Imidazole-pyrazole derivatives as antibacterial agents

Abstract

The present invention relates to a compound represented by general formula (I) and pharmaceutically acceptable salts thereof, wherein A and R 1 ~R 7 is as described herein: Formula (I). Further provided are pharmaceutical compositions comprising the compounds, processes for 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 resultant diseases.

Description

[Technical Field]

[0001] The present invention relates to novel imidazole-pyrazole derivatives that exhibit antibacterial properties, as well as methods of using these compounds for the treatment or prevention of bacterial infections and resulting diseases, particularly infections caused by Acinetobacter baumannii and resulting diseases. [Background technology]

[0002] Acinetobacter baumannii is a Gram-negative, aerobic, non-fermenting bacterium that has been recognized over the past few decades as an emerging pathogen with severely limited treatment options.

[0003] A. baumannii is considered a serious threat by the U.S. Centers for Disease Control and Prevention and currently causes the majority of hospital-acquired infections, belonging to the so-called "ESKAPE" pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli) that effectively "escape" the activity of antimicrobial agents.

[0004] A. baumannii occurs most frequently in intensive care units and surgical wards, where widespread antibiotic use has allowed it to select for resistance to all known antimicrobial agents and can cause infections such as bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0005] A. baumannii has an extraordinary ability to upregulate and acquire resistance determinants and exhibits environmental persistence that allows it to survive and spread in hospital environments, making this organism a frequent cause of infectious disease outbreaks and a local healthcare-associated pathogen.

[0006] Due to increasing antibiotic resistance to most, if not all, available therapeutic options, multidrug-resistant (MDR) A. baumannii infections, particularly those caused by carbapenem-resistant A. baumannii, are extremely difficult or even impossible to treat, resulting in increased morbidity and length of stay in intensive care units, as well as high mortality.

[0007] According to the Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA), 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." Thus, there is a high demand and need to identify compounds suitable for the treatment of diseases and infections caused by Acinetobacter baumannii.

[0008] The present invention provides novel compounds that exhibit activity against drug-susceptible and drug-resistant strains of Acinetobacter baumannii. Summary of the Invention

[0009] In a first aspect, the present invention provides a compound of formula (I): [ka] (Wherein, A and R 1 ~R 7 are as described herein) or a pharmaceutically acceptable salt thereof.

[0010] In one aspect, the present invention provides a process for making a compound of formula (I) described herein.

[0011] In a further aspect, the present invention provides a compound of formula (I) as described herein when prepared according to the process described herein.

[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 as a therapeutically active substance.

[0013] 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.

[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 as an antibiotic.

[0015] 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 resultant diseases.

[0016] 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 resulting diseases caused by Gram-negative bacteria.

[0017] 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 infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or combinations thereof. DETAILED DESCRIPTION OF THE INVENTION

[0018] 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 in this specification (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 in this specification (including any accompanying claims, abstract, and drawings), or any novel or any novel combination of steps of any method or process so disclosed.

[0019] 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.

[0020] The term "alkyldiyl," as used herein, refers to a saturated, straight- or branched-chain divalent hydrocarbon radical of about 1 to 6 carbon atoms (C1-C6). Examples of alkyldiyl groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and the like. Alkyldiyl groups are sometimes referred to as "alkylene" groups.

[0021] 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 yet 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.

[0022] 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).

[0023] The term "aminoalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced with 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 with amino groups. Preferred, but non-limiting, examples of aminoalkyl are aminomethyl and 1-aminoethyl.

[0024] The term "aminoalkoxy" refers to an alkoxy group in which at least one of the alkoxy group's hydrogen atoms has been replaced with an amino group. Preferably, "aminoalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group have been replaced with amino groups. Preferred, but non-limiting, examples of aminoalkoxy are aminomethoxy and 1-aminoethoxy.

[0025] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic, preferably a monocyclic ring system of 3 to 10 ring atoms, preferably 3 to 8 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. "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 via one common ring atom. Some non-limiting examples of heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, pyrrolidinyl (e.g., pyrrolidin-2-yl), 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, piperazinyl, pyrrolidinyl, and 3-azabicyclo[3.1.0]hexan-6-yl.

[0026] 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 to 10-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5 to 10-membered heteroaryl containing 1 to 2 heteroatoms independently selected from O and N. Some preferred, but non-limiting, examples of heteroaryl include pyrimidinyl, pyrazolyl, pyridyl, pyrazinyl, imidazolyl, pyridazinyl, thiazolyl, and 1H-pyrazolo[3,4-d]pyrimidin-6-yl. Preferred, but non-limiting, examples of heteroaryl include pyridyl.

[0027] The term "hydroxy" refers to the group --OH.

[0028] The term "amino" refers to the group --NH.sub.2.

[0029] The term "cyano" refers to a -CN (nitrile) group.

[0030] The term "nitro" refers to the group -NO2.

[0031] The term "carbamoyl" refers to the group -C(O)NH2.

[0032] The term "carbonyl" refers to a carbon radical having two of its four covalent bonds shared with oxygen atoms (C=O).

[0033] 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. A particularly preferred, but non-limiting example of haloalkoxy is trifluoromethyl.

[0034] The term "haloalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced with a halogen atom, preferably fluoro. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group have been replaced with a halogen atom, most preferably fluoro. Particularly preferred, but non-limiting, examples of haloalkoxy are difluoromethoxy and trifluoromethoxy.

[0035] The term "alkoxyalkoxy" refers to an alkoxy group in which at least one of the alkoxy group's hydrogen atoms has been replaced with an alkoxy group, preferably methoxy. Preferably, "alkoxyalkoxy" refers to an alkoxy group in which one, two, or three of the alkoxy group's hydrogen atoms have been replaced with an alkoxy group, most preferably methoxy. A particularly preferred, but non-limiting example of an alkoxyalkyl is 2-methoxyethyl.

[0036] The term "alkoxyalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced with an alkoxy group. Preferably, "alkoxyalkyl" refers to an alkyl group in which one, two, or three of the alkyl group's hydrogen atoms have been replaced with an alkoxy group. A specific, non-limiting example of an alkoxyalkyl group is methoxymethyl.

[0037] 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.

[0038] The term "carbamoylalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced by a carbamoyl group. Preferably, "carbamoylalkyl" refers to an alkyl group in which one, two, or three, and most preferably one, hydrogen atom of the alkyl group has been replaced by a carbamoyl group. Preferred, but non-limiting, examples of carbamoylalkyl are 2-amino-2-oxo-ethyl, 3-amino-3-oxo-propyl, and 4-amino-4-oxo-butyl.

[0039] 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 hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid), and trifluoroacetate.

[0040] 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.

[0041] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom may be of the "R" or "S" configuration.

[0042] 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 medication to treat a disease, the outcome need not necessarily be effective treatment.

[0043] The term "prophylaxis" as used herein includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition in a mammal, particularly a human, who may be affected by or predisposed to the condition, disorder or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder or condition.

[0044] 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 a particularly preferred embodiment, the term "mammal" refers to humans.

[0045] 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 may alternatively be 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.

[0046] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I): [ka] (In the formula, R 1 and R 2 together with the nitrogen atom to which they are attached, represent the formula (II), (III) or (IV) [ka] or forming a group of R 1 is based [ka] and R 2 is selected from hydrogen and C1-C6 alkyl; R 3 is selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy; R 4 and R 6 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy; R 5a , R 5b and R 5c are each independently selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, amino-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl-, C1-C6 alkoxy-C1-C6 alkoxy-, amino, C1-C6 alkyl-NH-, (C1-C6 alkyl)2N-, C1-C6 alkyl-NH-C(O)-, C1-C6 alkyl-NH-C(O)-C1-C6 alkyl-NH-, amino-C1-C6 alkyl-NH-, C1-C6 alkoxy-C1-C6 alkyl-NH-, carbamoyl-C1-C6 alkyl-NH-, carbamoyl, and nitro; R 7 is selected from hydrogen, C1-C6 alkyl, and halo-C1-C6 alkyl; In formula (II), R 8a is C1-C6 alkyl, carbamoyl-C1-C6 alkyl and groups [ka] is selected from In formula (III), R 8a is hydrogen, C1-C6 alkyl, carbamoyl-C1-C6 alkyl and the group [ka] is selected from R 8b is hydrogen, hydroxy, hydroxy-C1-C6 alkyl, [ka] is selected from R 8c , R 12a and R 12c are independently C1-C6 alkyl, R 9a , R 9b , R 10a , R 10b and R 12b are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino, nitro, and hydroxy; R 11a and R 11b are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino, nitro, hydroxy, and a group [ka] is selected from X is carbonyl and Y is a covalent bond, -NH-, -N(C1-C6 alkyl)-, or C1-C6 alkyldiyl; or X is a C1-C6 alkyldiyl and Y is a covalent bond; L 1 and L 3are each independently selected from a covalent bond, carbonyl, and C1-C6 alkyldiyl; L 2 and L 4 are each independently selected from a covalent bond, carbonyl, —O—, —NH—C(O)—, —C(O)—NH—, and C1-C6 alkyldiyl; A and E are each independently a 5- to 14-membered heteroaryl; B, C, D, F, and G are each independently 3- to 14-membered heterocyclyl. or a pharmaceutically acceptable salt thereof.

[0047] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: R 1 and R 2 together with the nitrogen atom to which they are attached, represent the formula (II) or (III) [ka] or forming a group of R 1 is based [ka] and R 2 is selected from hydrogen and C1-C6 alkyl; R 3 is selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy; R 4 and R 6 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy; R 5a , R 5b and R 5care each independently selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, amino-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl-, C1-C6 alkoxy-C1-C6 alkoxy-, amino, C1-C6 alkyl-NH-, (C1-C6 alkyl)2N-, C1-C6 alkyl-NH-C(O)-, amino-C1-C6 alkyl-NH-, C1-C6 alkoxy-C1-C6 alkyl-NH-, carbamoyl-C1-C6 alkyl-NH-, carbamoyl and nitro; R 7 is selected from hydrogen, C1-C6 alkyl, and halo-C1-C6 alkyl; R 8a is hydrogen, C1-C6 alkyl, carbamoyl-C1-C6 alkyl, and the group [ka] is selected from R 8b is hydrogen, hydroxy, hydroxy-C1-C6 alkyl, [ka] is selected from R 8c and R 12c are independently C1-C6 alkyl, R 9a , R 9b , R 10a , R 10b , R 12a and R 12b are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino, nitro, and hydroxy; R 11a and R 11b are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino, nitro, hydroxy, and a group [ka] is selected from X is carbonyl and Y is a covalent bond or C1-C6 alkyldiyl; or X is a C1-C6 alkyldiyl and Y is a covalent bond; L 1 and L 3 are each independently selected from a covalent bond, carbonyl, and C1-C6 alkyldiyl; L 2 and L 4 are each independently selected from a covalent bond, carbonyl, —O—, —NH—C(O)—, —C(O)—NH—, and C1-C6 alkyldiyl; A and E are each independently a 5- to 14-membered heteroaryl; B, C, D, F and G are each independently 3- to 14-membered heterocyclyl.

[0048] In one embodiment, the compound of formula (I) has formula (II) [ka] (In the formula, R 13 is the base [ka] or base [ka] and R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R 7 , R 8a and R 8b is as defined herein) or a pharmaceutically acceptable salt thereof.

[0049] In one embodiment, the compound of formula (I) has formula (I-II): [ka] (In the formula, R 13 is the base [ka] or base [ka] and R 3 , R 5a , R 5b , R 5c , R 8a and R 8b is as defined herein) or a pharmaceutically acceptable salt thereof.

[0050] In one embodiment, the compound of formula (I) has formula (I-III): [ka] (In the formula, R 13 is the base [ka] or base [ka] and R 3 , R 5a , R 5b , R 5c , R 8a and R 8b is as defined herein) or a pharmaceutically acceptable salt thereof.

[0051] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: R 1 and R 2 together with the nitrogen atom to which they are attached, represent the formula (II), (III) or (IV) [ka] or forming a group of R 1 is based [ka] and R 2 is hydrogen, R 9a , R 9b , R 10b and R 11b are hydrogen, In formula (II), R 8a is C1-C6 alkyl, carbamoyl-C1-C6 alkyl and groups [ka] is selected from In formula (III), R 8a is hydrogen, C1-C6 alkyl, carbamoyl-C1-C6 alkyl and the group [ka] is selected from R 8b is hydrogen, hydroxy and radicals [ka] is selected from R 8c , R 12a and R 12c are independently C1-C6 alkyl, R 10a is selected from amino and nitro; R 11a is based [ka] and R12b is selected from hydrogen and hydroxy; X is carbonyl, Y is a covalent bond or a C1-C6 alkyldiyl; L 1 is C1-C6 alkyldiyl, L 2 is -O-, L 3 is a covalent bond, L 4 is a carbonyl, B, C, D, F, and G are each independently 3- to 14-membered heterocyclyl; E is a 5- to 14-membered heterocyclyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: R 1 and R 2 together with the nitrogen atom to which they are attached, represent the formula (II) or (III) [ka] or forming a group of R 1 is based [ka] and R 2 is hydrogen, R 9a , R 9b , R 10b and R 11b are hydrogen, In formula (II), R 8a is C1-C6 alkyl, carbamoyl-C1-C6 alkyl and groups [ka] is selected from In formula (III), R 8a is hydrogen, C1-C6 alkyl, carbamoyl-C1-C6 alkyl and the group [ka] is selected from R 8b is hydrogen, hydroxy and radicals [ka] is selected from R 8c , R 12a and R 12c are independently C1-C6 alkyl, R 10a is selected from amino and nitro; R 11a is based [ka] and R 12b is selected from hydrogen and hydroxy; X is carbonyl, Y is a covalent bond or a C1-C6 alkyldiyl; L 1 is C1-C6 alkyldiyl, L 2 is -O-, L 3 is a covalent bond, L 4 is a carbonyl, B, C, D, F, and G are each independently 3- to 14-membered heterocyclyl; E is a 5- to 14-membered heterocyclyl.

[0052] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof: R 1 and R 2 together with the nitrogen atom to which they are attached, form the formula (II) [ka] forming a group of R 8a and R 8care each independently a C1-C6 alkyl; R 8b is selected from hydrogen and hydroxy; X is carbonyl, Y is a covalent bond, A and C each independently represent a 3- to 14-membered heterocycle.

[0053] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: R 1 and R 2 together with the nitrogen atom to which they are attached, form the formula (II) [ka] forming a group of R 8a and R 8c are all methyl, R 8b is selected from hydrogen and hydroxy; X is carbonyl, Y is a covalent bond, B is piperazinyl, C is selected from piperidyl and pyrrolidinyl.

[0054] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from halogen and C1-C6 alkyl.

[0055] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 3 is a halogen.

[0056] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is chloro.

[0057] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: R 4 is selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, and halo-C1-C6 alkyl; R 6 is selected from hydrogen and C1-C6 alkyl.

[0058] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof: R 4 is halo-C1-C6 alkyl, R 6 is hydrogen.

[0059] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: R 4 is CF3, R 6 is hydrogen.

[0060] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is a 5- to 9-membered heteroaryl and the other substituents of formula (I) are as defined in any of the other embodiments herein.

[0061] In a further preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is a 5- to 9-membered heteroaryl selected from pyrimidinyl, pyrazolyl, pyridyl, pyrazinyl, imidazolyl, pyridazinyl, thiazolyl, and 1H-pyrazolo[3,4-d]pyrimidin-6-yl, and the other substituents of formula (I) are as defined in any of the other embodiments herein.

[0062] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: A is a 5-14 membered heteroaryl; R 5a is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl-, C1-C6 alkoxy-C1-C6 alkoxy-, amino, C1-C6 alkyl-NH-, (C1-C6 alkyl)2N-, C1-C6 alkyl-NH-C(O)-, C1-C6 alkyl-NH-C(O)-C1-C6 alkyl-NH-, amino-C1-C6 alkyl-NH-, C1-C6 alkoxy-C1-C6 alkyl-NH-, carbamoyl and nitro; R 5b is hydrogen or C1-C6 alkyl, R 5c is hydrogen.

[0063] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof: A is a 5-14 membered heteroaryl; R 5a is selected from C1-C6 alkoxy, hydroxy-C1-C6 alkyl, C1-C6 alkyl-NH-, amino-C1-C6 alkyl-NH- and amino; R 5b is hydrogen or C1-C6 alkyl, R 5c is hydrogen.

[0064] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: A is pyridyl; R 5a is selected from methoxy, hydroxymethyl, methylamino, 2-aminoethylamino, and amino; R 5b is hydrogen or methyl, R 5c is hydrogen.

[0065] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: A is a 5-14 membered heteroaryl; R 5a is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl-, C1-C6 alkoxy-C1-C6 alkoxy-, amino, C1-C6 alkyl-NH-, (C1-C6 alkyl)2N-, C1-C6 alkyl-NH-C(O)-, amino-C1-C6 alkyl-NH-, C1-C6 alkoxy-C1-C6 alkyl-NH-, carbamoyl, and nitro; R 5b and R 5c are both hydrogen.

[0066] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof: A is a 5-14 membered heteroaryl; R 5a is selected from C1-C6 alkoxy, hydroxy-C1-C6 alkyl, C1-C6 alkyl-NH-, and amino; R 5b and R 5c are both hydrogen.

[0067] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: A is pyridyl; R 5a is selected from methoxy, hydroxymethyl, methylamino and amino; R 5b and R 5c are both hydrogen.

[0068] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 7is halo-C1-C6 alkyl.

[0069] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl.

[0070] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: R 1 and R 2 together with the nitrogen atom to which they are attached, represent the formula (II), (III) or (IV) [ka] or forming a group of R 1 is based [ka] and R 2 is hydrogen, R 3 is selected from halogen and C1-C6 alkyl; R 4 is selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, and halo-C1-C6 alkyl; R 5a is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl-, C1-C6 alkoxy-C1-C6 alkoxy-, amino, C1-C6 alkyl-NH-, (C1-C6 alkyl)2N-, C1-C6 alkyl-NH-C(O)-, C1-C6 alkyl-NH-C(O)-C1-C6 alkyl-NH-, amino-C1-C6 alkyl-NH-, C1-C6 alkoxy-C1-C6 alkyl-NH-, carbamoyl and nitro; R 5b is hydrogen or C1-C6 alkyl, R 5c , R9a , R 9b , R 10b , R 11b and R 12b are hydrogen, R 6 is selected from hydrogen and halo-C1-C6 alkyl; R 7 is a C1-C6 alkyl; In formula (II), R 8a is C1-C6 alkyl, carbamoyl-C1-C6 alkyl and groups [ka] is selected from In formula (III), R 8a is hydrogen, C1-C6 alkyl, carbamoyl-C1-C6 alkyl and the group [ka] is selected from R 8b is hydrogen, hydroxy and radicals [ka] is selected from R 8c , R 12a and R 12c are independently C1-C6 alkyl, R 10a is selected from amino and nitro; R 11a is based [ka] and R 12b is selected from hydrogen and hydroxy; X is carbonyl, Y is a covalent bond or a C1-C6 alkyldiyl; L 1 is C1-C6 alkyldiyl, L 2 is -O-, L 3 is a covalent bond, L 4 is a carbonyl, A and E are each independently a 5- to 14-membered heteroaryl; B, C, D, F and G are each independently 3- to 14-membered heterocyclyl.

[0071] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof: R 1 and R 2 together with the nitrogen atom to which they are attached, form the formula (II) [ka] forming a group of R 3 is a halogen, R 4 is halo-C1-C6 alkyl, R 5a is selected from C1-C6 alkoxy, hydroxy-C1-C6 alkyl, C1-C6 alkyl-NH-, and amino; R 5b is hydrogen or C1-C6 alkyl, R 5c and R 6 are hydrogen, R 7 is a C1-C6 alkyl; R 8a and R 8c are each independently a C1-C6 alkyl; R 8b is selected from hydrogen and hydroxy; X is carbonyl, Y is a covalent bond, A is a 5-14 membered heteroaryl; A and C each independently represent a 3- to 14-membered heterocycle.

[0072] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: R 1 and R 2 together with the nitrogen atom to which they are attached, form the formula (II) [ka] forming a group of R 3 is chloro, R 4 is CF3, R 5a is selected from methoxy, hydroxymethyl, methylamino, and amino; R 5b is hydrogen or methyl, R 5c and R 6 are hydrogen, R 7 is methyl, R 8a and R 8c are both hydrogen, R 8b is selected from hydrogen and hydroxy; X is carbonyl, Y is a covalent bond, A is pyridyl; B is piperazinyl, C is selected from piperidyl and pyrrolidinyl.

[0073] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: R 1 and R 2 together with the nitrogen atom to which they are attached, represent the formula (II) or (III) [ka] or forming a group of R 1 is based [ka] and R 2 is hydrogen, R 3 is selected from halogen and C1-C6 alkyl; R 4 is selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, and halo-C1-C6 alkyl; R 5a is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl-, C1-C6 alkoxy-C1-C6 alkoxy-, amino, C1-C6 alkyl-NH-, (C1-C6 alkyl)2N-, C1-C6 alkyl-NH-C(O)-, amino-C1-C6 alkyl-NH-, C1-C6 alkoxy-C1-C6 alkyl-NH-, carbamoyl, and nitro; R 5b , R 5c , R 9a , R 9b , R 10b , R 11b and R 12b are hydrogen, R 6 is selected from hydrogen and halo-C1-C6 alkyl; R 7 is a C1-C6 alkyl; In formula (II), R 8a is C1-C6 alkyl, carbamoyl-C1-C6 alkyl and groups [ka] is selected from In formula (III), R 8a is hydrogen, C1-C6 alkyl, carbamoyl-C1-C6 alkyl and the group [ka] is selected from R 8b is hydrogen, hydroxy and radicals [ka] is selected from R 8c , R 12a and R 12c are independently C1-C6 alkyl, R 10a is selected from amino and nitro; R 11a is based [ka] and R 12b is selected from hydrogen and hydroxy; X is carbonyl, Y is a covalent bond or a C1-C6 alkyldiyl; L 1 is C1-C6 alkyldiyl, L 2 is -O-, L 3 is a covalent bond, L 4 is a carbonyl, A and E are each independently a 5- to 14-membered heteroaryl; B, C, D, F and G are each independently 3- to 14-membered heterocyclyl.

[0074] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof: R 1 and R 2 together with the nitrogen atom to which they are attached, form the formula (II) [ka] forming a group of R 3 is a halogen, R 4 is halo-C1-C6 alkyl, R 5ais selected from C1-C6 alkoxy, hydroxy-C1-C6 alkyl, C1-C6 alkyl-NH-, and amino; R 5b , R 5c and R 6 are hydrogen, R 7 is a C1-C6 alkyl; R 8a and R 8c are each independently a C1-C6 alkyl; R 8b is selected from hydrogen and hydroxy; X is carbonyl, Y is a covalent bond, A is a 5-14 membered heteroaryl; A and C each independently represent a 3- to 14-membered heterocycle.

[0075] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: R 1 and R 2 together with the nitrogen atom to which they are attached, form the formula (II) [ka] forming a group of R 3 is chloro, R 4 is CF3, R 5a is selected from methoxy, hydroxymethyl, methylamino and amino; R 5b , R 5c and R 6 are hydrogen, R 7 is methyl, R 8a and R 8c are all methyl, R 8b is selected from hydrogen and hydroxy; X is carbonyl, Y is a covalent bond, A is pyridyl; B is piperazinyl, C is selected from piperidyl and pyrrolidinyl.

[0076] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 6-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]pyridine-3-carboxamide; 6-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]-N-methyl-pyridine-3-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(difluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3R)-3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3R)-3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3R,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3S,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3S,4S)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3R,4S)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(4-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[[1-(1,1-dimethylpiperidin-1-ium-4-carbonyl)-4-piperidyl]methylcarbamoyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3S)-4,4-dimethylmorpholin-4-ium-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(2S,3S)-3-[(5-amino-2-pyridyl)oxy]-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S)-4-hydroxy-1,1-dimethyl-piperidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(hydroxymethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[3-(hydroxymethyl)-4,4-dimethyl-piperazin-4-ium-1-carbonyl]piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(4,4-dimethyl-2-oxo-piperazin-4-ium-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(difluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-cyano-pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-methyl-pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-ethyl-pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(6-aminopyridazin-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(4-methyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-[5-[(3-amino-3-oxo-propyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 4-(2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)-1,1-dimethylpiperazin-1-ium; rac-(2R,4S)-2-((1R,5S,6S)-6-(2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzamido)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-4-hydroxy-1,1-dimethylpyrrolidin-1-ium; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; (exo)-6-[[4-[[5-[1-(5-aminopyridin-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chlorobenzoyl]amino]-[(trans)-4-hydroxy-1,1-dimethylpyrrolidin-1-ium-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-[[3-keto-3-(methylamino)propyl]amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[[(exo)-3-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-aminopyrazin-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(methoxymethyl)-1H-pyrazol-3-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-3-fluoro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-4-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-6-fluoro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-6-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-4-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; and 5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide.

[0077] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3R)-3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3R,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3S,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3R,4S)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; and 5-[1-(5-amino-6-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide.

[0078] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein said compound of formula (I) is Example A1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate Example A2 6-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]pyridine-3-carboxamide; Formate Example A3 6-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]-N-methyl-pyridine-3-carboxamide; Formate Example A4 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example A5 5-[1-(5-amino-2-pyridyl)-3-(difluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetate Example A6 N-[3-chloro-4-[4-[2-[(3R)-3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example A7 N-[3-chloro-4-[4-[2-[(3R)-3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate Example B1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example B2 N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example B3 N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example B4 N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example B5 N-[3-chloro-4-[4-[(3S,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Example B6 N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate Example B7 N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example C1 N-[4-[4-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example C2 N-[4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example D1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D2 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D3 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D4 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; formate Example D5 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3R,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D6 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3S,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D7 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3S,4S)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D8 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3R,4S)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D10 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(4-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D11 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D12 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[[1-(1,1-dimethylpiperidin-1-ium-4-carbonyl)-4-piperidyl]methylcarbamoyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D13 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3S)-4,4-dimethylmorpholin-4-ium-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D14 N-[4-[4-[(2S,3S)-3-[(5-amino-2-pyridyl)oxy]-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate Example D15 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S)-4-hydroxy-1,1-dimethyl-piperidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example E1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example E2 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate Example E3 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate Example E4 N-[3-chloro-4-[4-(4-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example E5 N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example E6 N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example E7 N-[4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example E8 N-[3-chloro-4-[4-[(3S,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate Example F1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(hydroxymethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate Example G1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate Example H1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example H2 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[3-(hydroxymethyl)-4,4-dimethyl-piperazin-4-ium-1-carbonyl]piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example I1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(4,4-dimethyl-2-oxo-piperazin-4-ium-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example J1 5-[1-(5-amino-2-pyridyl)-3-(difluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetate Example J2 5-[1-(5-amino-2-pyridyl)-3-cyano-pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetate Example J3 5-[1-(5-amino-2-pyridyl)-3-methyl-pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; formate Example J4 5-[1-(5-amino-2-pyridyl)-3-ethyl-pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetate Example K1 5-[1-(6-aminopyridazin-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetate Example K2 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(4-methyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 2,2,2-trifluoroacetate; and Example L1 5-[1-[5-[(3-amino-3-oxopropyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate is selected from.

[0079] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein said compound of formula (I) is Example A1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate Example A7 N-[3-chloro-4-[4-[2-[(3R)-3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate Example B6 N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate Example D2 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D3 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D4 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; formate Example D5 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3R,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D6 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3S,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example D8 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3R,4S)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate Example E1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; formate and Example E6 N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate is selected from.

[0080] 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 an even more specific embodiment, the present invention provides a compound according to formula (I) described herein (i.e., as the "free base" or "free acid," respectively).

[0081] In some embodiments, compounds of formula (I) are isotopically labeled by having one or more atoms therein replaced by an atom 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. Examples of 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.

[0082] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may confer greater metabolic stability and may confer certain therapeutic advantages, for example, by increasing in vivo half-life or requiring lower dosages.

[0083] 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.

[0084] Manufacturing Process In one aspect, the present invention provides a process for making a compound of formula (I) described herein.

[0085] 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.

[0086] 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 exact reaction temperature is not critical to the invention. It is convenient to carry out the reactions described at temperatures ranging from -78°C to 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 is usually sufficient to obtain the intermediates and compounds described. The reaction sequence is not limited to the order 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.

[0087] The following abbreviations are used herein: ACN or MeCN acetonitrile BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene Boc t-butyloxycarbonyl CFU colony forming unit d day DCM dichloromethane DIPEA N,N-Diisopropylethylamine EtOAc or EA ethyl acetate FA formic acid h(s) or hr(s) time 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 NaBH3CN Sodium cyanoborohydride PE: Petroleum ether PdCl2(DPPF)[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) PG protecting group Precat Precatalyst Preparative HPLC Preparative High Performance Liquid Chromatography room temperature (rt) room temperature sat saturation SEM 2-Methoxyethyl(trimethyl)silane FA formic acid TEMPO(2,2,6,6-tetramethylpiperidin-1-yl)oxyl TFA: Trifluoroacetic acid wt weight X-PHOS 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0088] [ka] In the ceremony, P.G. 1 is a protecting group, e.g., a Boc protecting group, and R 3 and R 7 is as defined herein.

[0089] Compounds of formula Intermediate B1 can be prepared according to the synthetic route outlined in Scheme 1. 3 Protection of substituted 4-nitrobenzoic acid A with (Boc)2O gives compound B. Reduction of the nitro group of compound B can be achieved, for example, by using an ammonium chloride / iron system at room temperature to give amine C. Coupling of D and amine C with a condensing agent such as HATU / DIPEA in DMSO gives compounds of formula intermediate B1.

[0090] [ka] In the ceremony, P.G. 1 , P.G. 2 and PG 3 is a protecting group, in particular a Boc protecting group, R 1a and R 2a together with the nitrogen atom to which they are attached, represent the formula (IV), (V) or (VI) [ka] or forming a group of R 1a is based [ka] and R 2a is selected from hydrogen and C1-C6 alkyl; R 3 , R 7 , R 8a , R 8b , R 11a , R 11b , B, C, F, X, Y and L 3 is as defined herein.

[0091] Compounds of formula Intermediate B can be prepared according to Scheme 2. Hydrolysis of intermediate B1 provides acid E, which can be coupled with a variety of amines in the presence of a condensing agent, such as HATU / DIPEA in DMSO, to provide intermediate B.

[0092] [ka] In the ceremony, P.G. 1 , P.G. 2 and PG 3 is a protecting group, for example a Boc protecting group, R 1a and R 2a together with the nitrogen atom to which they are attached, represent the formula (IV), (V) or (VI) [ka] or forming a group of R 1a is based [ka] and R 2a is selected from hydrogen and C1-C6 alkyl; R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R 7 , R 8a , R 8b , R 11a , R 11b , A, B, C, F, X, Y and L 3 is as defined herein.

[0093] Compounds of formula C and D can be prepared according to Scheme 3. Suzuki coupling of intermediate B with a pyrazole boronic ester can be achieved using a palladium catalyst and a phosphine ligand to give intermediate C. This compound can be reacted with 100% methyl methyl ether under conditions known in the art, for example, in the presence of a base such as KCO in a solvent such as MeCN. o Further coupling with a halogen-substituted heteroaryl at C (microwave) for 2 hours affords intermediate D (Route 1 in Scheme 3). Intermediate D can also be prepared by Suzuki coupling reaction of intermediate B with a heteroaryl-substituted pyrazole bromine ester (Route 2 in Scheme 3).

[0094] In some cases, the order of the Suzuki coupling in Scheme 3 and the amidation reaction in Scheme 2 could be reversed.

[0095] [ka] In the ceremony, P.G. 1 , P.G. 2 and PG 3 is a protecting group, for example a Boc group, R 1a and R 2a together with the nitrogen atom to which they are attached, represent the formula (IV), (V) or (VI) [ka] or forming a group of R 1a is based [ka] and R 2a is selected from hydrogen and C1-C6 alkyl; R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R5c , R 6 , R 7 , R 8a , R 8b , R 11a , R 11b , A, B, C, F, X, Y and L 3 is as defined herein.

[0096] Compounds of the formula of Examples A-L can be prepared according to Scheme 4. Methylation of intermediate D can be achieved under conditions such as MeI with DIPEA in acetonitrile at room temperature to give Examples A-L. Removal of protecting groups (if present) can be done before or after the methylation step, based on different substitutions.

[0097] 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 resultant diseases caused by pathogens, particularly bacteria, more particularly Acinetobacter species, and most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0098] 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.

[0099] 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.

[0100] The compounds of the present invention can be used, alone or in combination with other drugs, for the treatment or prevention of infections and resulting 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.

[0101] 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.

[0102] 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.

[0103] 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 resultant diseases.

[0104] In certain embodiments, the nosocomial infection and resulting disease is selected from bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, or combinations thereof.

[0105] 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 resulting diseases caused by Gram-negative bacteria.

[0106] In certain embodiments, the infection and resulting disease caused by Gram-negative bacteria is selected from bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, or combinations thereof.

[0107] 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 infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or combinations thereof.

[0108] In a further aspect, the present invention provides a method for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or combinations thereof, comprising administering to a mammal a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0109] 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.

[0110] 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 infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0111] 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 infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or combinations thereof.

[0112] In certain embodiments, the infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, or E. coli, or a combination thereof, is selected from bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, or a combination thereof.

[0113] 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 and resulting diseases caused by pathogens, in particular bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0114] In a further aspect, the present invention provides a method for the treatment or prevention of infections and resultant diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infections and wound infections caused by pathogens, particularly bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, which method comprises administering to a mammal a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0115] 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 and resulting diseases caused by pathogens, in particular bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0116] 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 resulting diseases caused by pathogens, in particular 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.

[0117] 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 to 4.

[0118] 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 and resulting diseases caused by pathogens, in particular bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0119] 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, dragees, 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, such as intramuscularly or intravenously (e.g., in the form of injection or infusion solutions).

[0120] The compound of formula (I) and its pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic excipients for the preparation of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as excipients for tablets, sugar-coated tablets, and hard gelatin capsules, for example.

[0121] Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols etc.

[0122] Suitable excipients for the production of solutions and syrups are, by way of example, water, polyols, saccharose, invert sugar, glucose etc.

[0123] Suitable excipients for injection solutions are, by way of example, water, alcohols, polyols, glycerol, vegetable oils etc.

[0124] Suitable excipients for suppositories are, by way of example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0125] 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. The pharmaceutical formulations of the present invention may further contain other therapeutically valuable substances.

[0126] Dosage can vary widely and will of course be adapted to the individual requirements of each particular case.Generally, for oral administration, a daily dose 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 doses, for example, of the same amount.However, it is clear that the upper limit given herein can be exceeded in indicated cases.

[0127] Co-administration of compounds of formula (I) and other agents The compound of formula (I) or its salt, or the compounds disclosed herein or its pharmaceutically acceptable salt, 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 activities to the compound of formula (I) so that they do not adversely affect each other. The compounds can be administered together in a single pharmaceutical composition or separately. In one embodiment, the compound or pharmaceutically acceptable salt can be co-administered with an antibiotic, particularly for the treatment or prevention of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, or E. coli, or a combination thereof.

[0128] The term "co-administration" refers to simultaneous administration or any manner of separate, sequential administration of a compound of formula (I) or a salt thereof, or a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an additional active pharmaceutical ingredient, including an antibiotic. If not administered simultaneously, the compounds are administered close in time to each other. Furthermore, it does not matter 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.

[0129] Typically, any agent with antibacterial activity can be co-administered. Specific examples of such agents 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 WO2017072062A1, WO2019185572A1, and WO20192068531.

[0130] In one aspect, the present invention provides a pharmaceutical composition as described herein, further comprising an additional therapeutic agent.

[0131] In one aspect, the present invention provides a pharmaceutical combination comprising a compound of formula (I) as described herein and an additional therapeutic agent.

[0132] In one embodiment, the additional therapeutic agent is an antibiotic agent.

[0133] In one embodiment, the additional therapeutic agent is an antibiotic agent useful for the treatment or prevention of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, or E. coli, or a combination thereof.

[0134] 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 WO2017072062A1, WO2019185572A1, and WO2019206853A1. [Example]

[0135] 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.

[0136] 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.

[0137] Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere.

[0138] Intermediate A1 2-Bromo-5-chloro-2-ethyl-pyridine

[0139] In a 50 mL round-bottom flask, 6-bromopyridin-3-ol (310 mg, 1.8 mmol), 1-bromo-2-methoxyethane (369 mg, 2.65 mmol), and K2CO3 (367 mg, 2.65 mmol) were refluxed in acetonitrile (5 mL) for 5 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 25 mL of H2O and extracted with EtOAc (3 x 25 mL). The organic layers were combined and washed with saturated NaCl (1 x 25 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give the title product as a pale yellow oil (283 mg). MS [M+H]+: 232.2.

[0140] Intermediate A2 Benzyl 3-oxo-4-(4-piperidylmethyl)piperazine-1-carboxylate

[0141] Step 1: Benzyl 4-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]-3-oxo-piperazine-1-carboxylate

[0142] 3-Ketopiperazine-1-carboxylic acid benzyl ester (1.0 g, 4.3 mmol) was dissolved in N,N-dimethylformamide (ultra-dry) (28.5 mL). The solution was cooled to 0°C. To this solution, NaH (204.9 mg, 5.1 mmol) was added portionwise. The mixture was then stirred at the same temperature for 1 hour. The ice bath was removed, and stirring was continued at room temperature for 1 hour. 4-(iodomethyl)piperidine-1-carboxylic acid tert-butyl ester (1.7 g, 5.1 mmol) was then added in one portion. The mixture was stirred at room temperature for 18 hours. The solution was poured into 100 mL of water and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with 50 mL of brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography to give the title compound as a pale yellow oil, 854 mg. MS [M+H]: 454.2

[0143] Step 2: Benzyl 3-oxo-4-(4-piperidylmethyl)piperazine-1-carboxylate

[0144] 4-[(1-tert-Butoxycarbonyl-4-piperidyl)methyl]-3-keto-piperazine-1-carboxylic acid benzyl ester (850 mg, 2.0 mmol) was dissolved in dichloromethane (4 mL) and 1 mL of TFA. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was used in the next step without further purification (pale yellow oil, 600 mg). MS [M+H]: 332.4.

[0145] Intermediate A3 9H-Fluoren-9-ylmethyl N-(6-bromo-3-pyridyl)-N-(2-methoxyethyl)carbamate

[0146] Step 1: 6-Bromo-N-(2-methoxyethyl)pyridin-3-amine

[0147] 6-Bromopyridin-3-amine (500 mg, 2.89 mmol), sodium iodide (216.6 mg, 1.45 mmol), and 1-bromo-2-methoxy-ethane (482.02 mg, 325.91 uL) were dissolved in anhydrous tetrahydrofuran (28.9 mL). The solution was cooled to 0° C. To this solution was added NaH (138.72 mg, 3.47 mmol) in portions. The mixture was stirred at 0° C. for 4 hours. Then, additional NaH (138.72 mg, 3.47 mmol) was added, and the mixture was refluxed at 70° C. for 2 hours. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography to give 6-bromo-N-(2-methoxyethyl)pyridin-3-amine (373 mg). MS [M+H]: 231.1.

[0148] Step 2: 9H-Fluoren-9-ylmethyl N-(6-bromo-3-pyridyl)-N-(2-methoxyethyl)carbamate

[0149] A mixture of 6-bromo-N-(2-methoxyethyl)pyridin-3-amine (3.7 g, 16.01 mmol), 9H-fluoren-9-ylmethyl carbonochloridate (4.56 g, 17.61 mmol), and NaHCO (2.02 g, 24.02 mmol) was stirred in 1,4-dioxane (80.06 mL) at 0 °C for 18 hours. The solvent was removed in vacuo, and the residue was purified by flash chromatography to give 9H-fluoren-9-ylmethyl N-(6-bromo-3-pyridyl)-N-(2-methoxyethyl)carbamate (6.2 g) as a yellow oil. MS ([M+H] + ):453.2.

[0150] Intermediate A4 5-nitro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]pyridine

[0151] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (7.8 g, 30 mmol) in dimethyl sulfoxide (100 ml) and triethylamine (3.0 ml) was added 2-chloro-5-nitro-pyridine (4.8 g, 30 mmol). The mixture was then stirred at 130° C. for 3 hours. The mixture was poured into water, and the aqueous solution was extracted with DCM. The combined organic layers were washed with water and brine and dried over anhydrous NaSO. The organic layer was concentrated in vacuo, and the residue was purified by flash column chromatography to give 5-nitro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]pyridine (10 g) as a yellow solid. MS [M+H]: 385.1.

[0152] Intermediate A5 6-[3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyridin-3-amine

[0153] Step 1: 2-[4-Bromo-3-(difluoromethyl)pyrazol-1-yl]-5-nitro-pyridine

[0154] To a solution of 4-bromo-3-(difluoromethyl)-1H-pyrazole (800.0 mg, 4.06 mmol) in DMF (20.0 mL) was added sodium hydride (243.7 mg, 6.09 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes. Then, 2-chloro-5-nitro-pyridine (772.7 mg, 4.87 mmol) was added, and the mixture was stirred at 0° C. for 1 hour. The mixture was poured into water (50.0 mL), filtered, and the filter cake was washed with water (20.0 mL×3) and dried under reduced pressure to give 2-[4-bromo-3-(difluoromethyl)pyrazol-1-yl]-5-nitro-pyridine (1.0 g, 3.13 mmol, 77% yield) as a brown solid. MS ([M+H] + ):320.9.

[0155] Step 2: 6-[4-bromo-3-(difluoromethyl)pyrazol-1-yl]pyridin-3-amine To a solution of 2-[4-bromo-3-(difluoromethyl)pyrazol-1-yl]-5-nitro-pyridine (1.0 g, 3.13 mmol) in acetic acid (50.0 mL) was added iron (1.7 g, 31.34 mmol). The mixture was stirred at 20° C. for 3 hours. The reaction mixture was filtered, and the filter cake was washed with DCM (20.0 mL). The filtrate was concentrated in vacuo to give a residue, which was purified by silica gel column to give 6-[4-bromo-3-(difluoromethyl)pyrazol-1-yl]pyridin-3-amine (700.0 mg, 2.42 mmol) as a brown solid. MS ([M+2+H] + ):290.9.

[0156] Step 3: 6-[3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyridin-3-amine To a solution of 6-[4-bromo-3-(difluoromethyl)pyrazol-1-yl]pyridin-3-amine (300.0 mg, 1.04 mmol) and bis(pinacolato)diboron (289.9 mg, 1.14 mmol) in 1,4-dioxane (10.0 mL) was added potassium acetate (203.7 mg, 2.08 mmol) and Pd(dppf)Cl (113.8 mg, 0.17 mmol) in a glove box under argon. The mixture was stirred at 100° C. for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by flash column (0.1% FA as additive) and dried by lyophilization to give 6-[3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyridin-3-amine (150.0 mg, 0.45 mmol) as a yellow solid. MS [M+H] + :337.1.

[0157] Intermediate A6 tert-Butyl N-[6-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-3-pyridyl]carbamate

[0158] Step 1: 2-(3-Methoxypyrazol-1-yl)-5-nitro-pyridine To a solution of 3-methoxy-1H-pyrazole (0.9 g, 9.17 mmol) in DMF (20.0 mL) was added sodium hydride (550.5 mg, 13.76 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes. 2-Chloro-5-nitro-pyridine (1.7 g, 11.01 mmol) was added, and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was poured into water (50.0 mL), filtered, and the filter cake was washed with water (20.0 mL), then dried under reduced pressure to give 2-(3-methoxypyrazol-1-yl)-5-nitro-pyridine (1.8 g, 8.18 mmol) as a yellow solid. MS [M+H] + :220.9.

[0159] Step 2: 2-(4-Bromo-3-methoxy-pyrazol-1-yl)-5-nitro-pyridine

[0160] To a solution of 2-(3-methoxypyrazol-1-yl)-5-nitro-pyridine (0.8 g, 3.63 mmol) in DCM (1.0 mL) was added N-bromosuccinimide (0.8 g, 4.49 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into aqueous NaSO (10.0 mL) and extracted with EA (100.0 mL × 3). The organics were washed with water (50.0 mL × 2) followed by saturated brine solution (50.0 mL). The organics were then separated and dried (MgSO) before being concentrated to dryness to give 2-(4-bromo-3-methoxy-pyrazol-1-yl)-5-nitro-pyridine (1.0 g, 3.34 mmol) as a yellow solid. MS ([M+2+H] + ):300.9.

[0161] Step 3: 6-(4-Bromo-3-methoxy-pyrazol-1-yl)pyridin-3-amine

[0162] To a solution of 2-(4-bromo-3-methoxy-pyrazol-1-yl)-5-nitro-pyridine (1.0 g, 3.34 mmol) in acetic acid (30.0 mL) was added iron (1.9 g, 33.44 mmol). The mixture was stirred at 20° C. for 12 hours. The reaction mixture was filtered, and the filter cake was washed with DCM (20 mL×3). The filtrate was then concentrated in vacuo and purified by silica gel to give 6-(4-bromo-3-methoxy-pyrazol-1-yl)pyridin-3-amine (800.0 mg, 2.97 mmol) as a brown solid. MS([M+H] + ):268.9.

[0163] Step 4: tert-butyl N-[6-(4-bromo-3-methoxy-pyrazol-1-yl)-3-pyridyl]carbamate

[0164] To a solution of the obtained 6-(4-bromo-3-methoxy-pyrazol-1-yl)pyridin-3-amine (350.0 mg, 1.30 mmol) in methanol (30.0 mL) was added di-t-butyl dicarbonate (567.7 mg, 2.60 mmol). The mixture was stirred at 20 ° C. for 12 hours. The reaction mixture was filtered, and the filter cake was washed with DCM (20 mL × 3). The filtrate was then concentrated in vacuo and purified by silica gel column to give tert-butyl N-[6-(4-bromo-3-methoxy-pyrazol-1-yl)-3-pyridyl]carbamate (450 mg, 1.22 mmol) as a brown solid. MS [M+H] + :369.2.

[0165] Step 5: tert-butyl N-[6-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-3-pyridyl]carbamate

[0166] To a solution of tert-butyl N-[6-(4-bromo-3-methoxy-pyrazol-1-yl)-3-pyridyl]carbamate (450.0 mg, 1.22 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (340.4 mg, 1.34 mmol) in 1,4-dioxane (10.0 mL) was added potassium acetate (239.2 mg, 2.44 mmol) and Pd(dppf)Cl (133.6 mg, 0.18 mmol) under argon in a glove box. The mixture was stirred at 100° C. for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by flash column (0.1% FA as additive) and lyophilized to dryness to give tert-butyl N-[6-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-3-pyridyl]carbamate (150.0 mg, 0.36 mmol) as a yellow solid. MS [M+H] + :417.3.

[0167] Intermediate A7 tert-Butyl N-[6-[3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-3-pyridyl]carbamate

[0168] Step 1: 4-Bromo-1-(5-nitro-2-pyridyl)pyrazole-3-carbonitrile

[0169] To a solution of compound 4-bromo-1H-pyrazole-3-carbonitrile (1.0 g, 5.81 mmol) in DMF (8.0 mL) was added N,N-diisopropylethylamine (2.0 mL, 11.63 mmol) and 2-chloro-5-nitro-pyridine (0.7 mL, 6.40 mmol). The mixture was stirred under N at 80 °C for 12 hours. The reaction mixture was quenched with water (10 mL), and the residue was filtered and concentrated under reduced pressure to give 4-bromo-1-(5-nitro-2-pyridyl)pyrazole-3-carbonitrile (1.2 g, 4.08 mmol) as a brown solid.

[0170] Step 2: 1-(5-amino-2-pyridyl)-4-bromo-pyrazole-3-carbonitrile

[0171] To a solution of 4-bromo-1-(5-nitro-2-pyridyl)pyrazole-3-carbonitrile (1.5 g, 5.10 mmol) in acetic acid (20.0 mL) was added Fe (1.4 g, 25.50 mmol). The mixture was stirred under N at 25 °C for 6 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The crude product was purified by flash chromatography and concentrated to give 1-(5-amino-2-pyridyl)-4-bromo-pyrazole-3-carbonitrile (0.5 g, 1.89 mmol) as a white solid. MS [M+H] + :263.9.

[0172] Step 3: tert-butyl N-[6-(4-bromo-3-cyano-pyrazol-1-yl)-3-pyridyl]carbamate

[0173] To a solution of 1-(5-amino-2-pyridyl)-4-bromo-pyrazole-3-carbonitrile (0.5 g, 1.89 mmol) in DMF (5.0 mL) was added di-t-butyl dicarbonate (619.8 mg, 2.80 mmol). The mixture was stirred under N at 25 °C for 12 hours, and water (25 mL) was added to the reaction mixture, which was then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, and concentrated under reduced pressure to remove the solvent. The crude product was then purified by flash chromatography and concentrated to give tert-butyl N-[6-(4-bromo-3-cyano-pyrazol-1-yl)-3-pyridyl]carbamate (0.5 g, 1.37 mmol) as a yellow oil. MS [M+H] + :366.2.

[0174] Step 4: [1-[5-(tert-butoxycarbonylamino)-2-pyridyl]-3-cyano-pyrazol-4-yl]boronic acid

[0175] A mixture of the compounds tert-butyl N-[6-(4-bromo-3-cyano-pyrazol-1-yl)-3-pyridyl]carbamate (0.5 g, 1.37 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (418.4 mg, 1.65 mmol), potassium acetate (0.2 mL, 2.75 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (112.0 mg, 0.14 mmol) was added to the mixture via syringe. The flask was evacuated and purged with N gas four times. The mixture was then cooled to room temperature. 2.The mixture was stirred at 90° C. for 2 hours under reduced pressure. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The product was then purified by reverse phase chromatography (0.1% FA as an additive) and lyophilized to dryness to give [1-[5-(tert-butoxycarbonylamino)-2-pyridyl]-3-cyano-pyrazol-4-yl]boronic acid (268.0 mg, 0.81 mmol) as a white solid. MS [M+H] + :330.1.

[0176] Intermediate A8 tert-Butyl N-[6-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-3-pyridyl]carbamate

[0177] Step 1: 2-(4-Bromo-3-methyl-pyrazol-1-yl)-5-nitro-pyridine

[0178] To a solution of 4-bromo-3-methyl-1H-pyrazole (1.0 g, 6.21 mmol) in DMF (8.0 mL) was added NaH (871.3 mg, 9.32 mmol) and 2-chloro-5-nitro-pyridine (0.7 mL, 6.83 mmol) at 0 °C. The mixture was stirred under N at 25 °C for 3 h. The reaction mixture was quenched with water (10 mL), filtered through Celite, and the filtrate was washed with water and concentrated to give the crude product 2-(3-bromopyrazol-1-yl)-5-nitro-pyridine (1.5 g, 5.58 mmol) as a yellow solid. MS [M+H] + :282.9.

[0179] Step 2: 6-(4-bromo-3-methyl-pyrazol-1-yl)pyridin-3-amine

[0180] To a solution of 2-(3-bromopyrazol-1-yl)-5-nitro-pyridine (1.6 g, 5.83 mmol) in acetic acid (20.0 mL) was added Fe (2.6 g, 46.63 mmol). The mixture was stirred under N at 25 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The crude product was purified by flash chromatography and concentrated to give 6-(4-bromo-3-methyl-pyrazol-1-yl)pyridin-3-amine (0.6 g, 2.37 mmol) as a yellow solid. MS [M+H] + :254.9.

[0181] Step 3: tert-butyl N-[6-(4-bromo-3-methyl-pyrazol-1-yl)-3-pyridyl]carbamate

[0182] To a solution of 6-(4-bromo-3-methyl-pyrazol-1-yl)pyridin-3-amine (250.0 mg, 0.99 mmol) in methanol (0.5 mL) was added di-t-butyl dicarbonate (0.3 mL, 1.48 mmol). The mixture was stirred under N2 at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent and give crude product tert-butyl N-[6-(4-bromo-3-methyl-pyrazol-1-yl)-3-pyridyl]carbamate (280.0 mg, 0.79 mmol). MS [M+H] + :353.0.

[0183] Step 4: tert-butyl N-[6-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-3-pyridyl]carbamate

[0184] A mixture of tert-butyl N-[6-(4-bromo-3-methyl-pyrazol-1-yl)-3-pyridyl]carbamate (250.0 mg, 0.71 mmol), bis(pinacolato)diboron (179.7 mg, 0.71 mmol), potassium acetate (0.09 mL, 1.42 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (57.8 mg, 0.07 mmol) was placed in a flask. 1,4-Dioxane (5.0 mL) was added to the mixture via syringe. The flask was degassed and purged with N gas four times. The mixture was stirred under N at 90 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The product was then purified by reverse-phase chromatography (0.1% FA as an additive) and lyophilized to dryness to give tert-butyl N-[6-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-3-pyridyl]carbamate (120.0 mg, 0.30 mmol) as a white solid. MS [M+H] + :317.1.

[0185] Intermediate A9 tert-Butyl N-[6-[3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-3-pyridyl]carbamate

[0186] Step 1: 2-(3-Bromopyrazol-1-yl)-5-nitro-pyridine

[0187] To a solution of 3-bromo-1H-pyrazole (1.0 g, 6.8 mmol) in THF (20.0 mL) was slowly added 60% sodium hydride in oil (299.3 mg, 7.48 mmol) at 0 °C. After the addition, the reaction mixture was stirred at 0 °C for 0.5 h. 2-Chloro-5-nitro-pyridine (1.2 g, 7.48 mmol) was added to the mixture at 0 °C. The reaction mixture was stirred at 25 °C for 2.5 h. The reaction was quenched with saturated aqueous NH Cl (50.0 mL) and extracted with EtOAc (30.0 mL × 3). The combined organic layers were dried over Na SO and concentrated to give the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 20:1) to give 2-(3-bromopyrazol-1-yl)-5-nitro-pyridine (1.5 g, 5.58 mmol) as a yellow solid. MS[M+H] + :268.8.

[0188] Step 2: 5-nitro-2-(3-vinylpyrazol-1-yl)pyridine

[0189] To a solution of 2-(3-bromopyrazol-1-yl)-5-nitro-pyridine (900.0 mg, 3.35 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (772.7 mg, 5.02 mmol), and potassium carbonate (924.6 mg, 6.69 mmol) in 1,4-dioxane (25.0 mL) and water (2.5 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (244.7 mg, 0.33 mmol) was added in one portion under N2. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to give a residue. The residue was diluted with EtOAc (100.0 mL) and washed with brine (20.0 mL × 2). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel chromatography to give 5-nitro-2-(3-vinylpyrazol-1-yl)pyridine (1.1 g, 5.09 mmol) as a yellow solid. MS [M+H] + :217.1.

[0190] Step 3: 6-(3-ethylpyrazol-1-yl)pyridin-3-amine

[0191] To a solution of 5-nitro-2-(3-vinylpyrazol-1-yl)pyridine (900.0 mg, 4.16 mmol, 1.0 equiv) in methanol (5.0 mL) was added palladium on carbon (10%) (443.0 mg, 0.42 mmol, 0.1 equiv) in one portion under N2. H2 was introduced into the system. The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was filtered, and the filtrate was concentrated to give 6-(3-ethylpyrazol-1-yl)pyridin-3-amine (740.0 mg, 3.93 mmol) as a colorless oil, which was used directly in the next step without further purification. MS [M+H] + :189.2.

[0192] Step 4: tert-butyl N-[6-(3-ethylpyrazol-1-yl)-3-pyridyl]carbamate

[0193] To a solution of 6-(3-ethylpyrazol-1-yl)pyridin-3-amine (900.0 mg, 4.78 mmol) and triethylamine (1.33 mL, 9.56 mmol) in ACN (20.0 mL) was added di-t-butyl dicarbonate (1.32 mL, 5.74 mmol) in one portion. The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to give the crude product. The crude product was purified by silica gel chromatography to give tert-butyl N-[6-(3-ethylpyrazol-1-yl)-3-pyridyl]carbamate (800.0 mg, 2.77 mmol) as a yellow oil. MS [M+H] + :289.2.

[0194] Step 5: tert-butyl N-[6-(4-bromo-3-ethyl-pyrazol-1-yl)-3-pyridyl]carbamate

[0195] To a solution of tert-butyl N-[6-(3-ethylpyrazol-1-yl)-3-pyridyl]carbamate (700.0 mg, 2.43 mmol) in ACN (20.0 mL) was added N-bromosuccinimide (432.0 mg, 2.43 mmol) in one portion. The reaction mixture was stirred at 25 °C for 2 h. The reaction was quenched with saturated aqueous NaSO (20.0 mL) and extracted with EtOAc (30.0 mL × 2). The combined organic layers were dried over NaSO and concentrated to give the crude product. The crude product was purified by preparative HPLC (neutral) to give tert-butyl N-[6-(4-bromo-3-ethyl-pyrazol-1-yl)-3-pyridyl]carbamate (220.0 mg, 0.6 mmol) as a red solid. MS [M+H] + :367.2.

[0196] Step 6: tert-butyl N-[6-[3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-3-pyridyl]carbamate

[0197] To a solution of bis(pinacolato)diboron (138.3 mg, 0.54 mmol), tert-butyl N-[6-(4-bromo-3-ethyl-pyrazol-1-yl)-3-pyridyl]carbamate (100.0 mg, 0.270 mmol) and potassium acetate (66.8 mg, 0.68 mmol) in 1,4-dioxane (2.0 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]

[0198] Dichloropalladium(II) (19.9 mg, 0.03 mmol) was added in one portion under N2. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by preparative TLC (PE: EtOAc = 1:1) to give tert-butyl N-[6-[3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-3-pyridyl]carbamate (120.0 mg, 0.29 mmol, 38% yield) as a yellow oil. MS [M+H] +:415.2.

[0199] Intermediate A10 tert-Butyl N-[6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]pyridazin-3-yl]carbamate

[0200] Step 1: tert-butyl N-(6-chloropyridazin-3-yl)carbamate

[0201] To a solution of 6-chloropyridazin-3-amine (6.0 g, 46.31 mmol), triethylamine (9.68 mL, 69.47 mmol), and 4-dimethylaminopyridine (2.8 g, 23.16 mmol) in ACN (20.0 mL) was added di-t-butyl dicarbonate (15.1 g, 69.47 mmol) in one portion. The reaction mixture was stirred at 80 °C for 16 h. The reaction was quenched with saturated aqueous NaCO (50.0 mL) and extracted with EtOAc (100.0 mL × 2). The combined organic layers were dried over NaSO and concentrated to give the crude product. The crude product was purified by silica gel chromatography to give tert-butyl N-(6-chloropyridazin-3-yl)carbamate (5.6 g, 24.38 mmol) as a pale yellow solid. MS ([M+H-CH] + :174.1.

[0202] Step 2: 6-[4-bromo-3-(trifluoromethyl)pyrazol-1-yl]pyridazin-3-amine

[0203] To a solution of tert-butyl N-(6-chloropyridazin-3-yl)carbamate (2.2 g, 9.3 mmol) and potassium carbonate (1.9 g, 13.96 mmol) in DMF (40.0 mL) was added compound 3 (2.0 g, 9.3 mmol) and cesium fluoride (141.3 mg, 0.930 mmol) in one portion. The reaction mixture was stirred at 120 °C for 48 h. The reaction mixture was diluted with EtOAc (200.0 mL) and washed with brine (50.0 mL × 3). The organic layer was dried over NaSO and concentrated to dryness. The crude product was purified by preparative HPLC (TFA) to give 6-[4-bromo-3-(trifluoromethyl)pyrazol-1-yl]pyridazin-3-amine (350.0 mg, 1.14 mmol) as a yellow solid. MS ([M+H] + :308.0.

[0204] Step 3: tert-butyl N-[6-[4-bromo-3-(trifluoromethyl)pyrazol-1-yl]pyridazin-3-yl]carbamate

[0205] To a solution of 6-[4-bromo-3-(trifluoromethyl)pyrazol-1-yl]pyridazin-3-amine (350.0 mg, 1.14 mmol), triethylamine (0.48 mL, 3.41 mmol), and 4-dimethylaminopyridine (138.8 mg, 1.14 mmol) in DMF (10.0 mL) was added di-t-butyl dicarbonate (297.5 mg, 1.36 mmol) in one portion. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with brine (20.0 mL) and extracted with EtOAc (10.0 mL × 3). The combined organic layers were dried over NaSO and concentrated to give the crude product. The crude product was purified by preparative HPLC (FA) to give tert-butyl N-[6-[4-bromo-3-(trifluoromethyl)pyrazol-1-yl]pyridazin-3-yl]carbamate (90.0 mg, 0.22 mmol) as a yellow solid. MS ([M+2+H] + :410.0.

[0206] Step 4: tert-butyl N-[6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]pyridazin-3-yl]carbamate

[0207] To a solution of tert-butyl N-[6-[4-bromo-3-(trifluoromethyl)pyrazol-1-yl]pyridazin-3-yl]carbamate (90.0 mg, 0.220 mmol), bis(pinacolato)diboron (83.9 mg, 0.33 mmol), and potassium acetate (43.2 mg, 0.44 mmol) in 1,4-dioxane (2.0 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16.1 mg, 0.02 mmol) was added in one portion under N. The reaction mixture was stirred at 100 °C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by prep-TLC (PE: EtOAc = 4:1) to give tert-butyl N-[6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]pyridazin-3-yl]carbamate (100.0 mg, 0.22 mmol, 42% yield) as a yellow solid. MS ([M+H] + :456.2.

[0208] Intermediate A11 Trimethyl-[2-[[4-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]pyrazol-1-yl]methoxy]ethyl]silane

[0209] Step 1: Trimethyl-[2-[(4-methylpyrazol-1-yl)methoxy]ethyl]silane

[0210] A solution of 4-methyl-1H-pyrazole (5.0 g, 60.9 mmol) in THF (50.0 mL) was degassed and purged with N2 three times. Sodium hydride (60%) (3.65 g, 91.35 mmol) was then added to the mixture at 0° C. The mixture was stirred at 0° C. for 0.5 h. 2-(trimethylsilyl)

[0211] Ethoxymethyl chloride (12.9 mL, 73.08 mmol) was added to the mixture at 0° C. The reaction mixture was stirred at 20° C. under a N atmosphere for 2 hours. The reaction was quenched with saturated aqueous NH4Cl (100.0 mL) and extracted with EtOAc (100.0 mL × 3). The combined organic layers were washed with brine (100.0 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product trimethyl-[2-[(4-methylpyrazol-1-yl)methoxy]ethyl]silane (15.0 g, 70.63 mmol) as a yellow solid, which was used directly in the next step. MS ([M+H] + :213.3.

[0212] Step 2: 2-[(3-bromo-4-methyl-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane

[0213] A solution of trimethyl-[2-[(4-methylpyrazol-1-yl)methoxy]ethyl]silane (5.0 g, 23.54 mmol) in ACN (50.0 mL) was degassed and purged with N2 three times. Then, N-bromosuccinimide (5.0 g, 28.25 mmol) was added to the mixture. The reaction mixture was stirred under N2 atmosphere at 20 °C for 16 h. The mixture was extracted with EtOAc (100.0 mL × 3). The combined organic layers were washed with brine (100.0 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 50 / 1 to 20 / 1) to give 2-[(3-bromo-4-methyl-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane (4.4 g, 15.11 mmol) as a yellow oil. MS ([M+H] + :293.0.

[0214] Step 3: [4-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]boronic acid

[0215] A mixture of 2-[(3-bromo-4-methyl-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane (2.5 g, 8.58 mmol), bis(pinacolato)diboron (5.4 g, 21.46 mmol), potassium acetate (1.61 mL, 25.75 mmol), and X-PHOS (409.1 mg, 0.86 mmol) in 1,4-dioxane (40.0 mL) was degassed and purged with N three times. Tris(dibenzylideneacetone)dipalladium(0) (393.0 mg, 0.43 mmol) was then added to the mixture. The reaction mixture was stirred at 100 °C under a N atmosphere for 16 hours. The mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (TFA) to give [4-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]boronic acid (970.0 mg, 3.79 mmol) as a yellow solid. MS ([M+H] + :257.2.

[0216] Step 4: 2-[[3-[4-bromo-3-(trifluoromethyl)pyrazol-1-yl]-4-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0217] To a solution of 4-bromo-3-(trifluoromethyl)-1H-pyrazole (400.0 mg, 1.86 mmol), [4-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]boronic acid (572.0 mg, 2.23 mmol), molecular sieves 4A (400.0 mg), and pyridine (0.3 mL, 3.72 mmol) in 1,2-dichloroethane (20.0 mL) was added copper(II) acetate monohydrate (74.3 mg, 0.37 mmol) in one portion. O (15 psi) was then introduced into the system. The reaction mixture was stirred at 60 °C for 6 h. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 100:1 to 50:1) to give 2-[[3-[4-bromo-3-(trifluoromethyl)pyrazol-1-yl]-4-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (360.0 mg, 0.85 mmol, 39% yield) as a yellow oil. MS ([M+H] + :425.0.

[0218] Step 5: Trimethyl-[2-[[4-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]pyrazol-1-yl]methoxy]ethyl]silane

[0219] To a solution of bis(pinacolato)diboron (322.4 mg, 1.27 mmol), 2-[[3-[4-bromo-3-(trifluoromethyl)pyrazol-1-yl]-4-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (360.0 mg, 0.85 mmol), and potassium acetate (166.1 mg, 1.69 mmol) in 1,4-dioxane (10.0 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (61.9 mg, 0.08 mmol) was added in one portion under N. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by preparative TLC (PE: EtOAc = 20:1) to give trimethyl-[2-[[4-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]pyrazol-1-yl]methoxy]ethyl]silane (300.0 mg, 0.64 mmol, 40% yield) as a yellow oil. MS ([M+H] + :473.0.

[0220] Intermediate A12 9H-Fluoren-9-ylmethyl N-(3-amino-3-oxopropyl)-N-(6-bromo-3-pyridyl)carbamate

[0221] Step 1: 6-Bromo-N-[3-[tert-butyl(dimethyl)silyl]oxypropyl]pyridin-3-amine

[0222] (6-Bromo-3-pyridyl)amine (2.4 g, 14.2 mmol), 3-[tert-butyl(dimethyl)silyl]oxypropionaldehyde (2.7 g, 14.2 mol), and acetic acid (170.1 mg, 162.1 uL, 2.8 mmol) were dissolved in dichloromethane (50 mL). To this solution, sodium triacetoxyborohydride (3.6 g, 17.0 mmol) was added in portions. After the addition, the mixture was stirred at room temperature for 1 hour. The mixture was poured into 100 mL of water and extracted with DCM (50 mL x 2). The extracts were combined, washed with brine, and dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash chromatography to give the title compound as a pale yellow solid, 3.0 g. MS [M+H] + :345.6.

[0223] Step 2: 9H-Fluoren-9-ylmethyl N-(6-bromo-3-pyridyl)-N-(3-hydroxypropyl)carbamate

[0224] (6-Bromo-3-pyridyl)-[3-[tert-butyl(dimethyl)silyl]oxypropyl]amine (3.0 g, 8.7 mmol) was dissolved in 5 mL of toluene, and this solution was added dropwise to a solution of chlorocarboxylic acid 9H-fluoren-9-ylmethyl ester (2.2 g, 8.7 mmol) in anhydrous toluene (ultra-dry, 20 mL) at 0° C. After the addition, the mixture was stirred at 0° C. for 1 hour and then at room temperature for an additional hour, at which time a yellow precipitate formed. The mixture was stirred overnight. The solvent was removed in vacuo, and the residue was purified by flash chromatography to give the title compound as a pale yellow oil, 2.0 g. MS [M+H] + :453.1.

[0225] Step 3: 3-[(6-bromo-3-pyridyl)-(9H-fluoren-9-ylmethoxycarbonyl)amino]propanoic acid

[0226] Iodobenzene diacetate (703.4 mg, 2.2 mmol), TEMPO (62.4 mg, 0.4 mmol), and N-(6-bromo-3-pyridyl)-N-(3-hydroxypropyl)carbamic acid 9H-fluoren-9-ylmethyl ester (900 mg, 2.0 mmol) were combined in a reaction vessel, and acetonitrile (11 mL) and water (6 mL) were added. The reaction mixture was stirred for 3 hours, after which another batch of iodobenzene diacetate (703.4 mg, 2.2 mmol) was added. Stirring was continued overnight (approximately 18 hours). The solvent was removed in vacuo, and the residue was purified by flash chromatography to give the title compound as a pale yellow foam, 778 mg. MS [M+H] + :467.1.

[0227] Step 4: 9H-Fluoren-9-ylmethyl N-(3-amino-3-oxo-propyl)-N-(6-bromo-3-pyridyl)carbamate

[0228] 3-[(6-Bromo-3-pyridyl)-(9H-fluoren-9-ylmethoxycarbonyl)amino]propionic acid (142 mg, 0.3 mmol), ammonium chloride (32.5 mg, 0.6 mmol), and DIEA (196.4 mg, 265.4 uL, 1.5 mmol) were stirred in N,N-dimethylacetamide (5 mL) for 1 minute. HATU (138.6 mg, 0.4 mmol) was added to the mixture, and the resulting solution was stirred at 25 °C for 1 hour. The mixture was poured into 100 mL of water and extracted with EtOAc (50 mL x 3). The extracts were combined, washed with 50 mL of brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography to give the title compound as a pale yellow oil, 114 mg. MS [M+H] + :466.1.

[0229] Intermediate A13 2-[[4-(methoxymethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0230] Step 1: Methyl 1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate

[0231] To a solution of methyl 1H-pyrazole-4-carboxylate (5.0 g, 39.65 mmol, 1 equiv) in THF (100 mL) was slowly added 60% sodium hydride in oil (1.9 g, 47.58 mmol, 1.2 equiv) at 0 °C. After the addition, the reaction mixture was stirred at 0 °C for 1 h. Then, 2-(trimethylsilyl)ethoxymethyl chloride (7.72 mL, 43.61 mmol, 1.1 equiv) was added to the mixture at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 15 h. The reaction was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated. Purification by silica gel chromatography (PE / EtOAc 10:1) afforded the title compound (10 g, 39.01 mmol, 79.65% yield) as a pale yellow oil. MS [M+H] + :257.0.

[0232] Step 2: [1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methanol

[0233] To a solution of methyl 1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (5.0 g, 19.5 mmol, 1 equiv.) in THF (100 mL) was added lithium aluminum hydride (1.11 g, 29.25 mmol, 1.5 equiv.) slowly at 0 °C. After the addition, the reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched with HO (1 mL) and NaOH (10%, 1 mL) at 0 °C. NaSO (5.0 g) was then added to the mixture. The mixture was stirred at 25 °C for 1 h. The mixture was filtered, and the filtrate was concentrated to give the crude title compound (5 g, 21.9 mmol, 112% yield) as a pale yellow oil, which was used directly in the next step without further purification. MS [M+H] + :229.1.

[0234] Step 3: 2-[[4-(methoxymethyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0235] To a solution of [1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methanol (5.0 g, 21.9 mmol, 1 equiv) in THF (100 mL) was slowly added 60% sodium hydride in oil (1.31 g, 32.84 mmol, 1.5 equiv) at 0 °C. After the addition, the reaction mixture was stirred at 0 °C for 1 h. Then, iodomethane (1.64 mL, 26.27 mmol, 1.2 equiv) was added to the mixture at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction was quenched with NH Cl (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over Na SO and concentrated. Purification by silica gel chromatography (PE / EtOAc 10:1) afforded the title compound (3.2 g, 13.2 mmol, 51.93% yield) as a pale yellow oil. MS [M+H] + :243.1.

[0236] Step 4: 2-[[3-bromo-4-(methoxymethyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0237] To a solution of 2-[[4-(methoxymethyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (1.0 g, 4.13 mmol, 1 equiv) in THF (15 mL) was added LDA (4.13 mL, 8.25 mmol, 2 equiv) under nitrogen at −78° C. The mixture was stirred at −78° C. for 1 h. Then, 1,2-dibromotetrachloroethane (2.0 g, 6.14 mmol, 1.49 equiv) in THF (15 mL) was added at −78° C. The mixture was stirred at −78° C. for 2 h. The reaction mixture was poured into aqueous HCl (0.5 M, 100 mL) and extracted with EA (3 × 50 mL). The organics were washed with brine, dried over NaSO, and concentrated to dryness. The crude product was then purified by flash column (0.1% FA as additive) and dried by lyophilization to give the title compound (700 mg, 2.18 mmol, 44.2% yield) as a light brown oil. MS [M-CH2CH2SiMe3+H] + :219.0.

[0238] Step 5: [4-(methoxymethyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]boronic acid

[0239] A mixture of 2-[[3-bromo-4-(methoxymethyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (3 g, 9.3 mmol, 1 equiv.), bis(pinacolato)diboron (2.61 g, 10.27 mmol, 1.1 equiv.), potassium acetate (0.88 mL, 14.01 mmol, 1.5 equiv.), and X-Phos (890.27 mg, 1.87 mmol, 0.200 equiv.) in 1,4-dioxane (20 mL) was degassed and purged with N2 three times. Tris(dibenzylideneacetone)dipalladium (855.04 mg, 0.930 mmol, 0.100 equiv.) was then added to the mixture. The reaction mixture was stirred at 100 °C under a N2 atmosphere for 16 h. The mixture was filtered and concentrated. Purification by preparative HPLC (0.1% FA as additive) gave the title compound (1.7 g, 64%) as a yellow oil. MS [M+H] + :287.1.

[0240] Step 6: 2-[[3-[4-bromo-3-(trifluoromethyl)pyrazol-1-yl]-4-(methoxymethyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0241] A mixture of [4-(methoxymethyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]boronic acid (1.2 g, 4.19 mmol, 1 equiv.), 4-bromo-3-(trifluoromethyl)-1H-pyrazole (1.2 g, 5.58 mmol, 1.33 equiv.), copper(II) acetate monohydrate (0.84 g, 4.19 mmol, 1 equiv.), and 4 Å molecular sieves (1.0 g) was added to a flask. The flask was evacuated and purged with N gas four times. DMF (14 mL) and pyridine (1.7 mL, 20.96 mmol, 5 equiv.) were added. The mixture was stirred under oxygen at 80 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column (0.1% FA as additive) and dried by lyophilization to give the title compound (1 g, 2.2 mmol, yield 52.38%) as a green oil. MS [M-30+H] + :425.2.

[0242] Step 7: 2-[[4-(methoxymethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0243] To a mixture of 2-[[3-[4-bromo-3-(trifluoromethyl)pyrazol-1-yl]-4-(methoxymethyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (900.0 mg, 1.98 mmol, 1 equiv.) in THF (9 mL) under nitrogen at 0 °C was added iPrMgCl·LiCl (3.6 mL, 4.68 mmol, 2.37 equiv.). The mixture was stirred at 20 °C for 2 h. Then, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (489.62 mg, 2.63 mmol, 1.33 equiv.) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction was poured into 0.5 M HCl (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried (MgSO), filtered and concentrated to give the crude title compound (1500 mg, 2.99 mmol, 99.7% yield) as a yellow oil, which was used directly in the next step without further purification. MS [M-30+H] + :471.4.

[0244] Intermediate B1.1 tert-Butyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate

[0245] Step 1: tert-Butyl 2-chloro-4-nitro-benzoate

[0246] To a mixture of 2-chloro-4-nitro-benzoic acid (15.0 g, 74.42 mmol), N,N-dimethylpyridin-4-amine (2.73 g, 22.33 mmol), and N,N-diethylethanamine (31.12 mL, 223.26 mmol) in THF (80 mL) was added a solution of tert-butoxycarbonyl tert-butyl carbonate (24.36 g, 111.63 mmol) in THF (20 mL) at −10° C. The resulting mixture was warmed to 25° C. and stirred for an additional 14 h. The mixture was concentrated. The residue was treated with EA (50 mL) and HO (50 mL). The mixture was extracted with EA. The combined organic layers were concentrated. The crude product was then purified by flash column chromatography to give tert-butyl 2-chloro-4-nitro-benzoate (18.8 g) as a colorless solid.

[0247] Step 2: tert-Butyl 4-amino-2-chloro-benzoate

[0248] To a mixture of tert-butyl 2-chloro-4-nitro-benzoate (18.8 g, 72.96 mmol) and ammonium chloride (19.51 g, 364.81 mmol) in ethanol (200 mL) and water (200 mL) was added iron (20.37 g, 364.81 mmol). The mixture was stirred at 25 °C for 14 h. The mixture was filtered through Celite. The filtrate was concentrated to remove ethanol. The mixture was extracted with EA. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give tert-butyl 4-amino-2-chloro-benzoate (16.31 g) as a pale yellow solid. MS [M+H] + :228.1.

[0249] Step 3: tert-butyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate

[0250] A mixture of 5-bromo-1-methyl-imidazole-2-carboxylic acid hydrochloride (7.0 g, 28.99 mmol), tert-butyl 4-amino-2-chloro-benzoate (6.0 g, 26.35 mmol), HATU (13.23 g, 34.79 mmol), and DIPEA (16.16 mL, 92.77 mmol) in DMF (15 mL) was stirred at 25 °C for 3 h. Water (10 mL) was added to the mixture, and it was extracted with EA. The combined organic layers were concentrated. The crude product was purified by FCC to give tert-butyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate (8 g, 19.29 mmol) as a white solid. MS [M+H] + :414.0.

[0251] The following intermediates were prepared similarly to intermediate B1.1: [Table 1]

[0252] Intermediate B2.1 5-Bromo-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-imidazole-2-carboxamide

[0253] Step 1: 4-(5-bromo-1-methyl-imidazole-2-carboxamido)-2-chlorobenzoic acid

[0254] In a 250 mL round-bottom flask, tert-butyl 4-(5-bromo-1-methyl-imidazole-2-carboxamido)-2-chlorobenzoate (5 g, 12.1 mmol) was combined with CHCl (30 mL) to give a light brown solution. TFA (41.2 g, 27.9 mL, 362 mmol) was added. The reaction was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated in vacuo to give 4-(5-bromo-1-methyl-imidazole-2-carboxamido)-2-chlorobenzoic acid (4.32 g). MS [M+H] + :359.8.

[0255] Step 2: tert-butyl 4-(4-(5-bromo-1-methyl-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxylate

[0256] In a 100 mL round-bottom flask, 4-(5-bromo-1-methyl-imidazole-2-carboxamido)-2-chlorobenzoic acid (2 g, 5.58 mmol), tert-butyl piperazine-1-carboxylate (1.19 g, 6.41 mmol), and DIEA (2.16 g, 2.92 mL, 16.7 mmol) were combined with DMF (15 mL) to give a colorless solution. HATU (2.76 g, 7.25 mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into 150 mL of HO and extracted with EtOAc (75 mL × 3). The organic layers were combined and washed with saturated NaCl (75 mL x 1), the organic layer was dried over Na2SO4 and concentrated in vacuo to give tert-butyl 4-(4-(5-bromo-1-methyl-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxylate (2.94 g). MS [M+H] + :527.9.

[0257] The following intermediates were prepared similarly to intermediate B2.1: [Table 2]

[0258] Intermediate B3.1 5-Bromo-N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-imidazole-2-carboxamide

[0259] In a 100 mL round-bottom flask, tert-butyl 4-(4-(5-bromo-1-methyl-imidazole-2-carboxamide)-2-chlorobenzoyl)piperazine-1-carboxylate (2.94 g, 5.58 mmol) was combined with THF (20 mL) to give a light brown solution. HCl (in water) (11.6 mL, 140 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 5-bromo-N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-imidazole-2-carboxamide (2.38 g). MS [M+H] + :427.8.

[0260] The following intermediates were prepared similarly to intermediate B2.1: [Table 3]

[0261] Intermediate B4 tert-Butyl 4-(4-(4-(5-bromo-1-methyl-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate

[0262] In a 100 mL round-bottom flask, 5-bromo-N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-imidazole-2-carboxamide (2.38 g, 5.58 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.05 g, 8.92 mmol), and DIEA (2.16 g, 2.92 mL, 16.7 mmol) were combined with DMF (15 mL) to give a light brown solution. HATU (3.39 g, 8.92 mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into 150 mL of HO and extracted with EtOAc (50 mL × 3). The organic layers were combined and washed with saturated NaCl (75 mL × 1), and the organic layer was dried over NaSO and concentrated in vacuo. tert-Butyl 4-(4-(4-(5-bromo-1-methyl-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (3.56 g). MS [M+H] + :638.9.

[0263] The following intermediates were prepared similarly to intermediate B4. [Table 4-1] [Table 4-2]

[0264] Intermediate B12 tert-Butyl 1-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperidine-4-carboxylate

[0265] Intermediate B1.1 (1200 mg, 3.2 mmol) was stirred in a 20% TFA / DCM solution at room temperature for 4 hours. The solvent was then removed in vacuo. The residue was dissolved in acetonitrile (17 mL). To this solution was added isonipecotic acid tert-butyl ester (744.0 mg, 4.0 mmol), HATU (1.4 g, 3.7 mmol), and DIEA (1.3 g, 1.8 mL, 10.0 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo, and the residue was purified by flash chromatography to give the title compound as an off-white solid (1.65 g). MS [M+H] + :527.1.

[0266] Intermediate C1 tert-Butyl 2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoate

[0267] In a 100 mL round-bottom flask, tert-butyl 4-(5-bromo-1-methyl-imidazole-2-carboxamido)-2-chlorobenzoate (2 g, 4.82 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (1.64 g, 6.27 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (314 mg, 482 μmol), and NaCO (1.53 g, 14.5 mmol) were combined with 1,4-dioxane (30 mL) and water (3 mL) and stirred at 100° C. under N for 15 hours. The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 10% MeOH in DCM) to give tert-butyl 2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-imidazole-2-carboxamido)benzoate (2 g). MS [M+H] + :470.7.

[0268] The following intermediates were prepared similarly to intermediate C1. [Table 5-1] [Table 5-2] [Table 5-3]

[0269] Intermediate C5 (exo)-6-[[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0270] Step 1: 2,2,2-trifluoroacetic acid compound and 2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoic acid

[0271] In a 50 ml flask, tert-butyl 2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoate (1.3 g, 2.77 mmol, 1 equiv.) was dissolved in DCM (15 ml). TFA (6.31 g, 4.26 ml, 55.3 mmol, 20 equiv.) was added. The reaction was stirred at room temperature. After 2 h, the crude reaction mixture was concentrated in vacuo. The residue was dissolved in approximately 20 mL of water. The precipitate was filtered off, washed with water, and dried under HV to give the title compound (1.23 g, 84%) as an off-white solid. MS[MH] - :412.2.

[0272] Step 2: (exo)-6-[[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0273] A mixture of 2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoic acid (550 mg, 1.33 mmol, 1 equiv.), rac-(exo)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (395.33 mg, 1.99 mmol, 1.5 equiv.), and HATU (758.18 mg, 1.99 mmol, 1.5 equiv.) was combined with N,N-dimethylformamide (ultra-dry, 10 mL). DIPEA (515.41 mg, 696.5 µL, 3.99 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture while cooling in an ice bath. Since the product did not precipitate, the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with 5% LiCl solution and brine. Sodium sulfate was added, and the mixture was filtered and evaporated to dryness. Purification by flash chromatography (12 g, MeOH / DCM 1:9 in DCM, 0-80%) afforded the title compound (769 mg, 95%) as a white solid. MS [MH] - :592.2.

[0274] Intermediate C6 (2S,4R)-2-[(exo)-6-[[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester

[0275] Step 1: N-[3-chloro-4-[[rac-(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; hydrochloride

[0276] To a solution of tert-butyl rac-(1S,5R)-6-[[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (730.0 mg, 1.23 mmol, 1 equiv.) in 1,4-dioxane (10 mL) was added hydrochloric acid in dioxane (14.6 mL, 58.4 mmol, 47.52 equiv.). The mixture was stirred at 20° C. for 2 hours. The mixture was concentrated in vacuo to give the title compound (652 mg, 1.23 mmol, 100.04% yield) as a pale yellow solid. MS [M+H] + :494.1

[0277] Step 2: (2S,4R)-2-[(exo)-6-[[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester

[0278] In a 25 ml round-bottom flask, N-[3-chloro-4-[[(exo)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide hydrochloride (135 mg, 0.234 mmol, 1 equiv.) and (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-proline (81.24 mg, 0.351 mmol, 1.5 equiv.) were combined with N,N-dimethylformamide (3 mL) to give a light brown solution. N,N-Diisopropylethylamine (46.81 mg, 63.09 uL, 0.362 mmol, 1.55 equiv) and HATU (133.57 mg, 0.351 mmol, 1.5 equiv) were added, and the reaction mixture was stirred at room temperature. After 2 h, 1 equiv of each reagent was added, and stirring was continued at room temperature. After 4 h, water was added, and the mixture was extracted with DCM. The combined organic layers were washed twice with 5% LiCl solution, brine, and dried over Na2SO4. After filtration and evaporation of the volatiles, the residue was purified by column chromatography on silica gel (4 g SiO2, 0% to 100% (DCM:MeOH; 9:1) in DCM) to give the title compound (156.8 mg, 91.85%) as an off-white solid. MS [M+H] + :707.2

[0279] Intermediate D1 tert-Butyl 4-(2-chloro-4-(1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate

[0280] To a 25 mL microwave vial was added tert-butyl 4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (1.5 g, 2.58 mmol), 2-chloro-5-nitropyridine (531 mg, 3.35 mmol), and K2CO3 (712 mg, 5.15 mmol) in MeCN (18 mL). The vial was capped and heated in a microwave at 100 °C for 2 h. The crude reaction mixture was concentrated in vacuo. 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, 0% to 10% MeOH in DCM) to give tert-butyl 4-(2-chloro-4-(1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (1.4 g). MS [M+H] + :704.2.

[0281] The following intermediates were prepared similarly to intermediate D1. [Table 6-1] [Table 6-2] [Table 6-3] Intermediate D10 tert-Butyl 4-[2-chloro-4-[[5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2 carbonyl]amino]benzoyl]piperazine-1-carboxylate

[0282] Under N protection, a mixture of tert-butyl 4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate (600 mg, 1.03 mmol), 2-bromo-5-methoxy-pyridine (581.54 mg, 3.09 mmol), CuI (196.35 mg, 1.03 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (219.97 mg, 1.55 mmol) in DMF (10 mL) was heated at 100 °C for 16 h. The mixture was concentrated, and the residue was purified by flash column chromatography to give tert-butyl 4-[2-chloro-4-[[5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2 carbonyl]amino]benzoyl]piperazine-1-carboxylate (500 mg). MS [M+H] + :689.4.

[0283] The following intermediates were prepared similarly to intermediate D10. [Table 7]

[0284] Intermediate D30 tert-Butyl 4-[4-[4-[[5-[1-(5-amino-3-fluoro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate

[0285] tert-Butyl 4-[4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (300.0 mg, 0.430 mmol, 1 equiv.), 2-(2,6-dimethylamino)- ... To a solution of (6-bromo-5-fluoro-pyridin-3-amine)-2-oxo-acetic acid (41.81 mg, 0.220 mmol, 0.500 equiv.), 6-bromo-5-fluoro-pyridin-3-amine (90.94 mg, 0.480 mmol, 1.1 equiv.), phosphoric acid, potassium salt (0.11 mL, 1.3 mmol, 3 equiv.) was added copper(I) iodide (0.01 mL, 0.430 mmol, 1 equiv.) under N2. The mixture was degassed and then stirred at 120 °C under N2 for 16 h. The mixture was poured into water (30 mL), then filtered, and the cake was washed with EtOAc (4 × 30 mL). The organic layer was separated and then washed with brine (3 × 30 mL), dried over sodium sulfate, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (FA conditions) to give tert-butyl 4-[4-[4-[[5-[1-(5-amino-3-fluoro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (90 mg, 0.110 mmol, 25.89% yield) as a pale yellow solid. MS [M+H] + :803.3.

[0286] The following intermediates were prepared similarly to intermediate D30. [Table 8]

[0287] Intermediate D40 tert-Butyl (1R,5S,6s)-6-(2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0288] Step 1: 2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoic acid

[0289] In a 50 mL round-bottom flask, tert-butyl 2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoate (583 mg, 1.06 mmol, 1 equiv.) and TFA (6.07 g, 4.1 ml, 53.2 mmol, 50 equiv.) were combined with DCM (2 ml) to give a light brown solution. TFA (6.07 g, 4.1 ml, 53.2 mmol, 50 equiv.) was added. The reaction was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated in vacuo to give the crude title compound (523 mg, 1.06 mmol, 99.9% yield), which was used directly in the next step. MS [M] + :491.9

[0290] Step 2: tert-Butyl (1R,5S,6s)-6-(2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0291] In a 50 mL round-bottom flask, 2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoic acid (340 mg, 691 μmol, 1 equiv.), tert-butyl (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (206 mg, 1.04 mmol, 1.5 equiv.), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (394 mg, 1.04 mmol, 1.5 equiv.), and DIPEA (179 mg, 241 μL, 1.38 mmol, 2 equiv.) were combined with DMF (5 mL) to give a light brown solution. The reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into 25 mL of HO and extracted with EtOAc (3 × 25 mL). The organic layers were combined and washed with saturated NaCl (1 × 25 mL). The organic layer was dried over NaSO and concentrated in vacuo to give the title compound (240 mg, 51.7% yield). MS [M+H] + :672.2.

[0292] Intermediate E1 N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide

[0293] In a 100 mL round-bottom flask, tert-butyl 4-(2-chloro-4-(1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carboxylate (1.4 g, 1.99 mmol) was combined with THF (8 mL) to give a light brown solution. Aqueous HCl (6.63 mL, 79.5 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 N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide (1.2 g). MS[M+H] + :604.2.

[0294] The following intermediates were prepared similarly to intermediate E1. [Table 9-1] [Table 9-2] [Table 9-3]

[0295] Intermediate F1 N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidin-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide

[0296] Step 1: N-[3-chloro-4-[4-(2-chloroacetyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide

[0297] To a solution of N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide.1:1 2,2,2-trifluoroacetic acid (300 mg, 0.42 mmol) in acetonitrile (5 mL) was added sodium carbonate (132.9 mg, 1.3 mmol), followed by 0.05% chloroacetyl chloride (47.2 mg, 0.42 mmol). o C was added dropwise. The reaction was stirred for 2 hours and then warmed to room temperature. The reaction mixture was washed with brine and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in the next step without further purification. MS [M+H] + :680.2.

[0298] Step 2: N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidin-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide

[0299] To a solution of N-[3-chloro-4-[4-(2-chloroacetyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide (230 mg, 0.34 mmol) in acetonitrile (3 mL) was added 3-pyrrolidinol (29.5 mg, 0.34 mmol) and TEA (68.4 mg, 0.68 mmol), and the reaction was stirred for 70 minutes. o C for 30 minutes. The reaction mixture was cooled to room temperature. The reaction mixture was washed with brine and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in the next step without further purification. MS [M+H] + :731.2.

[0300] The following intermediates were prepared similarly to intermediate F1. [Table 10]

[0301] Intermediate G1 tert-Butyl 4-(4-(4-(5-(1-(5-aminopyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-1-methyl-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate

[0302] In a 100 mL round-bottom flask, tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (47 mg, 57.7 μmol) was combined with EtOH (6 mL) / water (6 mL) to give a pale yellow color. Zinc (75.4 mg, 1.15 mmol) and NH4Cl (61.7 mg, 1.15 mmol) were added at room temperature. The reaction was stirred at room temperature for 1 hour. The reaction mixture was filtered through glass fiber paper. The filtrate was poured into 20 mL of HO and extracted with EtOAc (25 mL × 3). The organic layers were combined and washed with saturated NaCl (25 mL × 1). The organic layer was dried over Na2SO4 and concentrated in vacuo to give tert-butyl 4-(4-(4-(5-(1-(5-aminopyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-1-methyl-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (45.3 mg). MS [M+H] + :785.0.

[0303] The following intermediates were prepared similarly to intermediate G1. [Table 11]

[0304] Intermediate G7 tert-Butyl 4-[4-[4-[[5-[1-(5-amino-4-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate

[0305] To a solution of tert-butyl 4-[4-[2-chloro-4-[[1-methyl-5-[1-(4-methyl-5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (60.0 mg, 0.070 mmol, 1 equiv.) and saturated NH4Cl in water (1.0 mL) in methanol (2 mL) was added iron powder (80.82 mg, 1.45 mmol, 20 equiv.). The mixture was stirred at 30°C for 16 hours. The mixture was diluted with water (20 mL) and EtOAc (20 mL) and filtered. The filtrate was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give tert-butyl 4-[4-[4-[[5-[1-(5-amino-4-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (60 mg, 0.080 mmol, 98.56% yield) as a light brown solid. MS [M+H-Boc] + :699.3.

[0306] The following intermediates were prepared similarly to intermediate G7. [Table 12]

[0307] Intermediate H1 tert-Butyl 4-[4-[2-chloro-4-[[5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate

[0308] To a solution of tert-butyl 4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (460 mg, 0.586 mmol) in methanol (30 mL) was added 5 M acetaldehyde in THF (228.47 mg, 292.91 μL, 1.46 mmol) and acetic acid (211.07 mg, 201.21 μL, 3.51 mmol) at 0° C. The solution was then stirred at 0° C. for 30 minutes. NaBH3CN (184.07 mg, 2.93 mmol) was then added and stirred at 0° C. for 2 hours. Excess water was slowly added, and the solution was neutralized (pH = approx. 8) by the addition of 3N aqueous sodium hydroxide solution. The mixture was stirred for 1 hour. The aqueous layer was extracted with DCM. The combined organic layers were concentrated, and the residue was purified by flash column chromatography to give tert-butyl 4-[4-[2-chloro-4-[[5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (410 mg) as a yellow solid. MS [M+H] + :813.6.

[0309] Intermediate I1 (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid

[0310] To a solution of L-hydroxyproline (2.49 g, 19 mmol, 1 equiv.) in THF (26 mL) / water (13 mL) was added sodium hydroxide (13.67 mL, 38 mmol, 2 equiv.), followed by di-t-butyl dicarbonate (6.22 g, 28.5 mmol, 1.5 equiv.) at 15°C and stirred at 30°C for 16 h. While the pH was approximately 9-10, the reaction mixture was extracted with EtOAc. The aqueous layer was adjusted to pH 1-2 with 2.0 N aqueous HCl and then lyophilized. 100 mL of CH3CN and 50 mL of EtOAc were added and stirred at room temperature. After 2 h, the mixture was filtered and concentrated to give the title compound (3.8 g, 86.49% yield) as a white solid.

[0311] Example A1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate [ka]

[0312] In a 50 mL round-bottom flask, N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-5-(1-(5-methoxypyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-1-methyl-imidazole-2-carboxamide (78 mg, 111 μmol), MeI (79.1 mg, 34.8 μl, 557 μmol) and DIPEA (72 mg, 97.3 μl, 557 μmol) were combined with MeCN (5 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. The crude material was purified by preparative HPLC to give N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; formate salt (22.3 mg). MS [M+H] + :728.2.

[0313] The following compounds were prepared similarly to Example A1: [Table 13-1] [Table 13-2] [Table 13-3]

[0314] Example B1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate [ka]

[0315] Step 1: tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate

[0316] In a 50 mL round-bottom flask, N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide (110 mg, 196 μmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (58.6 mg, 255 μmol), HATU (97.1 mg, 255 μmol), and DIPEA (50.8 mg, 393 μmol) were combined with DMF (3 mL) to give a light brown solution. The reaction mixture was poured into 50 mL of HO and extracted with EtOAc (25 mL × 3). The organic layers were combined and washed with saturated NaCl (25 mL × 1). The organic layer was dried over Na2SO4 and concentrated in vacuo to give tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (150 mg). MS [M+H] + :771.6.

[0317] Step 2: N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide

[0318] In a 50 mL round-bottom flask, tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (150 mg, 195 μmol) was combined with THF (2 mL) to give a light brown solution. HCl (1.3 mL, 15.6 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 N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide (131 mg). MS [M+H] + :670.7.

[0319] Step 3: N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; formate

[0320] In a 50 mL round-bottom flask, N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide (65 mg, 96.9 μmol), MeI (68.7 mg, 30.3 μl, 484 μmol) and DIPEA (62.6 mg, 484 μmol) were combined with MeCN (5 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. The crude material was purified by preparative HPLC to give N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; formate salt (16.1 mg). MS [M+H] + :699.9.

[0321] The following compounds were prepared similarly to Example B1: [Table 14-1] [Table 14-2]

[0322] Example C1 N-[4-[4-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; Formate [ka]

[0323] Step 1: tert-butyl 3-((4-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidin-1-yl)methyl)azetidine-1-carboxylate

[0324] In a 50 mL round-bottom flask, N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide (143 mg, 213 μmol), tert-butyl 3-formylazetidine-1-carboxylate (59.2 mg, 320 μmol), and NaBHCN (26.8 mg, 426 μmol) were combined with MeOH (5 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. 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×1). The organic layer was dried over Na2SO4 and concentrated in vacuo to give tert-butyl 3-((4-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (179 mg). MS [M+H] + :840.5.

[0325] Step 2: tert-Butyl 3-[[4-[4-[2-chloro-4-[[1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-methyl-piperidin-1-ium-1-yl]methyl]azetidine-1-carboxylate; iodide

[0326] In a 50 mL round-bottom flask, tert-butyl 3-((4-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (80 mg, 95.2 μmol), MeI (67.6 mg, 29.8 μl, 476 μmol) and DIPEA (61.5 mg, 476 μmol) were combined with MeCN (5 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. The crude product was used directly in the next step to give tert-butyl 3-[[4-[4-[2-chloro-4-[[1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-methyl-piperidin-1-ium-1-yl]methyl]azetidine-1-carboxylate; iodide (81.4 mg). MS [M+H] + :854.3.

[0327] Step 3: N-[4-[4-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; formate salt

[0328] In a 50 mL round-bottom flask, 1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-4-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)-1-methylpiperidin-1-ium (81 mg, 94.7 μmol) was combined with THF (3 mL) to give a light brown solution. HCl (631 μl, 7.58 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-[4-[4-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; formate salt (16 mg). MS: 754.1.

[0329] The following compounds were prepared similarly to Example C1: [Table 15]

[0330] Example D1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate [ka]

[0331] Step 1: tert-butyl (2S,4R)-2-(4-(2-chloro-4-(1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate

[0332] In a 50 mL round-bottom flask, N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide (72 mg, 119 μmol), (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (33.1 mg, 143 μmol), HATU (54.4 mg, 143 μmol), and DIPEA (46.2 mg, 358 μmol) were combined with DMF (3 mL) to give a pale yellow solution. 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 x 1), the organic layer was dried over Na2SO4 and concentrated in vacuo to give tert-butyl (2S,4R)-2-(4-(2-chloro-4-(1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate (97.4 mg). MS [M+H] + :817.3.

[0333] Step 2: N-(3-chloro-4-(4-((2S,4R)-4-hydroxypyrrolidine-2-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide

[0334] In a 50 mL round-bottom flask, tert-butyl (2S,4R)-2-(4-(2-chloro-4-(1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate (97 mg, 119 μmol) was combined with THF (2 mL) to give a pale yellow solution. Aqueous HCl (989 μl, 11.9 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 N-(3-chloro-4-(4-((2S,4R)-4-hydroxypyrrolidine-2-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide (85.1 mg). MS [M+H] + :717.1.

[0335] Step 3: N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; iodide

[0336] In a 50 mL round-bottom flask, N-(3-chloro-4-(4-((2S,4R)-4-hydroxypyrrolidine-2-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide (85 mg, 119 μmol), MeI (84.1 mg, 593 μmol), and DIPEA (76.6 mg, 593 μmol) were combined with MeCN (5 mL) to give a light brown solution. The reaction mixture was heated to 35° C. and stirred for 2 h.

[0337] The crude reaction mixture was concentrated in vacuo. The crude product was used directly in the next step to give N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; iodide (88.4 mg). MS [M+H] + :745.1.

[0338] Step 4: 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; formate

[0339] In a 50 mL round-bottom flask, (2S,4R)-2-(4-(2-chloro-4-(1-methyl-5-(1-(5-nitropyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)-4-hydroxy-1,1-dimethylpyrrolidin-1-ium (88 mg, 118 μmol) was combined with EtOH (6 mL) to give a pale yellow solution. Ammonium chloride (631 mg, 11.8 mmol) in water (2 mL) was added. Zinc (154 mg, 2.36 mmol) was added. The reaction was stirred at room temperature for 30 minutes. The crude reaction mixture was concentrated in vacuo. The product was washed with 30 mL of EA:MeOH (10:1) and the filtrate was concentrated in vacuo. The crude material was purified by preparative HPLC to give (2S,4R)-2-(4-(4-(5-(1-(5-aminopyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-1-methyl-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbonyl)-4-hydroxy-1,1-dimethylpyrrolidin-1-ium formate (15.1 mg). MS [M+H] + :715.3.

[0340] The following compounds were prepared similarly to Example D1. [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4]

[0341] Example D15 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S)-4-hydroxy-1,1-dimethyl-piperidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate [ka]

[0342] Step 1: tert-butyl (2S)-2-[4-[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-oxo-piperidine-1-carboxylate

[0343] Intermediate E1 (300 mg, 0.5 mmol), 1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (135.2 mg, 0.6 mmol), HATU (193.6 mg, 0.5 mmol), and DIEA (299.2 mg, 404.3 uL, 2.3 mmol) were stirred in acetonitrile (4.6 mL) at 25° C. for 0.5 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography to give the title compound as a pale yellow oil, 380 mg. MS [M+H] + :829.9.

[0344] Step 2: N-[3-chloro-4-[4-[(2S)-4-hydroxypiperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide

[0345] (2S)-2-[4-[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-keto-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 0.6 mmol) was dissolved in methanol (6.0 mL) and NaBH4 (22.8 mg, 0.6 mmol) was added in one portion. The mixture was stirred at room temperature for 30 minutes. Then, 5 mL of 1 M HCl / MeOH solution was added and stirring was continued for 3 hours. The solvent was removed in vacuo, and the residue was neutralized with TEA and purified by flash chromatography to give the title compound as a pale yellow oil, 350 mg. MS [M+H] + :731.4.

[0346] Step 3: 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S)-4-hydroxy-1,1-dimethyl-piperidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; formate

[0347] N-[3-chloro-4-[4-[(2S)-4-hydroxypiperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide (200 mg, 0.3 mmol), DIEA (354 mg, 448 μL, 2.7 mmol), and iodomethane (116 mg, 51.3 μL, 0.8 mmol) were stirred in ethanol (4 mL) at room temperature for 18 hours. The solvent was removed in vacuo. The residue was dissolved in ethanol (4 mL) and 1 mL of water. To this solution was added ammonium chloride (74.8 mg, 1.4 mmol) and zinc (182.9 mg, 2.8 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was filtered, the filtrate concentrated in vacuo, and the residue was dissolved in DMF and purified by preparative HPLC to give the title compound as a pale yellow powder, 19 mg. MS[M] + :729.5.

[0348] Example D18 (exo)-6-[[4-[[5-[1-(5-aminopyridin-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chlorobenzoyl]amino]-N-[rac-(trans)-4-hydroxy-1,1-dimethylpyrrolidin-1-ium-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; formate [ka]

[0349] Step 1: (trans)-3-[[(exo)-6-[[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester

[0350] 3-Amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (93.05 mg, 0.460 mmol, 1.5 equiv) was added to a stirred solution of CDI (74.6 mg, 0.460 mmol, 1.5 equiv) and EtN (155.18 mg, 213.75 L, 1.53 mmol, 5 equiv) in N,N-dimethylformamide (14.24 mL) at 0 °C. The reaction mixture was stirred for 0.5 h, then N-[4-[[(exo)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; hydrogen chloride (230 mg, 0.307 mmol, 1 equiv.) was added. The ice bath was removed, and the reaction mixture was stirred for 2 h and allowed to warm to room temperature. The reaction mixture was poured into water (20 mL) and then extracted with EtOAc. The organic layer was washed with 5% LiCl solution and brine and concentrated. The crude residue was purified by flash chromatography (MeOH / DCM 1:9, 0-70%, 12 g) to give the title compound (106 mg, 40.94%) as an orange solid. MS [MH] - :842.2.

[0351] Step 2: (exo)-6-[[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(trans)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; hydrogen chloride

[0352] (trans)-3-[[(exo)-6-[[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (45 mg, 0.053 mmol, 1 equiv.) was combined with dichloromethane (1 mL). 4M HCl in dioxane (79.96 mg, 66.63 uL, 0.267 mmol, 5 equiv.) was added, and the reaction mixture was stirred for 2 hours. Evaporation of the solvent afforded the crude product (42 mg, 99.9%) as a yellow solid, which was used directly in the next step. MS [M+H] + :744.2.

[0353] Step 3: (exo)-6-[[4-[[5-[1-(5-aminopyridin-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chlorobenzoyl]amino]-N-[rac-(trans)-4-hydroxy-1,1-dimethylpyrrolidin-1-ium-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; formate salt

[0354] A mixture of (exo)-6-[[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(trans)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (41.6 mg, 0.053 mmol, 1 equiv.) in acetonitrile (2.88 mL) was treated with DIPEA (20.66 mg, 27.92 µL, 0.160 mmol, 3 equiv.) and iodomethane (18.91 mg, 8.33 µL, 0.133 mmol, 2.5 equiv.). The mixture was stirred at room temperature for 1 h, after which the solvent was evaporated under high vacuum, and the crude residue was used directly in the next step. A mixture of the crude residue (40 mg, 0.052 mmol, 1 equiv.) was combined with ammonium chloride (138.19 mg, 2.58 mmol, 50 equiv.), water (0.500 mL), and ethanol (1.5 mL). Zinc (67.56 mg, 1.03 mmol, 20 equiv.) was added, and the reaction mixture was stirred overnight. The reaction mixture was filtered and then purified by preparative HPLC to give the title compound (25 mg, 60%) as an off-white solid. MS [M] + :742.5.

[0355] Example E1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl] Phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide;Formate [ka]

[0356] Step 1: tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(5-(methylamino)pyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate

[0357] To a 25 mL microwave vial was added tert-butyl 4-(4-(4-(5-(1-(5-aminopyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-1-methyl-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (240 mg, 306 μmol), formaldehyde (275 mg, 9.17 mmol), and sodium methoxide (495 mg, 9.17 mmol) in MeOH (10 mL). The vial was capped and heated in a microwave at 50° C. for 15 h. The reaction was cooled to RT and NaBH (405 mg, 10.7 mmol) was added. The reaction was stirred at RT for 2 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 25 mL of saturated NH4Cl and extracted with EtOAc (25 mL × 3) and saturated NaCl (25 mL × 1). The organic layer was dried over Na2SO4 and concentrated in vacuo to give tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(5-(methylamino)pyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (169 mg). MS [M+H]+: 799.7.

[0358] Step 2: tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(5-(2,2,2-trifluoro-N-methylacetamido)pyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate

[0359] In a 50 mL round-bottom flask, tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(5-(methylamino)pyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (160 mg, 200 μmol), 2,2,2-trifluoroacetic anhydride (84.1 mg, 400 μmol) and DIPEA (129 mg, 1 mmol) were combined with DCM (3 mL) to give a pale yellow solution. 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 tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(5-(2,2,2-trifluoro-N-methylacetamido)pyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (179 mg). MS [M+H] + :895.3.

[0360] Step 3: N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(5-(2,2,2-trifluoro-N-methylacetamido)pyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide

[0361] In a 50 mL round-bottom flask, tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(5-(2,2,2-trifluoro-N-methylacetamido)pyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (170 mg, 190 μmol) was combined with THF (1 mL) to give a pale yellow solution. Aqueous HCl (3.46 g, 94.9 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 N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(5-(2,2,2-trifluoro-N-methylacetamido)pyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide (151 mg). MS [M+H] + :795.5.

[0362] Step 4: N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-[methyl-(2,2,2-trifluoroacetyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; iodide

[0363] In a 100 mL round-bottom flask, N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(5-(2,2,2-trifluoro-N-methylacetamido)pyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamide (151 mg, 190 μmol) was combined with MeCN (6 mL) to give a pale yellow solution. DIPEA (73.6 mg, 570 μmol) and MeI (135 mg, 950 μmol) were 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 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-[methyl-(2,2,2-trifluoroacetyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; iodide (157 mg). MS [M+H] + :823.4.

[0364] Step 5: N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl) Pyrazol-4-yl]imidazole-2-carboxamide; Formate

[0365] In a 100 mL round-bottom flask, 4-(4-(2-chloro-4-(1-methyl-5-(1-(5-(2,2,2-trifluoro-N-methylacetamido)pyridin-2-yl)-3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)-1,1-dimethylpiperidin-1-ium (150 mg, 182 μmol) was combined with MeOH (6 mL) to give a pale yellow solution. KCO (2.52 g, 18.2 mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was filtered through glass fiber paper. The filtrate was concentrated in vacuo. The crude material was purified by preparative HPLC to give N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; formate salt (31 mg). MS: 727.3.

[0366] The following compounds were prepared similarly to Example E1. [Table 17-1] [Table 17-2]

[0367] Example F1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(hydroxymethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate [ka]

[0368] Step 1: tert-Butyl 4-[4-[2-chloro-4-[[5-[1-[5-(hydroxymethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl] Piperazine-1-carbonyl]piperidine-1-carboxylate

[0369] 4-[4-[2-chloro-4-[[5-[1-(5-formyl-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (69 mg, 0.086 mmol) was dissolved in methanol (5 mL) and NaBH4 (32.7 mg, 0.864 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo, and the crude product was used directly in the next step to give tert-butyl 4-[4-[2-chloro-4-[[5-[1-[5-(hydroxymethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl] Piperazine-1-carbonyl]piperidine-1-carboxylate (69 mg) was obtained. MS [M+H] + :800.7.

[0370] Step 2: N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(hydroxymethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide

[0371] 4-[4-[2-chloro-4-[[1-methyl-5-[1-(5-methylol-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (69 mg, 0.086 mmol) was dissolved in tetrahydrofuran (2 mL) and 12 M aqueous HCl (718.54 μL, 8.62 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and the crude product was used directly in the next step to give N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(hydroxymethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide (60.3 mg). [M+H] + :700.3.

[0372] Step 3: N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(hydroxymethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; formate

[0373] N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-1-methyl-5-[1-(5-methylol-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide (60.3 mg, 0.086 mmol) was dissolved in acetonitrile (2 mL). Acetonitrile (2 mL), DIEA (55.66 mg, 0.431 mmol), and iodomethane (61.13 mg, 0.431 mmol) were added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and the crude product was purified by HPLC to give N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(hydroxymethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; formate salt (18 mg). MS: [M+H] + :728.4.

[0374] Example G1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formate [ka]

[0375] Step 1: tert-butyl 4-[4-[2-chloro-4-[[5-[1-[5-(2-methoxyethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate

[0376] Under N2 protection, a mixture of tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-pyrazol-4-yl)-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (200 mg, 0.3 mmol), 2-bromo-5-(2-methoxyethoxy)pyridine (133.9 mg, 0.6 mmol), copper(I) iodide (54.9 mg, 0.3 mmol), and trans-n,n'-dimethylcyclohexane-1,2-diamine (82.1 mg, 0.6 mmol) in N,N-dimethylformamide (ultra-dry, 3.3 mL) was heated at 100°C for 1 hour. The mixture was then concentrated, and the residue was purified by flash column chromatography to give the title compound (220 mg) as a black oil. MS [M+H] + :845.3.

[0377] Step 2: N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; formic acid

[0378] Tert-butyl 4-[4-[2-chloro-4-[[5-[1-[5-(2-methoxyethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (300 mg, 0.4 mmol) was stirred in 1 M HCl / MeOH solution (1.8 mL) at room temperature for 4 hours. The solvent was then concentrated, and the residue was purified by preparative HPLC to give 46 mg of the title compound as a white powder. MS [M+H]: 744.4.

[0379] Step 3: N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; formate

[0380] Under N2 protection, a mixture of N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; formic acid (300 mg, 0.4 mmol), iodomethane (127 mg, 1.2 mmol), and DIEA (521 mg, 4.0 mmol) was stirred in ethanol (4.0 mL) at room temperature for 18 hours. The mixture was then concentrated, and the residue was purified by preparative HPLC to give 50 mg of the title compound as an off-white powder. MS [M] + :772.4.

[0381] Example H1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate [ka]

[0382] Step 1: N-[3-chloro-4-[4-(4-methylpiperazine-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide

[0383] tert-Butyl 1-[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxylate (200 mg, 0.3 mmol) was dissolved in 20% TFA / DCM solution (5 mL) and stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue, 1-methylpiperazine (37.2 mg, 41.2 μL, 0.4 mmol), HATU (129.3 mg, 0.3 mmol), and DIEA (119.9 mg, 162.0 μL, 0.9 mmol) were stirred in acetonitrile (3.1 mL) at room temperature for 30 minutes. The solvent was removed in vacuo, and the residue was purified by flash chromatography to give the title compound as a pale yellow oil (224 mg). MS[M+H] + :729.3.

[0384] Step 2: N-[3-chloro-4-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; iodide

[0385] N-[3-chloro-4-[4-(4-methylpiperazine-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide (220 mg, 0.3 mmol) was dissolved in acetonitrile (3.1 mL). To this solution was added iodomethane (85.7 mg, 37.7 μL, 0.6 mmol). The mixture was stirred at 25° C. for 18 hours. The solvent was removed in vacuo, and the crude product was used in the next step without purification. MS [M+H] + :745.3.

[0386] Step 3: 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; formate

[0387] N-[3-chloro-4-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide (200 mg, 0.3 mmol) and ammonium chloride (718.8 mg, 13.4 mmol) were suspended in ethanol (4.0 mL) and water (1.3 mL). The mixture was stirred at room temperature for 1 hour. Zinc (351.4 mg, 5.4 mmol) was then added, and the mixture was stirred at room temperature for an additional hour. Upon completion, the reaction was filtered through Celite, and the filtrate was concentrated in vacuo. The crude material was dissolved in 5 mL of DMAc, filtered, and purified by preparative HPLC to give the title compound as an off-white powder. MS [M] + :713.4.

[0388] The following compounds were prepared similarly to Example H1: [Table 18]

[0389] Example I1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(4,4-dimethyl-2-oxo-piperazin-4-ium-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate [ka]

[0390] Step 1: 2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoic acid

[0391] Tert-butyl 1-[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxylate (180 mg, 0.3 mmol) was dissolved in 20% TFA / DCM solution (5 mL) and stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was used in the next step without further purification.

[0392] Step 2: Benzyl 4-[[1-[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-4-piperidyl]methyl]-3-oxo-piperazine-1-carboxylate

[0393] 2-Chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoic acid (165 mg, 0.3 mmol), benzyl 3-oxo-4-(4-piperidylmethyl)piperazine-1-carboxylate (144.7 mg, 0.4 mmol), DIEA (217.1 mg, 293.4 uL, 1.7 mmol), and HATU (153.3 mg, 0.4 mmol) were stirred in acetonitrile (5 mL) at room temperature for 1 hour. The solvent was removed in vacuo, and the residue was purified by flash chromatography to give the title compound as a pale yellow oil (250 mg). MS [M+H] + :849.6.

[0394] Step 3: N-[3-chloro-4-[4-[(2-oxopiperazin-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide

[0395] Benzyl 4-[[1-[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-4-piperidyl]methyl]-3-oxo-piperazine-1-carboxylate (250 mg, 0.3 mmol) in TFA (5 mL) was heated at 100° C. for 1 hour under microwave irradiation. The solvent was removed in vacuo. The residue was used in the next step without purification. MS [M+H] + :715.4.

[0396] Step 4: 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(4,4-dimethyl-2-oxo-piperazin-4-ium-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; formate

[0397] N-[3-chloro-4-[4-[(2-oxopiperazin-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide (100 mg, 0.1 mmol), DIEA (180.7 mg, 244.2 μL, 1.4 mmol), and iodomethane (79.4 mg, 35.0 μL, 0.6 mmol) were stirred in ethanol (4 mL) at room temperature for 18 hours. The solvent was removed in vacuo. The residue was dissolved in ethanol (4 mL) and 1 mL of water. To this solution was added ammonium chloride (74.8 mg, 1.4 mmol) and zinc (182.9 mg, 2.8 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was filtered, the filtrate concentrated in vacuo, and the residue was dissolved in DMF and purified by preparative HPLC to give the title compound as a pale yellow powder, 40 mg. MS[M] + :713.5.

[0398] Example J1 5-[1-(5-amino-2-pyridyl)-3-(difluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetate [ka]

[0399] Step 1: 5-[1-(5-amino-2-pyridyl)-3-methoxy-pyrazol-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

[0400] A solution of compound tert-butyl N-[6-[4-[2-[[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-methoxy-pyrazol-1-yl]-3-pyridyl]carbamate (100.0 mg, 0.13 mmol) in HCl / dioxane (2.0 mL, 8.00 mmol) was stirred at 20° C. for 2 hours. The reaction mixture was concentrated in vacuo to give a residue that was purified by preparative HPLC (0.1% TFA as an additive) and lyophilized to dryness to give 5-[1-(5-amino-2-pyridyl)-3-methoxy-pyrazol-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid (50.0 mg, 0.06 mmol, 53% yield) as a yellow solid. MS [M+H] + :661.3.

[0401] Step 2: 5-[1-(5-amino-2-pyridyl)-3-methoxy-pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetate (RW-40-57)

[0402] To a solution of 5-[1-(5-amino-2-pyridyl)-3-methoxy-pyrazol-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid (30.0 mg, 0.05 mmol) in ACN (2.0 mL) was added DIEA (58.5 mg, 0.45 mmol) and iodomethane (32.2 mg, 0.23 mmol). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by flash column (0.1% TFA as additive) and lyophilized to dryness to give 5-[1-(5-amino-2-pyridyl)-3-methoxy-pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetate (17.3 mg) as a yellow solid. MS [M+H] + :675.3.

[0403] The following compounds were prepared similarly to Example J1. [Table 19]

[0404] Example K1 5-[1-(6-aminopyridazin-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetate [ka]

[0405] Step 1: tert-Butyl N-[6-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]pyridazin-3-yl]carbamate; iodide

[0406] To a solution of intermediate D22 (50.0 mg, 0.06 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.11 mL, 0.62 mmol, 10.0 equiv) in ACN (2.0 mL) was added iodomethane (0.04 mL, 0.62 mmol, 10.0 equiv) in one portion under N. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture is concentrated to give tert-butyl N-[6-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]pyridazin-3-yl]carbamate; iodide (60.0 mg, 0.06 mmol, 102% yield) as a brown solid (crude), which is used directly in the next step without further purification. MS[M+H] + :814.1.

[0407] Step 2: 5-[1-(6-aminopyridazin-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetate

[0408] A mixture of tert-butyl N-[6-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]pyridazin-3-yl]carbamate; iodide (60.0 mg, 0.06 mmol, 1.0 equiv) in hydrochloric acid in dioxane (4 M) (0.5 mL, 2.0 mmol, 31.41 equiv) was stirred for 1 hour at 25° C. The reaction mixture was concentrated to give the crude product. The crude product was purified by preparative HPLC (TFA) to give 5-[1-(6-aminopyridazin-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetate (12.2 mg, 0.01 mmol, 21% yield) as a white solid. MS [M+H] + :714.2.

[0409] The following compounds were prepared analogously to Example K1. The order of the steps can be reversed. [Table 20]

[0410] Example L1 5-[1-[5-[(3-amino-3-oxopropyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Formate [ka]

[0411] Step 1: tert-butyl 4-[4-[4-[[5-[1-[5-[(3-amino-3-oxo-propyl)-(9H-fluoren-9-ylmethoxycarbonyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate

[0412] 4-[4-[4-[[5-[1-[5-[(3-amino-3-keto-propyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (426 mg, 0.5 mmol), chlorocarboxylic acid 9H-fluoren-9-ylmethyl ester (154.4 mg, 0.6 mmol), and sodium bicarbonate (62.7 mg, 0.7 mmol) were stirred in 1,4-dioxane (10 mL) at room temperature for 24 hours. The solvent was removed in vacuo. The residue was purified by flash chromatography to give 432 mg of the title compound as a pale yellow foam. MS [M+H] + :1078.4.

[0413] Step 2: 9H-Fluoren-9-ylmethyl N-(3-amino-3-oxo-propyl)-N-[6-[4-[2-[[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]carbamate

[0414] 4-[4-[4-[[5-[1-[5-[(3-amino-3-keto-propyl)-(9H-fluoren-9-ylmethoxycarbonyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.4 mmol) was dissolved in 5 mL of 1 M HCl / MeOH solution. The solution was stirred at room temperature for 18 hours. The solvent was removed in vacuo to give the crude product. MS [M+H] + :978.2.

[0415] Step 3: 5-[1-[5-[(3-amino-3-oxo-propyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; formate

[0416] N-(3-amino-3-keto-propyl)-N-[6-[4-[2-[[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]carbamic acid 9H-fluoren-9-ylmethyl ester (360 mg, 0.4 mmol), iodomethane (208.9 mg, 92.0 µL, 1.5 mmol), and DIEA (475.5 mg, 642.6 µL, 3.7 mmol) were stirred in N,N-dimethylacetamide (5 mL) at room temperature for 30 minutes. 1 mL of piperidine was added to the solution, and stirring was continued for 15 minutes. The product was directly purified by preparative HPLC to give 50 mg of the title compound as a white powder. MS [M] + :784.3.

[0417] The following compounds were prepared similarly to Example L1: [Table 21]

[0418] Example M1 5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide;2,2,2-Trifluoroacetic acid;2,2,2-Trifluoroacetate [ka]

[0419] Step 1: 4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

[0420] A mixture of 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-imidazole-2-carboxamide; hydrogen chloride (100 mg, 0.162 mmol, 1 equiv.) and 1-[(9H-fluoren-9-ylmethoxy)carbonyl]piperidine-4-carboxylic acid (59.84 mg, 0.170 mmol, 1.05 equiv.) in N,N-dimethylformamide (2 mL) was treated with N-ethyldiisopropylamine (83.84 mg, 113 μL, 0.649 mmol, 4 equiv.) followed by PyAOP (101.47 mg, 0.195 mmol, 1.2 equiv.) and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was transferred to half-saturated NaHCO3 (50 mL) and extracted with EtOAc (3 x 22 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and evaporated. Purification by MPLC (15-85% EtOAc / EtOH 3:1 in heptane) afforded the title compound (137 mg, 85.65%) as a pale yellow solid. MS [M+2H] 2+ :454.6.

[0421] Step 2: 4-[4-[4-[[5-[1-[5-[2-(tert-butoxycarbonylamino)ethylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

[0422] A mixture of 4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (137 mg, 0.139 mmol, 1 equiv) in dichloromethane (2 mL) was treated with molecular sieves, 3a (?, 0.139 mmol, 1 equiv), N-(2-ketoethyl)carbamic acid tert-butyl ester (33.17 mg, 0.208 mmol, 1.5 equiv) and acetic acid (16.68 mg, 15.9 uL, 0.278 mmol, 2 equiv), cooled to 0 °C and stirred for 10 min. Sodium triacetoxyborohydride (51.52 mg, 0.243 mmol, 1.75 equiv) was then added portionwise over 30 min, after which stirring was continued at room temperature for 2 h. The mixture was diluted with EtOAc and half-saturated NaHCO3 (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and evaporated. Purification by MPLC (10-90% EtOAc / EtOH in heptane 3:1) afforded the title compound (128 mg, 78.94%) as an off-white solid, which appeared to contain some impurities by NMR, but was carried forward without further purification. MS [M+HC00] - :1094.9.

[0423] Step 3: N-[2-[[6-[4-[2-[[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]amino]ethyl]carbamic acid tert-butyl ester

[0424] A mixture of 4-[4-[4-[[5-[1-[5-[2-(tert-butoxycarbonylamino)ethylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (128 mg, 0.110 mmol, 1 equiv) in acetonitrile (2.5 mL) was treated with 2 M dimethylamine in THF (548.3 uL, 1.1 mmol, 10 equiv) and the mixture was stirred at room temperature for 3 hours and evaporated. Purification by MPLC (0-100% DCM / MeOH / EtN 8:2:0.2 in DCM) gave a residue that was dissolved in 0.1 M NaOH (25 mL) and extracted with EtOAc (3 x 12 mL). The combined organic layers were washed with brine (12 mL), dried (NaSO), filtered, and evaporated to give the title compound (60 mg, 60.77%) as a white solid. MS [M+HCOO] - :872.6.

[0425] Step 4: 5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid; 2,2,2-trifluoroacetate

[0426] A mixture of N-[2-[[6-[4-[2-[[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]amino]ethyl]carbamic acid tert-butyl ester (34 mg, 0.038 mmol, 1 equiv) in N,N-dimethylformamide (2.5 mL) was treated with KCO (20.88 mg, 0.151 mmol, 4 equiv) followed by iodomethane (21.44 mg, 9.45 uL, 0.151 mmol, 4 equiv). The mixture was stirred at 40° C. for 2.5 hours and evaporated to give crude N-[2-[[6-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]amino]ethyl]carbamic acid tert-butyl ester; iodide (37 mg, 86.6%) as an off-white solid, which was used directly in the next step. MS[M] + :856.6.

[0427] A mixture of N-[2-[[6-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]amino]ethyl]carbamic acid tert-butyl ester; iodide (37 mg, 0.033 mmol, 1 equiv.) and 4M HCl in dioxane (900 mg, 0.750 mL, 3 mmol, 91.73 equiv.) in dichloromethane (2.5 mL) was stirred at room temperature for 3 hours and evaporated. Purification by RPHPLC afforded the title compound (19.3 mg, 59.95%) as a white lyoph solid. MS [M+2HCOO] - :846.7.

[0428] 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:

[0429] The assay quantitatively measured the in vitro activity of compounds against Acinetobacter baumannii ATCC17961 using 10-point Iso-Sensitest broth medium. Stock compounds in DMSO were serially diluted two-fold in 384-well microtiter plates (e.g., final concentrations ranging from 50 to 0.097 μM) and inoculated with 49 μl of bacterial suspension in Iso-Sensitest medium for a final volume / well of 50 μl / well, approximately 5×10 (5) The final cell concentration was adjusted to CFU / ml. The microtiter plates were incubated at 35±2°C.

[0430] Bacterial cell growth was determined by measuring the optical density at λ = 600 nm every 20 minutes for 16 hours. Growth inhibition was calculated during the logarithmic growth of bacterial cells, and the concentrations that inhibited growth by 50% (IC50) and 90% (IC90) were determined.

[0431] 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.

[0432] Particular compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17961) ≦25 μmol / l.

[0433] More particular compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17961) ≦5 μmol / l.

[0434] Most particular compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17961) ≦1 μmol / l. Table 1 [Table 22]

[0435] Example 1 The compounds of formula (I) can be used in a manner known per se as active ingredient to prepare tablets of the following composition:

[0436] Per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0437] Example 2 The compound of formula (I) can be used as an active ingredient in a manner known per se to prepare 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

[0438] Example 3 The compounds of formula (I) can be used in a manner known per se as an active ingredient for the preparation of infusion solutions of the following composition: 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 Water for injection (WFI) to make 100ml

[0439] Example 4 The compounds of formula (I) can be used in a manner known per se as an active ingredient for the preparation of infusion solutions of the following composition: Active ingredient 100mg Hydroxypropyl-beta-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 Water for injection (WFI) to make 100ml

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, R １ and R ２ together with the nitrogen atom to which they are attached, represent a group of formula (II), (III) or (IV): 【Chemistry 2】 or forming a group of R １ is the base 【Transformation 3】 and R ２ is hydrogen and C １ ~C ６ alkyl, R ３ is hydrogen, halogen, C １ ~C ６ Alkyl, and C １ ~C ６ alkoxy; R ４ and R ６ are each independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, cyano, halo-C １ ~C ６ Alkyl and halo-C １ ~C ６ alkoxy; R ５ａ , R ５ｂ and R ５ｃ are each independently hydrogen, halogen, hydroxy, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, amino-C １ ~C ６ Alkoxy, hydroxy-C １ ~C ６ Alkyl, halo-C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy-C １ ~C ６ Alkyl-, C １ ~C ６ Alkoxy-C １ ~C ６ Alkoxy-, amino, C １ ~C ６ Alkyl-NH-, (C １ ~C ６ alkyl) ２ N-, C １ ~C ６ Alkyl-NH-C(O)-, C １ ~C ６ Alkyl-NH-C(O)-C １ ~C ６ Alkyl-NH-, amino-C １ ~C ６ Alkyl-NH-, C １ ~C ６ Alkoxy-C １ ~C ６ Alkyl-NH-, Carbamoyl-C １ ~C ６ selected from alkyl-NH-, carbamoyl and nitro; R ７ is hydrogen, C １ ~C ６ Alkyl and halo-C １ ~C ６ alkyl, In formula (II), R ８ａ is C １ ~C ６ Alkyl, carbamoyl-C １ ~C ６ Alkyl and groups 【Chemistry 4】 is selected from In formula (III), R ８ａ is hydrogen, C １ ~C ６ Alkyl, carbamoyl-C １ ~C ６ Alkyl and groups 【Transformation 5】 is selected from R ８ｂ is hydrogen, hydroxy, hydroxy-C １ ~C ６ alkyl, group 【Transformation 6】 is selected from R ８ｃ , R １２ａ and R １２ｃ are independently １ ~C ６ is alkyl, R ９ａ , R ９ｂ , R １０ａ , R １０ｂ and R １２ｂ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halo-C １ ~C ６ Alkyl, halo-C １ ~C ６ selected from alkoxy, amino, nitro and hydroxy; R １１ａ and R １１ｂ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halo-C １ ~C ６ Alkyl, halo-C １ ~C ６ Alkoxy, amino, nitro, hydroxy and groups 【Transformation 7】 is selected from X is a carbonyl, and Y is a covalent bond, -NH-, -N(C １ ~C ６ alkyl)-, or C １ ~C ６ alkyldiyl, or X is C １ ~C ６ alkyldiyl, and Y is a covalent bond; L １ and L ３ are each independently a covalent bond, a carbonyl, and C １ ~C ６ alkyldiyl; L ２ and L ４ are each independently a covalent bond, a carbonyl, —O—, —NH—C(O)—, —C(O)—NH—, and C １ ~C ６ alkyldiyl; A and E are each independently a 5- to 14-membered heteroaryl; B, C, D, F, and G are each independently 3- to 14-membered heterocyclyl. or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) is represented by formula (II) 【Transformation 8】 is a compound of During the ceremony, R １３ is the base 【Chemistry 9】 or base 【Chemistry 10】 and R ３ , R ４ , R ５ａ , R ５ｂ , R ５ｃ , R ６ , R ７ , R ８ａ and R ８ｂ is as defined in claim 1, 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) is represented by formula (I-II) 【Chemistry 11】 is a compound of During the ceremony, R １３ is the base 【Chemistry 12】 or base 【Chemistry 13】 and R ３ , R ５ａ , R ５ｂ , R ５ｃ , R ８ａ and R ８ｂ is as defined in claim 1, 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R １ and R ２ together with the nitrogen atom to which they are attached, represent a group of formula (II), (III) or (IV): 【Chemistry 14】 or forming a group of R １ is the base 【Chemistry 15】 and R ２ is hydrogen, R ９ａ , R ９ｂ , R １０ｂ and R １１ｂ are hydrogen, In formula (II), R ８ａ is C １ ~C ６ Alkyl, carbamoyl-C １ ~C ６ Alkyl and groups 【Chemistry 16】 is selected from In formula (III), R ８ａ is hydrogen, C １ ~C ６ Alkyl, carbamoyl-C １ ~C ６ Alkyl and groups 【Chemistry 17】 is selected from R ８ｂ is hydrogen, hydroxy and radicals [Chemistry 18] is selected from R ８ｃ , R １２ａ and R １２ｃ are independently １ ~C ６ is alkyl, R １０ａ is selected from amino and nitro; R １１ａ is the base 【Chemistry 19】 and R １２ｂ is selected from hydrogen and hydroxy; X is carbonyl; Y is a covalent bond or C １ ~C ６ alkyldiyl, L １ is C １ ~C ６ alkyldiyl, L ２ is -O-, L ３ is a covalent bond, L ４ is a carbonyl, B, C, D, F, and G are each independently 3- to 14-membered heterocyclyl; E is a 5-14 membered heteroaryl; 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R １ and R ２ together with the nitrogen atom to which they are attached, form the formula (II) 【Chemistry 20】 forming a group of R ８ａ and R ８ｃ are all independently C １ ~C ６ is alkyl, R ８ｂ is selected from hydrogen and hydroxy; X is carbonyl; Y is a covalent bond; B and C are each independently 3- to 14-membered heterocyclyl; 5. A compound of formula (I) according to claim 4 or a pharmaceutically acceptable salt thereof.

6. R １ and R ２ together with the nitrogen atom to which they are attached, form the formula (II) 【Chemistry 21】 forming a group of R ８ａ and R ８ｃ are all methyl, R ８ｂ is selected from hydrogen and hydroxy; X is carbonyl; Y is a covalent bond; B is piperazinyl; C is selected from piperidyl and pyrrolidinyl; 6. A compound of formula (I) according to claim 5 or a pharmaceutically acceptable salt thereof.

7. R ３ is halogen and C １ ~C ６ 7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R is selected from alkyl.

8. R ３ 8. The compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein is halogen.

9. R ３ 9. The compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt thereof, wherein is chloro.

10. R ４ is C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, cyano and halo-C １ ~C ６ alkyl, R ６ is hydrogen and halo-C １ ~C ６ selected from alkyl, A compound of formula (I) according to any one of claims 1, 2 and 4 to 9, or a pharmaceutically acceptable salt thereof.

11. R ４ Halo-C １ ~C ６ is alkyl, R ６ is hydrogen, 11. A compound of formula (I) according to claim 10 or a pharmaceutically acceptable salt thereof.

12. R ４ is CF ３ and R ６ is hydrogen, 12. A compound of formula (I) according to claim 11 or a pharmaceutically acceptable salt thereof.

13. A is a 5-14 membered heteroaryl; R ５ａ is hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, amino-C １ ~C ６ Alkoxy, hydroxy-C １ ~C ６ Alkyl, halo-C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy-C １ ~C ６ Alkyl-, C １ ~C ６ Alkoxy-C １ ~C ６ Alkoxy-, amino, C １ ~C ６ Alkyl-NH-, (C １ ~C ６ alkyl) ２ N-, C １ ~C ６ Alkyl-NH-C(O)-, C １ ~C ６ Alkyl-NH-C(O)-C １ ~C ６ Alkyl-NH-, amino-C １ ~C ６ Alkyl-NH-, C １ ~C ６ Alkoxy-C １ ~C ６ selected from alkyl-NH-, carbamoyl and nitro; R ５ｂ is hydrogen or C １ ~C ６ is alkyl, R ５ｃ is hydrogen, A compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. A is a 5-14 membered heteroaryl; R ５ａ is C １ ~C ６ Alkoxy, hydroxy-C １ ~C ６ Alkyl, C １ ~C ６ Alkyl-NH-, amino-C １ ~C ６ selected from alkyl-NH— and amino; R ５ｂ is hydrogen or C １ ~C ６ is alkyl, R ５ｃ is hydrogen, 14. A compound of formula (I) according to claim 13 or a pharmaceutically acceptable salt thereof.

15. A is pyridyl; R ５ａ is selected from methoxy, hydroxymethyl, methylamino, 2-aminoethylamino, and amino; R ５ｂ is hydrogen or methyl, R ５ｃ is hydrogen, 15. A compound of formula (I) according to claim 14 or a pharmaceutically acceptable salt thereof.

16. R ７ is C １ ~C ６ 16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2 and 4 to 15, wherein R is alkyl.

17. R ７ 17. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein is methyl.

18. R １ and R ２ together with the nitrogen atom to which they are attached, represent a group of formula (II), (III) or (IV): 【Chemistry 22】 or forming a group of R １ is the base 【Chemistry 23】 and R ２ is hydrogen, R ３ is halogen and C １ ~C ６ alkyl, R ４ is C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, cyano and halo-C １ ~C ６ alkyl, R ５ａ is hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, amino-C １ ~C ６ Alkoxy, hydroxy-C １ ~C ６ Alkyl, halo-C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy-C １ ~C ６ Alkyl-, C １ ~C ６ Alkoxy-C １ ~C ６ Alkoxy-, amino, C １ ~C ６ Alkyl-NH-, (C １ ~C ６ alkyl) ２ N-, C １ ~C ６ Alkyl-NH-C(O)-, C １ ~C ６ Alkyl-NH-C(O)-C １ ~C ６ Alkyl-NH-, amino-C １ ~C ６ Alkyl-NH-, C １ ~C ６ Alkoxy-C １ ~C ６ selected from alkyl-NH-, carbamoyl and nitro; R ５ｂ is hydrogen or C １ ~C ６ is alkyl, R ５ｃ , R ９ａ , R ９ｂ , R １０ｂ , R １１ｂ and R １２ｂ are hydrogen, R ６ is hydrogen and halo-C １ ~C ６ alkyl, R ７ is C １ ~C ６ is alkyl, In formula (II), R ８ａ is C １ ~C ６ Alkyl, carbamoyl-C １ ~C ６ Alkyl and groups 【Chemistry 24】 is selected from In formula (III), R ８ａ is hydrogen, C １ ~C ６ Alkyl, carbamoyl-C １ ~C ６ Alkyl and groups 【Chemistry 25】 is selected from R ８ｂ is hydrogen, hydroxy and radicals 【Chemistry 26】 is selected from R ８ｃ , R １２ａ and R １２ｃ are independently １ ~C ６ is alkyl, R １０ａ is selected from amino and nitro; R １１ａ is the base 【Chemistry 27】 and R １２ｂ is selected from hydrogen and hydroxy; X is carbonyl; Y is a covalent bond or C １ ~C ６ alkyldiyl, L １ is C １ ~C ６ alkyldiyl, L ２ is -O-, L ３ is a covalent bond, L ４ is a carbonyl, A and E are each independently a 5- to 14-membered heteroaryl; B, C, D, F and G are each independently 3- to 14-membered heterocyclyl; 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

19. R １ and R ２ together with the nitrogen atom to which they are attached, form the formula (II) 【Chemistry 28】 forming a group of R ３ is a halogen, R ４ Halo-C １ ~C ６ is alkyl, R ５ａ is C １ ~C ６ Alkoxy, hydroxy-C １ ~C ６ Alkyl, C １ ~C ６ selected from alkyl-NH— and amino; R ５ｂ is hydrogen or C １ ~C ６ is alkyl, R ５ｃ and R ６ are hydrogen, R ７ is C １ ~C ６ is alkyl, R ８ａ and R ８ｃ are all independently C １ ~C ６ is alkyl, R ８ｂ is selected from hydrogen and hydroxy; X is carbonyl; Y is a covalent bond; A is a 5-14 membered heteroaryl; B and C are each independently 3- to 14-membered heterocyclyl; 19. A compound of formula (I) according to claim 18 or a pharmaceutically acceptable salt thereof.

20. R １ and R ２ together with the nitrogen atom to which they are attached, form the formula (II) 【Chemistry 29】 forming a group of R ３ is chloro, R ４ is CF ３ and R ５ａ is selected from methoxy, hydroxymethyl, methylamino and amino; R ５ｂ is hydrogen or methyl, R ５ｃ and R ６ are hydrogen, R ７ is methyl, R ８ａ and R ８ｃ are all methyl, R ８ｂ is selected from hydrogen and hydroxy; X is carbonyl; Y is a covalent bond; A is pyridyl; B is piperazinyl; C is selected from piperidyl and pyrrolidinyl; 20. A compound of formula (I) according to claim 19 or a pharmaceutically acceptable salt thereof.

21. The compound of formula (I) N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 6-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]pyridine-3-carboxamide; 6-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]-N-methyl-pyridine-3-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(difluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3R)-3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3R)-3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-pyrimidin-2-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3R,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3S,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3S,4S)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3R,4S)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(4-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[[1-(1,1-dimethylpiperidin-1-ium-4-carbonyl)-4-piperidyl]methylcarbamoyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(3S)-4,4-dimethylmorpholin-4-ium-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(2S,3S)-3-[(5-amino-2-pyridyl)oxy]-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(2S)-4-hydroxy-1,1-dimethyl-piperidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S,4R)-3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(hydroxymethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[3-(hydroxymethyl)-4,4-dimethyl-piperazin-4-ium-1-carbonyl]piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-[(4,4-dimethyl-2-oxo-piperazin-4-ium-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-cyano-pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-methyl-pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-ethyl-pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(6-aminopyridazin-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(4-methyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-[5-[(3-amino-3-oxo-propyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 4-(2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)-1,1-dimethylpiperazin-1-ium; rac-(2R,4S)-2-((1R,5S,6S)-6-(2-chloro-4-(1-methyl-5-(1-(pyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzamido)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-4-hydroxy-1,1-dimethylpyrrolidin-1-ium; (exo)-6-[[4-[[5-[1-(5-aminopyridin-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chlorobenzoyl]amino]-[(trans)-4-hydroxy-1,1-dimethylpyrrolidin-1-ium-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-[[3-keto-3-(methylamino)propyl]amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[[(exo)-3-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-aminopyrazin-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(methoxymethyl)-1H-pyrazol-3-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-3-fluoro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-4-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-6-fluoro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-6-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-4-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; and 5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide 2. The compound of formula (I) according to claim 1, selected from: or a pharmaceutically acceptable salt thereof.

22. A process for preparing a compound of formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, comprising: Scheme 1 【Transformation 30】 wherein PG 1 is a protecting group, and R 3 and R 7 are as defined in any one of claims 1 to 20; Scheme 2 【Chemistry 31】 (R 1a and R 2a together with the nitrogen atom to which they are attached represent a group of formula (IV), (V) or (VI) 【Chemistry 32】 or forming a group of R 1a is a group 【Transformation 33】 and R 2a is selected from hydrogen and C 1 -C 6 alkyl; PG 2 and PG 3 are protecting groups and R 3 , R 7 , R 8a , R 8b , R 11a , R 11b , B, C, F, X, Y and L 3 are as defined in any one of claims 1 to 20); Scheme 3 【Transformation 34】 wherein R 1a and R 2a together with the nitrogen atom to which they are attached form a group represented by formula (IV), (V) or (VI): 【Chemistry 35】 or forming a group of R 1a is a group 【Transformation 36】 and R 2a is selected from hydrogen and C 1 -C 6 alkyl; PG 2 and PG 3 are protecting groups and R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R 7 , R 8a , R 8b , R 11a , R 11b , A, B, C, F, X, Y and L 3 are as defined in any one of claims 1 to 20); and Scheme 4 【Chemistry 37】 wherein R 1a and R 2a together with the nitrogen atom to which they are attached form a group represented by formula (IV), (V) or (VI): 【Transformation 38】 or forming a group of R 1a is a group 【Chemistry 39】 and R 2a is selected from hydrogen and C 1 -C 6 alkyl; PG 2 and PG 3 are protecting groups and R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R 7 , R 8a , R 8b , R 11a , R 11b , A, B, C, F, X, Y and L 3 are as defined in any one of claims 1 to 20. The process includes:

23. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 21 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 21 or a pharmaceutically acceptable salt thereof for use as an antibiotic.

26. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 21 for use in the treatment or prevention of nosocomial infections and the resulting diseases.

27. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of infections caused by Gram-negative bacteria and the resulting diseases.

28. 28. The pharmaceutical composition of claim 27, wherein the Gram-negative bacterium is selected from Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and E. coli.

29. 29. The pharmaceutical composition of claim 28, wherein the Gram-negative bacterium is Acinetobacter baumannii.

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

31. 24. A method for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, comprising administering to a non-human mammal a compound of formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

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

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