (amikacin), tetracyclines (tigecycline), colistin, sulbactam, sulbactam plus durrobactam, cefiderocol (fetroja), macrocyclic peptides, and macrolides (erythromycin), as exemplified, for example, in WO2017072062, WO2019185572, and WO2019206853.

[0146] In one aspect, the present invention provides a pharmaceutical composition as described herein, further comprising an additional therapeutic agent.

[0147] In one aspect, the present invention provides a pharmaceutical combination comprising a compound of formula (I) as described herein and an additional therapeutic agent.

[0148] In one embodiment, the additional therapeutic agent is an antibiotic agent.

[0149] In one embodiment, the additional therapeutic agent is an antibiotic agent useful for the treatment or prevention of infection and disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, or Escherichia coli, or a combination thereof.

[0150] In one embodiment, the additional therapeutic agent is an antibiotic agent selected from a carbapenem (meropenem), a fluoroquinolone (ciprofloxacin), an aminoglycoside (amikacin), a tetracycline (tigecycline), colistin, sulbactam, sulbactam plus durrobactam, cefiderocol (fetroja), a macrocyclic peptide, and a macrolide (erythromycin), as exemplified in WO2017072062, WO2019185572, and WO2019206853. [Example]

[0151] Example The present invention will be more fully understood by reference to the following examples, which, however, should not be construed as limiting the scope of the claims to the examples.

[0152] Where preparations are obtained as mixtures of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0153] Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere.

[0154] The abbreviations used herein are as follows: ACN or MeCN acetonitrile BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene CFU colony forming units d day DCM dichloromethane DIPEA N,N-Diisopropylethylamine EtOAc or EA ethyl acetate FA formic acid h(s) or hr(s) hours HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC: High-performance liquid chromatography HPLC-UV: High-performance liquid chromatography with ultraviolet detection IC50 half-maximal inhibitory concentration IC90 90% inhibitory concentration PE Petroleum Ether PdCl2(DPPF)1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) PG protecting group Precat Precatalyst prep-HPLC Preparative High Performance Liquid Chromatography rt room temperature sat saturation SEM 2-Methoxyethyl(trimethyl)silane FA formic acid TFA trifluoroacetic acid wt weight X-PHOS 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0155] Intermediate A1 1-(2-Methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole To a 25 mL microwave vial was added 3-methyl-4-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 9.61 mmol), 1-bromo-2-methoxyethane (1.74 g, 12.5 mmol), K2CO3 (1.73 g, 12.5 mmol), and potassium iodide (319 mg, 1.92 mmol) in DMF (15 mL). The vial was capped and heated in a microwave at 100 °C for 15 h. The reaction mixture was filtered through glass fiber paper. The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 40% EtOAc in hexanes) to give 2 g of crude product, which was purified by preparative HPLC to give 1-(2-methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (550 mg, 2.07 mmol, 21.5% yield) and 1-(2-methoxyethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (316 mg, 1.19 mmol, 12.4% yield). MS [M+H] + :280.3.

[0156] Intermediate A2 1-(2-Methoxyethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole To a 25 mL microwave vial was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 9.01 mmol), 1-bromo-2-methoxyethane (1.63 g, 11.7 mmol), K2CO3 (1.62 g, 11.7 mmol), and potassium iodide (299 mg, 1.8 mmol) in DMF (15 mL). The vial was capped and heated in a microwave at 100 °C for 15 h. The reaction mixture was filtered through glass fiber paper. The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 40% EtOAc in hexanes) to give 1-(2-methoxyethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.5 g, 5.35 mmol, 59.5% yield). MS [M+H] + :281.1.

[0157] Intermediate A3 Trimethyl-[2-[[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methoxy]ethyl]silane In a 100 mL round-bottom flask, 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 7.21 mmol), SEM-Cl (1.56 g, 1.66 mL, 9.37 mmol), and DIPEA (2.8 g, 3.78 mL, 21.6 mmol) were combined with DCM (30 mL) to give a colorless solution. The reaction was stirred at room temperature for 2 hours. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 30% DCM in PE). Trimethyl-[2-[[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methoxy]ethyl]silane (2.4 g, 98.4% yield) was obtained. MS [M+H] + :339.4.

[0158] Intermediate B1 2-[[4-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane Step 1: 2-[[4-(4-bromo-2,3-difluorophenyl)-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane To a 25 mL microwave vial was added 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1 g, 2.96 mmol), 1,4-dibromo-2,3-difluorobenzene (1.61 g, 5.91 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (193 mg, 296 μmol), and Na2CO3 (940 mg, 8.87 mmol) in dioxane (15 mL) / water (1.5 mL). The vial was capped and heated in a microwave at 100 °C for 2 h under N2. The reaction mixture was filtered through glass fiber paper. The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 25% to 80% DCM in PE) to give 2-[[4-(4-bromo-2,3-difluorophenyl)-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (324 mg, 803 μmol, 27.2% yield). MS [M+H] + :405.1.

[0159] Step 2: 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane In a 100 mL round-bottom flask, bis(pinacolato)diboron (265 mg, 1.04 mmol), 4-(4-bromo-2,3-difluorophenyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (324 mg, 803 μmol), PdCl(dppf)-CHCl adduct (58.8 mg, 80.3 μmol), and potassium acetate (237 mg, 2.41 mmol) were combined with dioxane (10 mL) to give a dark red solution. The mixture was heated to 80 °C and stirred under N for 15 h. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 30% to 80% PE in DCM) to give 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (350 mg, 777 μmol, 96.7% yield). MS [M+H] + :451.3.

[0160] The following intermediates were prepared similarly: [Table 1]

[0161] Intermediates C1 and C2 tert-Butyl 4-[[2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoyl] Amino]methyl]piperidine-1-carboxylate (Intermediate C1) 2-Ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]-N-(4-piperidylmethyl)benzamide (Intermediate C2) Step 1: 2-Ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoic acid 4-Amino-2-ethylbenzoic acid (3 g, 18.2 mmol) and 8-chloro-3-iodoimidazo[1,2-a]pyrazine (5.33 g, 19.1 mmol) were suspended in MeCN (33 mL) and AcOH (3.3 mL). The mixture was heated at 100 °C in a sealed microwave tube for 18 hours and then cooled to room temperature. The precipitate was collected by filtration and washed with ether (30 mL × 3). The cake was dried in vacuo to give the product, 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid (7.08 g, 95.5% yield).

[0162] Step 2: tert-butyl 4-((2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzamido)methyl)piperidine-1-carboxylate In a 50 mL round-bottom flask, 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid (287 mg, 703 μmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (196 mg, 914 μmol), HATU (348 mg, 914 μmol), and DIPEA (273 mg, 368 μl, 2.11 mmol) were combined with DMF (5 mL) to give a light brown solution. The reaction was stirred at room temperature for 30 minutes. The reaction mixture was poured into 25 mL of HO and extracted with EtOAc (25 mL × 3). The organics were combined, washed with saturated NaCl (25 mL), dried over NaSO, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 5% MeOH in DCM) to give tert-butyl 4-((2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzamido)methyl)piperidine-1-carboxylate (363 mg, 601 μmol, 85.4% yield). MS [M+H] + :605.4.

[0163] Step 3: 2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]-N-(4-piperidylmethyl)benzamide In a 50 mL round-bottom flask, tert-butyl 4-((2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzamido)methyl)piperidine-1-carboxylate (240 mg, 397 μmol) was combined with THF (4 mL) to give a pale yellow solution. HCl (in water) (1.65 mL, 19.9 mmol) was added. The reaction was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated in vacuo. The crude product was used directly in the next step to give 2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]-N-(4-piperidylmethyl)benzamide (200 mg, 397 μmol, 99.9% yield). MS [M+H] + :505.0

[0164] Intermediate C3 tert-Butyl 3-[[4-[[[2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate In a 100 mL round-bottom flask, 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)-N-(piperidin-4-ylmethyl)benzamide (200 mg, 397 μmol), tert-butyl 3-formylazetidine-1-carboxylate (220 mg, 1.19 mmol), and NaBHCN (125 mg, 1.98 mmol) were combined with MeOH (10 mL) to give a light brown solution. The reaction mixture was heated to 45 °C and stirred for 3 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 25 mL of HO and extracted with EtOAc (25 mL × 3). The organic layers were combined, washed with saturated NaCl (25 mL), dried over NaSO, and concentrated in vacuo to give tert-butyl 3-[[4-[[[2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate (160 mg, 238 μmol, 59.9% yield). MS [M+H] + :674.2.

[0165] Intermediate C4 tert-Butyl 2-[4-[[[2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoyl]amino]methyl]-1-piperidyl]acetate In a 50 mL round-bottom flask, 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)-N-(piperidin-4-ylmethyl)benzamide (120 mg, 238 μmol) and DIPEA (40 mg, 54 μl, 309 μmol) were combined with DMF (3 mL) to give a light brown solution, and tert-butyl 2-bromoacetate (60.3 mg, 309 μmol) was added. The reaction was stirred at room temperature for 1 h. The reaction mixture was poured into 25 mL of HO and extracted with EtOAc (25 mL × 3). The organic layers were combined and washed with saturated NaCl (25 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give tert-2-[4-[[[2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoyl]amino]methyl]-1-piperidyl]butyl acetate (112 mg, 181 μmol, 76.1% yield). MS [M+H] + :619.2.

[0166] Intermediate C5 N-[[1-(2-amino-2-oxo-ethyl)-4-piperidyl]methyl]-2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzamide In a 50 mL round-bottom flask, 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)-N-(piperidin-4-ylmethyl)benzamide (140 mg, 278 μmol) and DIPEA (46.6 mg, 63 μl, 361 μmol) were combined with DMF (3 mL) to give a light brown solution. 2-Iodoacetamide (56.5 mg, 305 μmol) was added. The reaction was stirred at room temperature for 1 h. The reaction mixture was poured into 25 mL of HO and extracted with EtOAc (25 mL × 3). The organic layers were combined and washed with saturated NaCl (25 mL). The organic layer was dried over NaSO and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to give N-[[1-(2-amino-2-oxo-ethyl)-4-piperidyl]methyl]-2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzamide (112 mg, 199 μmol, 71.9% yield). MS [M+H] + :562.2.

[0167] Intermediate D1 tert-Butyl 3-[[4-[[[4-[[3-[2,3-difluoro-4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate To a 25 mL microwave vial was added tert-butyl 3-((4-((2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzamido)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (75 mg, 111 μmol), 4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (100 mg, 223 μmol), PdCl(dppf)-CHCl adduct (8.15 mg, 11.1 μmol), and NaCO (35.4 mg, 334 μmol) along with dioxane (10 mL) and water (1 mL). The vial was capped and heated in a microwave at 100 °C for 2 hours under N2. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 10% MeOH in DCM) to give tert-butyl 3-[[4-[[[4-[[3-[2,3-difluoro-4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate (39 mg, 44.8 μmol, 40.3% yield). MS [M+H] + :870.6.

[0168] The following intermediates were prepared similarly: [Table 2-1] [Table 2-2]

[0169] Intermediate E1 tert-Butyl 3-[[4-[[[4-[[3-(6-chloro-2-fluoro-3-pyridyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate To a 25 mL microwave vial was added tert-butyl 3-((4-((2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzamido)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (100 mg, 148 μmol) and (6-chloro-2-fluoropyridin-3-yl)boronic acid (28.6 mg, 163 μmol), PdCl(DPPF)-CHCl adduct (21.7 mg, 29.7 μmol), and NaCO (47.2 mg, 445 μmol) in dioxane (10 mL) / water (1 mL). The vial was capped and heated in a microwave at 100 °C for 2 h under N. The reaction mixture was used directly in the next step. MS [M+H] + :677.5.

[0170] The following intermediates were prepared similarly: [Table 3]

[0171] Intermediate F1 tert-Butyl 3-[[4-[[[2-ethyl-4-[[3-[2-fluoro-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate To a 25 mL microwave vial was added tert-butyl 3-((4-((4-((3-(6-chloro-2-fluoropyridin-3-yl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (101 mg, 149 μmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (46.5 mg, 224 μmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (9.72 mg, 14.9 μmol) and NaCO (31.6 mg, 298 μmol) along with dioxane (10 mL) / water (1 mL). The vial was capped and heated in a microwave at 110 °C for 2 hours under N2. The reaction mixture was filtered through glass fiber paper. The crude filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 20% MeOH in DCM) to give tert-butyl 3-[[4-[[[2-ethyl-4-[[3-[2-fluoro-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate (60 mg, 83 μmol, 55.7% yield). MS [M+H] + :723.5.

[0172] The following intermediates were prepared similarly: [Table 4]

[0173] Intermediate G1 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-methyl-4-piperidyl)methyl]benzamide Step 1: 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-(4-piperidylmethyl)benzamide In a 50 mL round-bottom flask, tert-butyl 4-((4-((3-(2,3-difluoro-4-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)methyl)piperidine-1-carboxylate (275 mg, 377 μmol) was combined with THF (2 mL) to give a light brown solution. HCl (1.89 mL, 22.6 mmol) was added. The reaction was stirred at room temperature for 20 minutes. The crude reaction mixture was concentrated in vacuo. The crude product was used directly in the next step to give 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-(4-piperidylmethyl)benzamide (237 mg, 377 μmol, 99.9% yield). MS [M+H] + :629.5.

[0174] Step 2: 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-methyl-4-piperidyl)methyl]benzamide In a 50 mL round-bottom flask, 4-((3-(2,3-difluoro-4-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethyl-N-(piperidin-4-ylmethyl)benzamide (237 mg, 377 μmol), formaldehyde (153 mg, 1.88 mmol), and NaBHCN (118 mg, 1.88 mmol) were combined with MeOH (6 mL) to give a light brown solution. The reaction mixture was heated to 50 °C and stirred for 20 minutes. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 25 mL of saturated NaHCO and extracted with EtOAc (25 mL × 3). The organic layers were combined and washed with saturated NaCl (25 mL). Drying over Na2SO4 and concentration in vacuo gave 4-((3-(2,3-difluoro-4-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethyl-N-((1-methylpiperidin-4-yl)methyl)benzamide (242 mg, 377 μmol, 99.9% yield). MS [M+H] + :643.4.

[0175] The following intermediates were prepared similarly: [Table 5]

[0176] Example A1 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;Formic acid [ka] In a 100 mL round-bottom flask, tert-butyl 3-((4-((4-((3-(2,3-difluoro-4-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (39 mg, 44.8 μmol) was combined with DCM (3 mL) to give a light brown solution. 2,2,2-Trifluoroacetic acid (1.02 g, 8.96 mmol) was added. The reaction was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to give 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; formic acid (9 mg, 10.2 μmol, 22.7% yield). MS [M+H]+: 640.2.

[0177] Example A2 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;Formic acid;Formic acid salt [ka]

[0178] Step 1: tert-Butyl 3-[[4-[[[4-[[3-[2,3-difluoro-4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-methyl-piperidin-1-ium-1-yl]methyl]azetidine-1-carboxylate; iodide In a 50 mL round-bottom flask, tert-butyl 3-((4-((4-((3-(2,3-difluoro-4-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (29 mg, 33.3 μmol) and MeI (23.7 mg, 167 μmol) and DIPEA (21.5 mg, 167 μmol) were combined with MeCN (3 mL) to give a light brown solution. The reaction was stirred at room temperature for 2 hours. The crude reaction mixture was concentrated in vacuo to give tert-butyl 3-[[4-[[[4-[[3-[2,3-difluoro-4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-methyl-piperidin-1-ium-1-yl]methyl]azetidine-1-carboxylate; iodide (29.5 mg, 33.3 μmol, 100% yield). MS [M+H] + :884.9.

[0179] Step 2: 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; formic acid; formate salt In a 50 mL round-bottom flask, 1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-4-((4-((3-(2,3-difluoro-4-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)methyl)-1-methylpiperidin-1-ium (29.5 mg, 33.3 μmol) and HCl in water (1.11 mL, 13.3 mmol) were combined with THF (2 mL) to give a light brown solution. HCl in water (1.11 mL, 13.3 mmol) was added. The reaction was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to give 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; formic acid; formate salt (9.4 mg, 12.4 μmol, 37.1% yield). MS: 654.8.

[0180] The following compounds were prepared similarly: [Table 6-1] [Table 6-2] [Table 6-3]

[0181] Example B1 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;Formic acid;Formic acid salt [ka]

[0182] Step 1: tert-butyl 4-(5-(8-((4-(((1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)carbamoyl)-3-ethylphenyl)amino)imidazo[1,2-a]pyrazin-3-yl)-6-fluoropyridin-2-yl)-3-methyl-1H-pyrazole-1-carboxylate In a 50 mL round-bottom flask, BocO (24.2 mg, 111 μmol), tert-butyl 3-((4-((2-ethyl-4-((3-(2-fluoro-6-(3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)imidazo[1,2-a]pyrazin-8-yl)amino)benzamido)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (40 mg, 55.3 μmol), DMAP (2.03 mg, 16.6 μmol), and DIPEA (21.5 mg, 166 μmol) were combined with THF (3 mL) to give a light brown solution. The reaction mixture was stirred at 50° C. for 2 h. The crude reaction mixture was concentrated in vacuo to give tert-butyl 4-(5-(8-((4-(((1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)carbamoyl)-3-ethylphenyl)amino)imidazo[1,2-a]pyrazin-3-yl)-6-fluoropyridin-2-yl)-3-methyl-1H-pyrazole-1-carboxylate (45.5 mg, 55.3 μmol, 99.9% yield). MS: 823.7.

[0183] Step 2: tert-Butyl 3-[[4-[[[4-[[3-[6-(1,3-dimethylpyrazol-4-yl)-2-fluoro-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-methyl-piperidin-1-ium-1-yl]methyl]azetidine-1-carboxylate; iodide In a 50 mL round-bottom flask, tert-butyl 4-(5-(8-((4-(((1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)carbamoyl)-3-ethylphenyl)amino)imidazo[1,2-a]pyrazin-3-yl)-6-fluoropyridin-2-yl)-3-methyl-1H-pyrazole-1-carboxylate (45 mg, 54.7 μmol), MeI (38.8 mg, 17.1 μl, 273 μmol), and DIPEA (35.3 mg, 47.8 μl, 273 μmol) were combined with MeCN (5 mL) to give a pale red solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo. The crude product was used directly in the next step to give tert-butyl 3-[[4-[[[4-[[3-[6-(1,3-dimethylpyrazol-4-yl)-2-fluoro-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-methyl-piperidin-1-ium-1-yl]methyl]azetidine-1-carboxylate iodide (45.8 mg, 54.7 μmol, 100% yield). MS: 837.7.

[0184] Step 3: 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; formic acid; formate salt In a 50 mL round-bottom flask, 4-((4-((3-(6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrazol-4-yl)-2-fluoropyridin-3-yl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)methyl)-1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1-methylpiperidin-1-ium (45 mg, 53.7 μmol) was combined with THF (2 mL) to give a pale red solution. HCl (1.34 mL, 16.1 mmol) was added. The reaction was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to give 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; formic acid; formate salt (6.6 mg, 8.87 μmol, 16.5% yield). MS: 637.

[0185] The following compounds were prepared similarly: [Table 7-1] [Table 7-2]

[0186] Example C1 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; Formate [ka] In a 50 mL round-bottom flask, 4-((3-(2,3-difluoro-4-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethyl-N-((1-methylpiperidin-4-yl)methyl)benzamide (60 mg, 93.3 μmol), MeI (66.2 mg, 29.2 μl, 467 μmol) and DIPEA (60.3 mg, 81.5 μl, 467 μmol) were combined with MeCN (5 mL) to give a light brown solution. The reaction was stirred at room temperature for 15 hours. The crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to give 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; formate salt (10.6 mg, 14.8 μmol, 15.8% yield). MS: 657.5.

[0187] The following compounds were prepared similarly: [Table 8-1] [Table 8-2]

[0188] Example D1 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; formate [ka] Step 1: N-((1-(2-amino-2-oxoethyl)piperidin-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-ethylbenzamide In a 50 mL round-bottom flask, N-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-4-((3-(2,3-difluoro-4-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide (14 mg, 18.5 μmol) and HCl (462 μL, 5.54 mmol) were combined with THF (2 mL) to give a light brown solution. The reaction mixture was heated to 45° C. and stirred for 15 h. The crude reaction mixture was concentrated in vacuo to give N-((1-(2-amino-2-oxoethyl)piperidin-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-ethylbenzamide (11.6 mg, 18.5 μmol, 100% yield). MS [M+H] + :628.5.

[0189] Step 2: N-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-4-((3-(4-(1-(cyanomethyl)-3-methyl-1H-pyrazol-4-yl)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide In a 50 mL round-bottom flask, N-((1-(2-amino-2-oxoethyl)piperidin-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-ethylbenzamide (11.6 mg, 18.5 μmol), 3-bromoprop-1-yne (4.4 mg, 37 μmol), and DIPEA (7.17 mg, 9.68 μl, 55.4 μmol) were combined with DCM (2 mL) to give a light brown solution. The reaction was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated in vacuo to give N-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-4-((3-(4-(1-(cyanomethyl)-3-methyl-1H-pyrazol-4-yl)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide (12.3 mg, 18.4 μmol, 99.8% yield). MS [M+H] + :667.8

[0190] Step 3: 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; formate In a 50 mL round-bottom flask, N-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-4-((3-(4-(1-(cyanomethyl)-3-methyl-1H-pyrazol-4-yl)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide (12.3 mg, 18.4 μmol), MeI (13.1 mg, 92.2 μmol), and DIPEA (11.9 mg, 16.1 μl, 92.2 μmol, Formula 5) were combined with MeCN (3 mL) to give a pale yellow solution. The reaction mixture was heated to 45° C. and stirred for 15 hours. The crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to give 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; formate salt (6 mg, 7.84 μmol, 42.5% yield). MS: 681.5.

[0191] Assay procedure Antimicrobial susceptibility testing: Determination of 90% growth inhibitory concentration (IC90) The in vitro antibacterial activity of the compounds was determined according to the following procedure: The assay quantitatively measured the in vitro activity of compounds against Acinetobacter baumannii ATCC17961 and Pseudomonas aeruginosa ATCC27853 using 10-point Iso-Sensitest broth medium.

[0192] Stock compounds in DMSO were serially diluted 2-fold in 384-well microtiter plates (e.g., final concentrations ranging from 50 to 0.097 μM) and 49 μl of bacterial suspension was plated in Iso-Sensitest medium to give a final cell concentration of ∼5x10 in a final volume / well of 50 μl / well. (5) The microtiter plates were incubated at 35±2°C.

[0193] Bacterial cell growth was determined by measuring the optical density at λ = 600 nm every 20 min over a 16 h time course. Growth inhibition was calculated during the logarithmic growth of bacterial cells, and concentrations that inhibited growth by 50% (IC50) and 90% (IC90) were determined.

[0194] Table 1 provides the 90% growth inhibitory concentrations (IC90) in micromoles per liter of compounds of the present invention obtained against Acinetobacter baumannii ATCC 17961 strain.

[0195] Certain compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17961) ≦25 μmol / l.

[0196] More particular compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17961) ≦5 μmol / l.

[0197] Most specific compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17961) ≦1 μmol / l.

[0198] Table 2 shows the 90% growth inhibitory concentrations (IC90) in micromoles per liter of compounds of the invention obtained against Pseudomonas aeruginosa ATCC 27853 strain. [Table 9] [Table 10]

[0199] Example 1 The compounds of formula (I) can be used in a manner known per se as active ingredient to produce tablets of the following composition: Per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0200] Example 2 The compound of formula (I) can be used in a manner known per se as an active ingredient to produce capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg Example 2 Example 3 The compounds of formula (I) can be used in known manner as active ingredients for the production of injection solutions of the following compositions: Active ingredient 100mg Lactic acid 90% 100mg Add an appropriate amount of NaOH or HCl to adjust the pH to 4.0 Sodium chloride or glucose to adjust osmolality to 290mOsm / kg Add 100ml of water for injection (WFI)

[0201] Example 4 The compounds of formula (I) can be used in known manner as active ingredients for the preparation of injection solutions of the following compositions: Active ingredient 100mg Hydroxypropyl-β-cyclodextrin 10g Add an appropriate amount of NaOH or HCl to adjust the pH to 7.4 Sodium chloride or glucose to adjust osmolality to 290mOsm / kg Add 100ml of water for injection (WFI)

Claims

1. Compounds of formula (I) 【Chemistry 1】 (In the formula, X １ But, C-R ６ and X ２ But N or C-R ７ and X ３ But, C-R １１ and X ４ But, C-R １２ and R １ But 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 groups 【Chemistry 2】 is selected from R ２ But hydrogen, C １ -C ６ -alkyl, and carboxy-C １ -C ６ - alkyl, R ３ , R ４ , R １３ , R １４ and R １５ is hydrogen, R ５ But C １ -C ６ - alkyl, R ６ , R ７ , and R １１ are each independently hydrogen or halogen; R ８ But 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 is piperidyl, B is pyrazolyl; C is azetidinyl; L １ and L ２ However, each independently, C １ -C ６ -alkyldiyl) or a pharmaceutically acceptable salt thereof.

2. R １ But, 【Transformation 3】 That is, 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ２ But C １ -C ６ -alkyl, and carboxy-C １ -C ６ - selected from alkyl, 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R ２ is selected from methyl and carboxymethyl; A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. R ５ is ethyl, A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. R ６ is a halogen, A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. R ６ But it is fluoro. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. R ７ is a halogen, A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. R ７ But it is fluoro. A compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. R ８ But C １ -C ６ - alkyl or C １ -C ６ -alkoxy-C １ -C ６ - is alkyl, A compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. R ８ is methyl or 2-methoxyethyl; A compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. R ９ is hydrogen or methyl; 12. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. R １０ is hydrogen or methyl; A compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. R １１ is hydrogen, A compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. R １２ is hydrogen, A compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. L １ But -CH ２ -is, 16. A compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

17. L ２ But -CH ２ -is, 17. A compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

18. Compounds of formula (I) 【Chemistry 4】 (In the formula, X １ But, C-R ６ and X ２ But N or C-R ７ and X ３ But, C-R １１ and X ４ But, C-R １２ and R １ But, 【Transformation 5】 and R ２ But 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 is hydrogen, R ５ But C １ -C ６ - alkyl, R ６ and R ７ is a halogen, R ８ But 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 is piperidyl, B is pyrazolyl; C is azetidinyl; L １ and L ２ However, each independently, C １ -C ６ -alkyldiyl) or a pharmaceutically acceptable salt thereof.

19. Compounds of formula (I) 【Transformation 6】 (In the formula, X １ But, C-R ６ and X ２ But N or C-R ７ and X ３ But, C-R １１ and X ４ But, C-R １２ and R １ But, 【Transformation 7】 and R ２ is methyl or carboxymethyl, R ３ , R ４ , R １１ , R １２ , R １３ , R １４ and R １５ is hydrogen, R ５ is ethyl, R ６ and R ７ But it is 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; L １ and L ２ But -CH ２ - is) or a pharmaceutically acceptable salt thereof.

20. 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, A compound or a pharmaceutically acceptable salt thereof.

21. (i) heteroaryl halide C1 (wherein R １ From R ５ , A and L １ as defined in each claim, and "Hal" is halogen; 【Transformation 8】 Boronic acid (ester) B1 (wherein X １ From X ４ , R ８ From R １０ and Ring B is as defined in each claim, each R is independently hydrogen or alkyl, and two R groups together with the oxygen and boron atoms to which they are attached may form a cyclic boronic ester; 【Chemistry 9】 Suzuki coupling 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 give said compound of formula (I), or (ii) Aryl / heteroaryl halide E1 (wherein R １ From R ５ , A, L １ and X １ From X ４ is as defined in each claim, and "Hal" is halogen; 【Chemistry 10】 Boronic acid (ester) I1 (wherein R ８ From R １０ and Ring B is as defined in each claim, each R is independently hydrogen or alkyl, and two R groups together with the oxygen and boron atoms to which they are attached may form a cyclic boronic ester; 【Chemistry 11】 Suzuki coupling 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 give said compound of formula (I), A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20.

22. 22. The method of claim 21, wherein in the heteroaryl halide C1, "Hal" is iodine.

23. 22. The method of claim 21, wherein in the heteroaryl halide E1, "Hal" is chlorine.

24. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

25. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use as an antibiotic.

26. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of nosocomial infections and diseases resulting therefrom.

27. A pharmaceutical composition comprising a compound of formula (I) according to claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infectious diseases caused by gram-negative bacteria and diseases resulting therefrom.

28. 28. The pharmaceutical composition for use according to claim 27, wherein the Gram-negative bacteria is selected from Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species and Escherichia coli.

29. 29. The pharmaceutical composition for use according to claim 28, wherein the Gram-negative bacterium is Acinetobacter baumannii.

30. 21. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof.

31. A method for treating or preventing infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, or Escherichia coli, or a combination thereof, comprising administering to a mammal other than a human a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

32. 21. Use of a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of infections in non-humans caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, and diseases resulting therefrom.

33. 21. Use of a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment or prevention of infections and diseases resulting therefrom caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof.

Images