Imidazole derivatives and their use as antibiotics

Abstract

The present invention relates to a compound represented by the general formula (I) TIFF2024525793000346.tif7477 (where X, D, R 1 ~R 4 , and R 6 ~R 10 are as described herein) The present invention provides novel heterocyclic compounds having the formula: and pharma- ceutically acceptable salts thereof. Further provided are pharmaceutical compositions comprising the compounds, processes for making the compounds, and methods of using the compounds as medicaments, in particular as antibiotics for the treatment or prevention of bacterial infections and resulting diseases.

Description

[Technical Field]

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

[0002] Background of the Invention 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. It belongs 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, especially 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] (In the formula, X, D, R 1 ~R 4 , and R 6 ~R 10 is as defined herein) or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0010] In one aspect, the present invention provides a process for making a compound of formula (I) as described herein, wherein the process is a method as described in any one of Schemes 1 to 6 as 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 resulting 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. Particularly preferred, but non-limiting, examples of alkyl include methyl and ethyl.

[0020] As used herein, the term "alkyldiyl" 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 "cycloalkyl," as used herein, refers to a saturated or partially unsaturated, monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms ("C3-C 10 In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbocyclic rings having two common carbon atoms, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., the two rings are joined through one common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and spiro[2.3]hexan-5-yl.

[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 monocyclic, ring system of 3 to 14 ring atoms, preferably 3 to 10 ring atoms, more 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, piperidyl, piperazinyl, pyrrolidinyl, 2-oxopyrrolidin-1-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, 5-oxopyrrolidin-3-yl, 2-oxo-1-piperidyl, 2-oxo-3-piperidyl, 2-oxo-4-piperidyl, 6-oxo-2-piperidyl, 6-oxo-3-piperidyl, 1-piperidinyl, 2-piperidinyl, 3- Examples include piperidinyl, 4-piperidinyl, morpholino, morpholin-2-yl, morpholin-3-yl, pyrrolidinyl (e.g., pyrrolidin-3-yl), 3-azabicyclo[3.1.0]hexan-6-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl, and 3-aza-6-azoniaspiro[5.5]undecane.

[0026] The term "heterocyclylalkyl" refers to a heterocyclyl group attached to the parent moiety via an alkylene group. A preferred, but non-limiting example of a heterocyclylalkyl group is azetidin-3-ylmethyl.

[0027] The term "aryl" refers to a group having 6 to 10 total ring members ("C6-C 10 A particularly preferred, but non-limiting example of aryl is phenyl.

[0028] 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, and 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 non-limiting examples of heteroaryl include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1,2-benzoxazol-3-yl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl, 1,2-benzoxazol-7-yl, Examples include 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-4-yl, 1,2,4-oxadiazol-3-yl, 1H-triazol-5-yl, 1H-triazol-4-yl, and triazol-1-yl. Most preferably, "heteroaryl" refers to pyridyl and pyrimidinyl.

[0029] The term "hydroxy" refers to the group --OH.

[0030] The term "carboxy" refers to the group -C(O)2H, a carboxylic acid group.

[0031] The term "oxo" refers to an oxygen atom attached to the parent moiety through a double bond (=O).

[0032] The term "amino" refers to the group --NH.sub.2.

[0033] The term "cyano" refers to a -CN (nitrile) group.

[0034] The term "carbamoyl" refers to the group -C(O)NH2.

[0035] The term "carbonyl" refers to a carbon radical having two of its four covalent bonds shared with oxygen atoms (C=O).

[0036] 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. Non-limiting examples of haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, 2-fluoroethyl, and 2,2-difluoroethyl. A particularly preferred, but non-limiting example of haloalkoxy is trifluoromethyl.

[0037] The term "cyanoalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced with a cyano group. Preferably, "cyanoalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group have been replaced with a cyano group. Most preferably, "cyanoalkyl" refers to an alkyl group in which one hydrogen atom of the alkyl group has been replaced with a cyano group. A particularly preferred, but non-limiting, example of a cyanoalkyl is cyanomethyl.

[0038] 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 hydrogen atoms of the alkyl group have been replaced with an alkoxy group. Most preferably, "alkoxyalkyl" refers to an alkyl group in which one hydrogen atom of the alkyl group has been replaced with an alkoxy group. A preferred, but non-limiting, example of an alkoxyalkyl is 2-methoxyethyl.

[0039] The term "haloalkoxy" refers to an alkoxy group in which at least one of the alkoxy group's hydrogen atoms 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 fluoromethoxy (FCHO-), difluoromethoxy (FCHO-), and trifluoromethoxy (FCO-).

[0040] 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 hydrogen atoms of the alkyl group have been replaced by a carbamoyl group. Most preferably, "carbamoylalkyl" refers to an alkyl group in which one hydrogen atom of the alkyl group has been replaced by a carbamoyl group. A preferred, but non-limiting, example of a carbamoylalkyl group is 2-amino-2-oxo-ethyl.

[0041] The term "carboxyalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced with a carboxy group. Preferably, "carboxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group have been replaced with a carboxy group. Most preferably, "carboxyalkyl" refers to an alkyl group in which one hydrogen atom of the alkyl group has been replaced with a carboxy group. A preferred, but non-limiting, example of a carboxyalkyl group is carboxymethyl.

[0042] 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.

[0043] 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, particularly hydrochloric acid, and organic acids such as formic acid, 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. Furthermore, 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, formate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid), and trifluoroacetate.

[0044] 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.

[0045] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom may be of the "R" or "S" configuration.

[0046] 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 of at least one clinical symptom or subclinical disease thereof or its recurrence); 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 treated patient 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 may not necessarily be effective treatment.

[0047] 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.

[0048] 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.

[0049] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I): [ka] (In the formula, X is N or CR 5 and R 1 and R 2 together with the nitrogen atom to which they are attached, form the group [ka] or R 1 is based [ka] and R 2 is hydrogen, R 3 is halogen or C1-C6-alkyl, R 4 is selected from hydrogen, halogen, C1-C6-alkyl and C1-C6-alkoxy, R 5 is selected from hydrogen, halogen and C1-C6-alkyl, R 6 is hydrogen, C1-C6-alkyl, carbamoyl-C1-C6-alkyl-NH-, amino, halogen, hydroxy-C1-C6-alkyl, halo-C1-C6-alkyl and groups [ka] is selected from R 7 is hydrogen, C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl, halo-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, C1-C6-alkyl-NH-C(O)-C1-C6-alkyl-, C1-C6-alkyl-NH-C(O)-NH-C1-C6-alkyl-, cyano-C1-C6-alkyl, C1-C6-alkyl-SO2-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, amino-C1-C6-alkoxy-C1-C6-alkyl- and groups [ka] Selected from R 8 is selected from hydrogen, halogen, C1-C6-alkyl, halo-C1-C6-alkyl and C1-C6-alkoxy-C1-C6-alkyl, or R 7 and R 8form, together with the atoms to which they are attached, a 3- to 14-membered heterocyclic ring, R 9 and R 10 are each independently hydrogen or halogen; R A is hydrogen, C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, (R A6 )3N + -C1-C6-alkyl-C(O)- and groups [ka] is selected from R A1 is hydrogen, hydroxy, amino, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, H2N-SO2-C1-C6-alkyl-, H2N-NH-C(O)-C1-C6-alkyl-, C1-C6-alkoxy, oxo, carbamoyl and groups [ka] is selected from R A2 is selected from hydrogen, hydroxy, amino, C1-C6-alkyl, carboxy-C1-C6-alkyl and carbamoyl-C1-C6-alkyl, R A3 , R A4 , R A5 , R C2 , and R C3 are each independently selected from hydrogen and C1-C6-alkyl; Each R A6 is independently selected from C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkyl-NH-C1-C6-alkyl-, (C1-C6-alkyl)2N-C1-C6-alkyl-, carboxy-C1-C6-alkyl, and (3- to 14-membered heterocyclyl)-C1-C6-alkyl-; R A7is selected from hydrogen and C1-C6-alkyl, R B1 is selected from hydrogen, halogen, cyano, amino, oxo, C1-C6-alkyl, C1-C6-alkoxy, and 3- to 14-membered heterocyclyl; R B2 is selected from hydrogen, halogen and C1-C6-alkyl, R C is hydrogen, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)3N + -C1-C6-alkyl-C(O)- and groups [ka] is selected from R C1 is hydroxy, R E is selected from C1-C6-alkyl, C1-C6-alkoxy and halogen, L A is selected from -C1-C6-alkyldiyl-, carbonyl, -C(O)-NH-, -NH-C(O)-, -C(O)-N(C1-C6-alkyl)-, -N(C1-C6-alkyl)-C(O)-, -C1-C6-alkyldiyl-NH-C(O)-, -SO2-NH-, -NH-SO2-, -C1-C6-alkyldiyl-C(O)-, and -C(O)-C1-C6-alkyldiyl-C(O)-; L B is selected from a covalent bond, —C1-C6-alkyldiyl-, —NH—C(O)—C1-C6-alkyldiyl-, —C(O)—NH—C1-C6-alkyldiyl-, —NH—C(O)—NH—C1-C6-alkyldiyl-, —C(O)—C1-C6-alkyldiyl-, and —SO2—NH—C1-C6-alkyldiyl-, L C and L E are each independently a covalent bond or -C1-C6-alkyldiyl-, L C1 is —NH—C(O)— or carbonyl, A, C, and C1 are each independently 3- to 14-membered heterocyclyl; A2 is 3- to 14-membered heterocyclyl and C6-C 10 -aryl, A1 is a 3- to 14-membered heterocyclyl, a 5- to 14-membered heteroaryl, and a C3-C 10 -cycloalkyl, B is a 5- to 14-membered heteroaryl, a 3- to 14-membered heterocyclyl, a C3-C 10 -Cycloalkyl and C6-C 10 -aryl, D is a 5- to 14-membered heteroaryl; E is 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, and C6-C 10 -aryl, The wavy lines represent the points of attachment of each R group to the remainder of formula (I). or a pharmaceutically acceptable salt thereof,

[0050] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: X is N or CR 5 and R 1 and R 2 together with the nitrogen atom to which they are attached, form the group [ka] or R 1 is the base [ka] and R 2 is hydrogen, R 3 is halogen or C1-C6-alkyl, R 4 is selected from hydrogen, halogen, C1-C6-alkyl and C1-C6-alkoxy, R 5is selected from hydrogen, halogen and C1-C6-alkyl, R 6 is hydrogen, C1-C6-alkyl, carbamoyl-C1-C6-alkyl-NH-, amino, halogen, hydroxy-C1-C6-alkyl, halo-C1-C6-alkyl and groups [ka] is selected from R 7 is hydrogen, C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl, halo-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, C1-C6-alkyl-NH-C(O)-C1-C6-alkyl-, C1-C6-alkyl-NH-C(O)-NH-C1-C6-alkyl-, cyano-C1-C6-alkyl, C1-C6-alkyl-SO2-C1-C6-alkyl-, halo-C1-C6-alkoxy-C1-C6-alkyl-, amino-C1-C6-alkoxy-C1-C6-alkyl- and groups [ka] Selected from R 8 is selected from hydrogen, halogen, C1-C6-alkyl, halo-C1-C6-alkyl and C1-C6-alkoxy-C1-C6-alkyl, or R 7 and R 8 form, together with the atoms to which they are attached, a 3- to 14-membered heterocyclic ring, R 9 and R 10 are each independently hydrogen or halogen; R A is hydrogen, C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, (R A6 )3N + -C1-C6-alkyl-C(O)- and groups [ka] is selected from RA1 is hydrogen, hydroxy, amino, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, H2N-SO2-C1-C6-alkyl-, H2N-NH-C(O)-C1-C6-alkyl-, C1-C6-alkoxy, oxo, carbamoyl and groups [ka] is selected from R A2 is selected from hydrogen, hydroxy, amino, C1-C6-alkyl, carboxy-C1-C6-alkyl and carbamoyl-C1-C6-alkyl, R A3 , R A4 , R A5 , R C2 , and R C3 are each independently selected from hydrogen and C1-C6-alkyl; Each R A6 is independently selected from C1-C6-alkyl, amino-C1-C6-alkyl, carboxy-C1-C6-alkyl, and (3- to 14-membered heterocyclyl)-C1-C6-alkyl-; R B1 is selected from hydrogen, halogen, cyano, amino, oxo, C1-C6-alkyl and C1-C6-alkoxy, R B2 is selected from hydrogen, halogen and C1-C6-alkyl, R C is hydrogen, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)3N + -C1-C6-alkyl-C(O)- and groups [ka] is selected from R C1 is hydroxy, R Eis selected from C1-C6-alkyl, C1-C6-alkoxy and halogen, L A is selected from -C1-C6-alkyldiyl-, carbonyl, -C(O)-NH-, and -C1-C6-alkyldiyl-C(O)-; L B is selected from a covalent bond, —C1-C6-alkyldiyl-, —NH—C(O)—C1-C6-alkyldiyl-, —C(O)—NH—C1-C6-alkyldiyl-, —NH—C(O)—NH—C1-C6-alkyldiyl-, —C(O)—C1-C6-alkyldiyl-, and —SO2—NH—C1-C6-alkyldiyl-; L C and L E are each independently a covalent bond or -C1-C6-alkyldiyl-, L C1 is —NH—C(O)— or carbonyl, A, A2, C, and C1 are each independently 3- to 14-membered heterocyclyl; A1 is 3- to 14-membered heterocyclyl and C3-C 10 -cycloalkyl, B is a 3- to 14-membered heteroaryl, a 3- to 14-membered heterocyclyl, a C3-C 10 -Cycloalkyl and C6-C 10 -aryl, D is a 3- to 14-membered heteroaryl; E is 3- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, and C6-C 10 -aryl, The wavy lines represent the points of attachment of each R group to the remainder of formula (I).

[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, form the group [ka] Forming R A is (R A6 )3N + -C1-C6-alkyl-C(O)-, and groups [ka] is selected from R A1 is hydroxy, C1-C6-alkyl, carbamoyl-C1-C6-alkyl, and [ka] is selected from R A2 is selected from C1-C6-alkyl, carboxy-C1-C6-alkyl and carbamoyl-C1-C6-alkyl, R A3 is selected from hydrogen and C1-C6-alkyl, R A4 and R A5 is hydrogen, Each R A6 is independently selected from amino-C1-C6-alkyl and carboxy-C1-C6-alkyl, L A is a carbonyl, A, A1 and A2 are each independently 3- 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 group [ka] or base [ka] Forming R A is (RA6 )3N + -(CH2)3-C(O)- and groups [ka] is selected from R A1 is a hydroxy, methyl, 2-amino-2-oxo-ethyl, and [ka] is selected from R A2 is selected from methyl, carboxymethyl, and 2-amino-2-oxo-ethyl; R A3 is selected from hydrogen and methyl; R A4 and R A5 is hydrogen, Each R A6 is independently selected from aminopropyl and carboxymethyl; L A is a carbonyl, A1 is selected from pyrrolidinyl, piperazinyl, piperidinyl and 3-azabicyclo[3.1.0]hexan-6-yl; A2 is azetidinyl.

[0053] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 together with the nitrogen atom to which they are attached, form the group [ka] or base [ka] (In the formula, R A is as defined herein).

[0054] In a preferred embodiment, the present invention provides L Ais selected from —C1-C6-alkyldiyl-, carbonyl, —C(O)—NH—, —NH—C(O)—, —C(O)—N(C1-C6-alkyl)-, —C1-C6-alkyldiyl-NH—C(O)—, —SO2-NH—, —NH—SO2-, —C1-C6-alkyldiyl-C(O)—, and —C(O)—C1-C6-alkyldiyl-C(O)—, or a pharmaceutically acceptable salt thereof.

[0055] In a preferred embodiment, the present invention provides L A is selected from —C1-C6-alkyldiyl, carbonyl, —C(O)—NH—, —SO2—NH—, and —C1-C6-alkyldiyl-C(O)—, or a pharmaceutically acceptable salt thereof.

[0056] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: R 1 is the base [ka] and R 2 is hydrogen, R C is hydrogen, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)3N + -C1-C6-alkyl-C(O)- and groups [ka] is selected from R C1 is hydroxy, R C2 and R C3 are each independently selected from hydrogen and C1-C6-alkyl; L C is a covalent bond or -C1-C6-alkyldiyl-, L C1is —NH—C(O)— or carbonyl, C and C1 are each independently 3- to 14-membered heterocyclyl.

[0057] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: R 1 is the base [ka] and R 2 is hydrogen, R C is hydrogen, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)3N + -C1-C6-alkyl-C(O)- and groups [ka] is selected from R C1 is hydroxy, R C2 and R C3 are each independently selected from hydrogen and C1-C6-alkyl; L C1 is —NH—C(O)— or carbonyl, C1 is a 3- to 14-membered heterocyclyl.

[0058] In a further 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 group [ka] which forms [ka] (In the formula, R Ais as defined herein).

[0059] In a further 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 group [ka] which forms [ka] (In the formula, R A is as defined herein).

[0060] In one embodiment, the present invention provides a compound comprising R 3 is a halogen; or a pharmaceutically acceptable salt thereof.

[0061] In a preferred embodiment, the present invention provides R 3 is chloro or fluoro, or a pharmaceutically acceptable salt thereof.

[0062] In a particularly preferred embodiment, the present invention provides 3 is chloro; or a pharmaceutically acceptable salt thereof.

[0063] In one embodiment, the present invention provides a compound comprising R 3 is C1-C6-alkyl; or a pharmaceutically acceptable salt thereof.

[0064] In a preferred embodiment, the present invention provides R 3 is methyl; or a pharmaceutically acceptable salt thereof.

[0065] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: X is CR 5 and R 4 and R 5 are both halogens, R 9 is hydrogen.

[0066] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof: X is CR 5 and R 4 is fluoro or chloro, R 5 is fluoro, R 9 is hydrogen.

[0067] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: X is CR 5 and R 4 is selected from halogen and C1-C6-alkyl, R 5 is a halogen, R 9 is hydrogen.

[0068] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof: X is CR 5 and R 4 is selected from methyl, fluoro and chloro; R 5 is fluoro, R 9 is hydrogen.

[0069] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: R 6 is hydrogen, C1-C6 alkyl, and [ka] is selected from R 7 is hydrogen, C1-C6-alkoxy-C1-C6-alkyl-, and the group [ka] is selected from R 8 is selected from hydrogen, halogen, C1-C6-alkyl, and halo-C1-C6-alkyl, R B1 is selected from hydrogen and halogen; R B2 is hydrogen, R E is a halogen, L B is selected from -C1-C6-alkyldiyl- and -NH-C(O)-C1-C6-alkyldiyl-, L E is a covalent bond, B and D are each independently a 3- to 14-membered heteroaryl; E is C6 to C 10 -aryl.

[0070] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof: R 6 is a hydrogen, methyl, and [ka] is selected from R 7 is hydrogen, 2-methoxyethyl, and the group [ka] is selected from R 8is selected from hydrogen, chloro, methyl, and difluoromethyl; R B1 is selected from hydrogen and fluoro; R B2 is hydrogen, R E is fluoro, L B is selected from —CH— and —NH—C(O)—CH—; L E is a covalent bond, B is selected from pyridyl and pyridazinyl; D is pyrazolyl; E is phenyl.

[0071] In a preferred embodiment, the present invention provides R 10 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0072] In a preferred embodiment, the present invention provides a compound comprising the group [ka] Based on [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: X is CR 5 and R 1 and R 2 together with the nitrogen atom to which they are attached, form the group [ka] Forming R 3 , R 4 , R 5 and R Eare each independently a halogen; R 6 is hydrogen, C1-C6 alkyl, and [ka] is selected from R 7 is hydrogen, C1-C6-alkoxy-C1-C6-alkyl-, and the group [ka] is selected from R 8 is selected from hydrogen, halogen, C1-C6-alkyl, and halo-C1-C6-alkyl, R 9 , R 10 , R A4 , R A5 , and R B2 is hydrogen, R A is (R A6 )3N + -C1-C6-alkyl-C(O)-, and groups [ka] is selected from R A1 is hydroxy, C1-C6-alkyl, carbamoyl-C1-C6-alkyl, and [ka] is selected from R A2 is selected from C1-C6-alkyl, carboxy-C1-C6-alkyl and carbamoyl-C1-C6-alkyl, R A3 is selected from hydrogen and C1-C6-alkyl, Each R A6 is independently selected from amino-C1-C6-alkyl and carboxy-C1-C6-alkyl, R B1 is selected from hydrogen and halogen; L A is a carbonyl, L B is selected from -C1-C6-alkyldiyl- and -NH-C(O)-C1-C6-alkyldiyl-, L E is a covalent bond, A, A1, and A2 are each independently 3- to 14-membered heterocyclyl; B and D are each independently a 3- to 14-membered heteroaryl; E is C6 to C 10 -aryl.

[0073] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: X is CR 5 and R 1 and R 2 together with the nitrogen atom to which they are attached, form the group [ka] or base [ka] Forming R 3 is chloro, R 4 is fluoro or chloro, R 5 and R E is fluoro, R 6 is a hydrogen, methyl, and [ka] is selected from R 7 is hydrogen, 2-methoxyethyl, and the group [ka] is selected from R 8is selected from hydrogen, chloro, methyl and difluoromethyl; R 9 , R 10 , R A4 , R A5 , and R B2 is hydrogen, R A is (R A6 )3N + -(CH2)3-C(O)- and groups [ka] is selected from R A1 is a hydroxy, methyl, 2-amino-2-oxo-ethyl, and [ka] is selected from R A2 is selected from methyl, carboxymethyl, and 2-amino-2-oxo-ethyl; R A3 is selected from hydrogen and methyl; Each R A6 is independently selected from aminopropyl and carboxymethyl; R B1 is selected from hydrogen and fluoro; L A is a carbonyl, L B is selected from —CH— and —NH—C(O)—CH—; L E is a covalent bond, A1 is selected from pyrrolidinyl, piperazinyl, piperidinyl, and 3-azabicyclo[3.1.0]hexan-6-yl; A2 is azetidinyl; B is selected from pyridyl and pyridazinyl; D is pyrazolyl; E is phenyl.

[0074] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: X is CR 5 and R 1 and R 2 together with the nitrogen atom to which they are attached, form the group [ka] Forming R 3 , R 4 , and R 5 are each independently a halogen; R 7 is C1-C6-alkoxy-C1-C6-alkyl-, R 8 is C1-C6-alkyl, R 6 , R 9 , R 10 , R A3 , R A4 , and R A5 is hydrogen, R A is the base [ka] and R A1 is the base [ka] and R A2 is carboxy-C1-C6-alkyl, L A is a carbonyl, A, A1, and A2 are each independently 3- to 14-membered heterocyclyl; D is a 3- to 14-membered heteroaryl.

[0075] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: X is CR5 and R 1 and R 2 together with the nitrogen atom to which they are attached, form the group [ka] Forming R 3 is chloro, R 4 and R 5 are all fluoro, R 7 is 2-methoxyethyl, R 8 is methyl, R 6 , R 9 , R 10 , R A3 , R A4 , and R A5 is hydrogen, R A is the base [ka] and R A1 is the base [ka] and R A2 is carboxymethyl, L A is a carbonyl, A1 is piperidyl, A2 is azetidinyl; D is pyrazolyl.

[0076] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: X is CR 5 and R 1 and R 2 together with the nitrogen atom to which they are attached, form the group [ka] Forming R 3 and R 5 are each independently a halogen; R 4 is C1-C6-alkyl, R 7 is C1-C6-alkoxy-C1-C6-alkyl-, R 8 is C1-C6-alkyl, R 6 , R 9 , R 10 , R A3 , R A4 , and R A5 is hydrogen, R A is the base [ka] and R A1 is the base [ka] and R A2 is carboxy-C1-C6-alkyl, L A is a carbonyl, A, A1, and A2 are each independently 3- to 14-membered heterocyclyl; D is a 3- to 14-membered heteroaryl.

[0077] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: X is CR 5 and R 1 and R 2 together with the nitrogen atom to which they are attached, form the group [ka] Forming R 3 is chloro, R 4 is methyl, R 5 is fluoro, R 7 is 2-methoxyethyl, R 8 is methyl, R 6 , R 9 , R 10 , R A3 , R A4 , and R A5 is hydrogen, R A is the base [ka] and R A1 is the base [ka] and R A2 is carboxymethyl, L A is a carbonyl, A1 is piperidyl, A2 is azetidinyl; D is pyrazolyl.

[0078] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the formula (II): [ka] (In the formula, X, D, R 3 , R 4 , and R 6 ~R 10 is as defined herein; Y is CH or N, most preferably N; RY is hydrogen, [ka] [ka] [ka] [ka] (The wavy line is R Y (indicating the point of attachment to Y) (selected from is a compound of

[0079] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or (II) has the formula (III): [ka] (In the formula, X, R 1 ~R 4 , R 9 and R 10 is as defined herein; R Z teeth, [ka] [ka] [ka] [ka] [ka] [ka] [ka] (The wavy line indicates the R Z (indicating the attachment point of (selected from is a compound of

[0080] 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-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-1,1-dimethylpyrrolidin-1-ium-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; [2-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]-trimethyl-ammonium; [2-[4-[[[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]methyl]-1-piperidyl]-2-oxo-ethyl]-trimethyl-ammonium; N-[3-chloro-4-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S)-4-(hydroxymethyl)-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-methoxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[4-[1-(2,2-difluoroethyl)-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-methoxyethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 2-[4-[1-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]-1-methyl-piperazin-1-ium-1-yl]acetic acid; 2-[1-(2-amino-2-oxo-ethyl)-4-[1-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]piperazin-1-ium-1-yl]acetic acid; N-[4-[4-[4-(2-amino-2-oxo-ethyl)-4-methyl-piperazin-4-ium-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(2-amino-2-oxo-ethyl)-4-hydroxy-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydrazino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 2-[1-(Azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; N-[3-chloro-4-[4-[1-[(1,1-dimethylazetidin-1-ium-3-yl)methyl]-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; diformate; 2-[1-(Azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; N-[4-[4-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 2-[1-(Azetidin-3-ylmethyl)-4-[1-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]piperazin-1-ium-1-yl]acetic acid; N-[4-[4-[4-(azetidin-3-ylmethyl)-4-methyl-piperazin-4-ium-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[4-(2-amino-2-oxo-ethyl)-4-(azetidin-3-ylmethyl)piperazin-4-ium-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(1R,5S)-3,3-dimethyl-3-azoniabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(1R,5S)-3,3-dimethyl-3-azoniabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1-(3-hydroxypropyl)-1-methyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; iodide; 2-[1-(Azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[3-chloro-2-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(Azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; N-[3-chloro-4-[4-[1-[(1,1-dimethylazetidin-1-ium-3-yl)methyl]piperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2,2-difluoroethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-sulfamoylethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-methyl-1-(2-sulfamoylethyl)piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1-(2-hydroxyethyl)-1-methyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; 2-[1-(Azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2-chloro-3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(Azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperazin-1-ium-1-yl]acetic acid; 2-[1-(Azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(Azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[5-chloro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(3-amino-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(3-amino-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-[(3S,4S)-3-amino-4-methoxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-[3-(aminomethyl)-3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(3-carbamoyl-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3R,4R)-3,4-dihydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3R,4R)-3,4-dihydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-[(3R,4R)-3-amino-4-methoxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(1-methylpyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[3-(hydroxymethyl)-4,4-dimethyl-piperazin-4-ium-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2R,4S)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2R,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4S)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[1-(3-methoxypropyl)-3-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[1-(3-methoxypropyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S)-4,4-dimethylmorpholin-4-ium-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(3-methoxypropyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(4,4-dimethyl-2-oxo-piperazin-4-ium-1-yl)methyl]piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(1-methylpyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(4-hydroxy-1,1-dimethyl-piperidin-1-ium-4-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[4-hydroxy-4-(hydroxymethyl)-1-methyl-piperidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-amino-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(4,4-dimethyl-2-oxo-piperazin-4-ium-1-yl)methyl]piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-N-[4-[4-(3-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]amino]piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S)-5-oxopyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(2-oxopiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(2-pyrrolidin-1-ylacetyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(pyrrolidine-2-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminobicyclo[1.1.1]pentane-1-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]-4-piperidyl]methylcarbamoyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; [2-[4-[2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]-trimethyl-ammonium; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(1,1-dimethylpiperidin-1-ium-4-yl)sulfonylamino]piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[(1R,5S)-3-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[(1S,5R)-3-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; Bis(3-aminopropyl)-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]ammonium; Bis(azetidin-3-ylmethyl)-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]ammonium; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-methoxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-(2,2-difluoroethyl)-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2-chloro-3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-(difluoromethoxy)ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2,3-Difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-N-[4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-(4-piperidylmethylcarbamoyl)phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[3-fluoro-4-[3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-(methoxymethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]-3-methyl-phenyl]-5-[4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-6-[5-(4-methoxyphenyl)-1H-pyrazol-4-yl]-3-pyridyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-6-(1H-pyrazol-4-yl)-3-pyridyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(1-methylpyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; (1S,5R)-6-[[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[4-(1H-pyrazol-4-yl)phenyl]imidazole-2-carboxamide; 5-[4-[1-(3-amino-3-oxo-propyl)-3-(trifluoromethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2-chloro-3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-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-[2,3-difluoro-4-[1-(3-hydroxy-3-methyl-butyl)-5-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[3-methyl-1-[2-(methylamino)-2-oxo-ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-(difluoromethoxy)ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(3-hydroxy-2-methyl-propyl)-3-(trifluoromethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[(2S)-2,3-dihydroxypropyl]-3-(trifluoromethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[4-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[4-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2,3-difluoro-4-[3-isopropyl-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]-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-[4-[5-(difluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2,3-Difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-N-[4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-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-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[1-(3-hydroxypropyl)-3-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[1-(3-hydroxypropyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-methoxy-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-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-[4-[5-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(4-hydroxybutyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-chloro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[3-fluoro-2-methoxy-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(4-hydroxy-1,1-dimethyl-piperidin-1-ium-4-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-(hydroxymethyl)-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[3-amino-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2,3-difluoro-4-(3-phenyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide;chloride; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[5-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methylsulfonylethyl)-3-(trifluoromethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-hydroxypropyl)-3-(trifluoromethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-(4-amino-4-oxo-butyl)-3-(trifluoromethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-(2-amino-2-oxo-ethyl)-3-(trifluoromethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-(trifluoromethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-morpholinoethyl)-5-(trifluoromethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(3-methoxypropyl)-3-(trifluoromethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-(tetrahydropyran-4-ylmethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-(5-amino-2-pyridyl)-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; chloride; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-(2-pyridylmethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-(1H-pyrazol-4-yl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-[(5-amino-2-pyridyl)methyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; chloride; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-(2-methylpyrazol-3-yl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-(3-fluorophenyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-(2-oxo-1-pyridyl)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-(1-methylpyrazol-4-yl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-(1H-pyrazol-4-yl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-phenyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-(2-pyridyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; [2-[4-[2-chloro-4-[[1-methyl-5-[4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]-trimethyl-ammonium; [2-[4-[2-chloro-4-[[5-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]-trimethyl-ammonium; 4-chloro-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-(6-methoxy-2-pyridyl)ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[(6-methoxy-2-pyridyl)methyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-(1H-triazol-4-ylmethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-3-pyridyl]-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-[4-[1-(3-cyanopropyl)-3,5-dimethyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-6-[5-(4-methoxyphenyl)-1H-pyrazol-4-yl]-3-pyridyl]-1-methyl-imidazole-2-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; 5-[4-[5-[(3-amino-3-oxo-propyl)amino]-2-pyridyl]-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-(5-amino-3-methyl-2-pyridyl)-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-(5-amino-2-pyridyl)-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; (1S,5R)-6-[[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-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-[2-fluoro-6-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]-3-pyridyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-(isopropylamino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-[2-(tert-butylamino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-[2-(1-bicyclo[1.1.1]pentanylamino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[4-[1-[2-[(3-cyano-1-bicyclo[1.1.1]pentanyl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-(2-anilino-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2,3-difluoro-4-[1-[2-(2-fluoroanilino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-(2-methoxyanilino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-(4-fluoroanilino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-(cyclohexylamino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(thiazol-2-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(1H-pyrazol-4-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-[(1-methylpyrazol-4-yl)amino]-2-oxo-ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-(3-fluoroanilino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide;chloride; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(2-pyridylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-[(1-methylpyridin-1-ium-3-yl)amino]-2-oxo-ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide;diformate; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(pyrimidin-2-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(4-pyridylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide;chloride; 5-[4-[1-[2-(tert-butylamino)-2-oxo-ethyl]-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2,3-difluoro-4-[5-methyl-1-[2-oxo-2-(2-pyridylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(tetrahydrofuran-3-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(tetrahydropyran-2-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(tetrahydropyran-3-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(pyridazin-3-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-[(1,1-dimethylpiperidin-1-ium-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; diformate; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[5-methyl-1-[2-oxo-2-(pyridazin-3-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-[(4,4-difluorocyclohexyl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(3-pyridylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-[(5-methoxy-2-pyridyl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(1-piperidyl)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)anilino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-[(6-fluoropyridazin-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-[[(1S,2S)-2-methoxycyclohexyl]amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(pyridazin-4-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-[(6-cyano-3-pyridyl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[2-[4-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluoro-phenyl]-5-methyl-pyrazol-1-yl]ethyl]pyridine-2-carboxamide; N-[2-[4-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluoro-phenyl]-3-methyl-pyrazol-1-yl]ethyl]pyridine-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-[(4-fluorophenyl)sulfonylamino]ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-[2-(tert-butylcarbamoylamino)ethyl]-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-[2-(tert-butylcarbamoylamino)ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2,3-difluoro-4-[5-methyl-1-[2-(2-pyridylcarbamoylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-(2-pyridylcarbamoylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-(pyrrolidine-1-carbonylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(2-pyridyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(4-methoxyphenyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(3-methoxyphenyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(2-methoxyphenyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(5-thiazol-4-yl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(5-tetrahydropyran-4-yl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[5-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-[2-(2-aminoethoxy)ethyl]-3,5-dimethyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-1λ 5 -azolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-(difluoromethoxy)ethyl]-3,5-dimethyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[4-[1-[(2,2-difluorocyclopropyl)methyl]-3,5-dimethyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-benzyl-3-aza-6-azoniaspiro[5.5]undecane-9-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-[2-[(6-fluoropyridazin-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-[(6-methyl-3-pyridyl)carbamoylamino]ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-oxo-3-aza-6-azoniaspiro[5.5]undecane-9-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[3-fluoro-4-[1-[2-[(6-fluoropyridazin-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-[(6-fluoropyridazin-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; Bis(4-aminobutyl)-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-3-methyl-piperazino]-4-keto-butyl]ammonium; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-[(6-methylpyridazin-3-yl)amino]-2-oxo-ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-[(6-methoxypyridazin-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-[(6-morpholinopyridazin-3-yl)amino]-2-oxo-ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[2-(3-aminopropyl)-4-[3-[[1-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]isonipecotoyl]amino]propyl]pyridin-1-ium-1-yl]acetic acid; Azetidin-3-ylmethyl-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[4-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-3-fluoro-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-ammonium;Formic acid; 2-[1-(Azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[4-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-3-fluoro-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 3-Aminopropyl-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[4-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-3-fluoro-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-ammonium; 2-[1-(Azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; Carboxymethyl-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-bis[2-(dimethylamino)ethyl]ammonium; cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[4-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetate; Bis(3-aminopropyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-ammonium; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; 3-Aminopropyl-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazino]-4-keto-butyl]-methyl-ammonium.1:1 2,2,2-trifluoroacetic acid; Bis(4-aminobutyl)-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]ammonium; cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; trans 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(Azetidin-3-ylmethyl)-4-[5-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazino]-5-keto-pentanoyl]piperazin-1-ium-1-yl]acetic acid; 2-[1-(3-aminopropyl)-4-[5-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazino]-5-keto-pentanoyl]piperazin-1-ium-1-yl]acetic acid; 2-[1-(Azetidin-3-ylmethyl)-4-[(1S,5R)-6-[[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(Azetidin-3-ylmethyl)-4-[[1-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-4-piperidyl]-methyl-carbamoyl]piperidin-1-ium-1-yl]acetic acid; Azetidin-3-ylmethyl-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-ammonium; cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methylpyrazol-4-yl]phenyl]-1-methylimidazole-2-carbonyl]amino]-2-methylbenzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; and Cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methylpyrazol-4-yl]-2-methylphenyl]-1-methylimidazole-2-carbonyl]amino]-2-methylbenzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid is selected from.

[0081] 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-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[4-(2-amino-2-oxo-ethyl)-4-(azetidin-3-ylmethyl)piperazin-4-ium-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(1R,5S)-3,3-dimethyl-3-azoniabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 2-[1-(Azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2R,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; Bis(3-aminopropyl)-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]ammonium; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-chloro-3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; and N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-[5-(difluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide is selected from.

[0082] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is N-[4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide.

[0083] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1 -carbonyl]piperidin-1-ium-1-yl]acetic acid, in particular cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid formate.

[0084] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is N-[3-chloro-4-[4-[(2R,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide.

[0085] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide.

[0086] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid.

[0087] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide.

[0088] 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).

[0089] 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.

[0090] 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.

[0091] 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.

[0092] Manufacturing Process The preparation of the compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the compounds of the present invention is shown in the following scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indicators used in the following description of the process have the significance previously described herein, unless otherwise specified. More specifically, the compounds of formula (I) can be prepared by the methods shown below, the methods shown in the Examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. For literature-described reaction conditions affecting the described reactions, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition, Richard C. Larock, John Wiley & Sons, New York, NY. 2018). The inventors have found it convenient to carry out the reaction in the presence or absence of a solvent. There are no particular limitations on the nature of the solvent used, as long as it does not adversely affect the reaction or the reagents involved and is capable of dissolving the reagents to at least some extent. The reactions described can occur over a wide range of temperatures, and the precise reaction temperature is not critical to the 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 will usually be 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.

[0093] All substituents, especially X, D, and R 1 ~R 9is as defined above and in the claims unless otherwise specified. Furthermore, unless expressly stated otherwise, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to one skilled in the art of organic chemistry.

[0094] [ka]

[0095] In the ceremony, P.G. 3 is a protecting group, for example BOC.

[0096] Intermediate A can be prepared according to Scheme 1. Protection of substituted 4-nitrobenzoic acid A with, for example, (BOC)2O affords compound B. Reduction of the nitro group of compound B, for example, using the well-known ammonium chloride / iron system at room temperature, affords amine C. Coupling of carboxylic acid D with amine C in the presence of a condensing agent such as HATU / DIPEA in a solvent such as DMSO affords intermediate A.

[0097] [ka]

[0098] In the ceremony, P.G. 1 is a protecting group such as BOC, or PG 1 is H (no protection)

[0099] PG 3 is a protecting group such as BOC.

[0100] Intermediates B, C, and D can be prepared according to Scheme 2. Intermediate A can be hydrolyzed to give carboxylic acid E, which can be coupled with a variety of amines in the presence of a condensing agent such as HATU / DIPEA in a solvent such as DMSO to give intermediates B, C, and D.

[0101] [ka]

[0102] In the ceremony, P.G. 2 is a protecting group, e.g., BOC, SEM, TBS, or PG 2 H (no protection).

[0103] Intermediate G can be prepared according to Scheme 3. Thus, for example, Suzuki coupling of intermediate E with boronic ester F using a palladium catalyst and a phosphine ligand provides intermediate F. Intermediate F can be further reacted with bis(pinacolato)diboron using a palladium catalyst and a phosphine ligand to provide intermediate G (in some cases, the boronic ester will directly hydrolyze to the boronic acid in situ).

[0104] [ka]

[0105] In the ceremony, P.G. 1 is a protecting group such as BOC, or PG 1 is H (unprotected), PG 2 is a protecting group, e.g., BOC, SEM, TBS, or PG 2 is H (unprotected).

[0106] Intermediates HK and MQ can be prepared according to Scheme 4. Thus, Suzuki coupling of intermediates B, C, and D with the boronic ester intermediate G in the presence of a palladium catalyst and a phosphine ligand provides intermediates HK and MQ.

[0107] [ka]

[0108] In the ceremony, P.G. 1 is a protecting group such as BOC, or PG 1 is H (unprotected), PG 2is a protecting group, e.g., BOC, SEM, TBS, or P 2 is H (unprotected).

[0109] In addition to the procedures outlined in Scheme 4, intermediates H-K and M-Q can also be prepared according to Scheme 5. Thus, Suzuki coupling of intermediate A with boronic ester intermediate G in the presence of a palladium catalyst and a phosphine ligand provides compound G. Hydrolysis of compound G provides carboxylic acid intermediate L, which is then coupled with a variety of amines in the presence of a condensing agent such as HATU / DIPEA in a solvent such as DMSO to provide intermediates H-K and M-Q.

[0110] [ka]

[0111] In the ceremony, P.G. 1 is a protecting group such as BOC, or PG 1 is H (unprotected), PG 2 is a protecting group, e.g., BOC, SEM, TBS, or P 2 is H (unprotected).

[0112] Examples can be prepared according to Scheme 6. Thus, intermediates HK and MQ can be converted to PG 2 (PG 2 (if not hydrogen) to give compound H. Subsequent PG 1 Removal of (PG 1 is not hydrogen) to finally obtain the Example. The order of the deprotection steps can also be reversed via Compound I. In some cases, the final Example is achieved by alkylation of a particular intermediate, for example, methylation using MeI in the presence of DIPEA in acetonitrile at room temperature. The protecting group PG 1 and P.G. 2 The removal of can be carried out before or after the alkylation step, depending on the requirements of the substitution pattern.

[0113] In one aspect, the present invention provides a process for preparing a compound of formula (I) as described herein, the process being as depicted in any one of Schemes 1 to 6 above.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as an antibiotic.

[0121] 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.

[0122] In certain embodiments, the nosocomial infection and resulting disease is selected from bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, or combinations thereof.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, as an antibiotic.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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 resultant 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.

[0132] 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.

[0133] 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, particularly bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0134] 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, particularly bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections. Such a medicament comprises a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0135] Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described above and one or more pharmaceutically acceptable excipients. Exemplary pharmaceutical compositions are described in Examples 1-4.

[0136] 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.

[0137] 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).

[0138] 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.

[0139] Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols etc.

[0140] Suitable excipients for the production of solutions and syrups are, by way of example, water, polyols, saccharose, invert sugar, glucose etc.

[0141] Suitable excipients for injection solutions are, by way of example, water, alcohols, polyols, glycerol, vegetable oils etc.

[0142] Suitable excipients for suppositories are, by way of example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0143] 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. Pharmaceutical preparations may also contain other therapeutically valuable substances.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] In one aspect, the present invention provides a pharmaceutical composition described herein, further comprising an additional therapeutic agent.

[0149] In one embodiment, the additional therapeutic agent is an antibiotic agent.

[0150] 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.

[0151] In one embodiment, the additional therapeutic agent is an antibiotic selected from carbapenem (meropenem), fluoroquinolone (ciprofloxacin), aminoglycoside (amikacin), tetracycline (tigecycline), colistin, sulbactam, sulbactam plus durrobactam, cefiderocol (fetroja), macrocyclic peptides, and macrolides (erythromycin), as exemplified in WO2017072062A1, WO2019185572A1, and WO2019206853A1. [Example]

[0152] 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.

[0153] 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.

[0154] Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere.

[0155] The abbreviations used herein are as follows: ACN or MeCN acetonitrile BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene 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(s) HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC: High-performance liquid chromatography HPLC-UV: High-performance liquid chromatography with ultraviolet detection IC50 half-maximal inhibitory concentration IC90 90% inhibitory concentration PE Petroleum Ether PdCl2(DPPF)[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) PG protecting group Precat Precatalyst prep-HPLC Preparative High Performance Liquid Chromatography RBF Round Bottom Flask rt room temperature sat saturation SEM 2-Methoxyethyl(trimethyl)silane FA formic acid TFA trifluoroacetic acid wt weight X-PHOS 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0156] Intermediate A1 tert-Butyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate [ka]

[0157] Step 1: tert-Butyl 2-chloro-4-nitro-benzoate

[0158] 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.

[0159] Step 2: tert-Butyl 4-amino-2-chloro-benzoate

[0160] 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.

[0161] Step 3: tert-butyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate

[0162] 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.

[0163] The following intermediates were prepared similarly to intermediate A1. [Table 1]

[0164] Intermediate B1 5-Bromo-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-imidazole-2-carboxamide [ka]

[0165] Step 1: 4-(5-bromo-1-methyl-1h-imidazole-2-carboxamido)-2-chlorobenzoic acid

[0166] In a 250 mL round-bottom flask, tert-butyl 4-(5-bromo-1-methyl-1h-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-1h-imidazole-2-carboxamido)-2-chlorobenzoic acid (4.32 g). MS [M+H] + :359.8.

[0167] Step 2: tert-butyl 4-(4-(5-bromo-1-methyl-1h-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxylate

[0168] In a 100 mL round-bottom flask, 4-(5-bromo-1-methyl-1h-imidazole-2-carboxamido)-2-chlorobenzoic acid (2 g, 5.58 mmol), tert-butyl piperazine-1-carboxylate (1.19 g, 6.41 mmol), and DIPEA (2.16 g, 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 (3 × 75 mL). The organic layers were combined and washed with saturated NaCl (1 × 75 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give tert-butyl 4-(4-(5-bromo-1-methyl-1h-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxylate (2.94 g). MS [M+H] + :527.9.

[0169] The following intermediates were prepared similarly to intermediate B1. [Table 2]

[0170] Intermediate C1 5-Bromo-N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-1h-imidazole-2-carboxamide [ka]

[0171] In a 100 mL round-bottom flask, tert-butyl 4-(4-(5-bromo-1-methyl-1h-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-1h-imidazole-2-carboxamide (2.38 g). MS [M+H] + :427.8.

[0172] The following intermediates were prepared similarly to intermediate C1. [Table 3]

[0173] Intermediate D1 tert-Butyl 4-(4-(4-(5-bromo-1-methyl-1h-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate [ka]

[0174] In a 100 mL round-bottom flask, 5-bromo-N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-1h-imidazole-2-carboxamide (2.38 g, 5.58 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.05 g, 8.92 mmol), and DIPEA (2.16 g, 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 (3 × 50 mL). The organic layers were combined and washed with saturated NaCl (1 × 75 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give tert-butyl 4-(4-(4-(5-bromo-1-methyl-1h-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (3.56 g). MS [M+H] + :638.9.

[0175] The following intermediates were prepared similarly to intermediate D1. [Table 4-1] [Table 4-2]

[0176] Intermediate D10 tert-Butyl 4-[4-[4-[(5-bromo-4-chloro-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate [ka]

[0177] Step 1: 5-Bromo-4-chloro-1-methyl-imidazole

[0178] 4-Chloro-1-methyl-imidazole (466 mg, 4 mmol) was dissolved in N,N-dimethylformamide (8 mL), and NBS (498.13 mg, 2.8 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated NaHCO3 solution (20 mL) and extracted twice with EtOAc (30 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated to dryness. The crude product was used directly in the next step to give 5-bromo-4-chloro-1-methyl-imidazole (284 mg, 36.34%) as a light brown solid. MS [M+H] + :196.9.

[0179] Step 2: 5-Bromo-4-chloro-1-methyl-imidazole-2-carboxylic acid methyl ester

[0180] 5-Bromo-4-chloro-1-methyl-imidazole (284 mg, 1.45 mmol) was dissolved in tetrahydrofuran (5 mL) and 2 M lithium diisopropylamide (871.88 uL, 1.74 mmol) was added at −78° C. The reaction was stirred at −78° C. for 30 minutes and methyl chloroformate (164.79 mg, 1.74 mmol) was added at −78° C. The mixture was allowed to warm to room temperature with stirring for 1 hour.

[0181] The reaction mixture was diluted with water (20 mL) and extracted twice with EtOAc (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated to dryness. The crude product was used directly in the next step to give 5-bromo-4-chloro-1-methyl-imidazole-2-carboxylic acid methyl ester (360 mg) as a light brown oil. MS [M+H] + :254.9.

[0182] Step 3: 5-Bromo-4-chloro-1-methyl-imidazole-2-carboxylic acid

[0183] 5-Bromo-4-chloro-1-methyl-imidazole-2-carboxylic acid methyl ester (360 mg, 1.42 mmol) was dissolved in methanol (9 mL) and water (3 mL), and NaOH (284.05 mg, 7.1 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to 6. The reaction was concentrated to dryness. The crude product was used directly in the next step to give 5-bromo-4-chloro-1-methyl-imidazole-2-carboxylic acid (340 mg) as a pale yellow solid. MS [M+H] + :240.9.

[0184] Step 4: 4-(1-tert-butoxycarbonylisonipecotoyl)piperazine-1-carboxylic acid benzyl ester

[0185] 1-tert-Butoxycarbonylisonipecotic acid (2.5 g, 10.9 mmol) was dissolved in N,N-dimethylformamide (31.25 mL), and benzyl 1-piperazinecarboxylate (2.64 g, 11.99 mmol), HATU (4.98 g, 13.09 mmol), and DIEA (2.82 g, 21.81 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted twice with EtOAc (30 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (5% MeOH in DCM) to give 4-(1-tert-butoxycarbonylisonipecotoyl)piperazine-1-carboxylic acid benzyl ester (3 g, 63.76%) as a colorless oil. MS[M+H] + :454.2.

[0186] Step 5: 4-(Piperazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester

[0187] 4-(1-tert-Butoxycarbonylisonipecotoyl)piperazine-1-carboxylic acid benzyl ester (3 g, 6.95 mmol) was dissolved in methanol (50 mL), and palladium hydroxide on carbon (97.63 mg, 0.695 mmol) was added at room temperature. The mixture was purged three times with a H2 balloon and stirred at room temperature for 15 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The crude product was used directly in the next step to give 4-(piperazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (2.07 g) as a colorless oil. MS [M+H] + :298.2.

[0188] Step 6: 4-[4-(4-amino-2-chloro-benzoyl)piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester

[0189] 4-(Piperazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (1 g, 3.36 mmol) was dissolved in N,N-dimethylformamide (7 mL), and 4-amino-2-chlorobenzoic acid (576.95 mg, 3.36 mmol), HATU (1.53 g, 4.04 mmol), and DIEA (869.16 mg, 1.17 mL, 6.73 mmol) were added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (40 mL) and extracted twice with EtOAc (30 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (10% MeOH in DCM) to give 4-[4-(4-amino-2-chloro-benzoyl)piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (1.09 g) as a white solid. MS [M+H] + :351.2.

[0190] Step 7: 4-[4-[4-[(5-bromo-4-chloro-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester

[0191] 4-[4-(4-amino-2-chloro-benzoyl)piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.887 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 5-bromo-4-chloro-1-methyl-imidazole-2-carboxylic acid (212.39 mg, 0.887 mmol), HATU (472.17 mg, 1.24 mmol), and DIEA (229.27 mg, 1.77 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted twice with EtOAc (30 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (10% MeOH in DCM) to give 4-[4-[4-[(5-bromo-4-chloro-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (277 mg) as a light brown solid. MS [M+H] + :573.1.

[0192] Intermediate D11 tert-Butyl (3R,4R)-3-[[(1S,5R)-6-[[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylate [ka]

[0193] In a 25 mL round-bottom flask equipped with a magnetic stir bar, a N2-balloon, and a cetum cap, tert-butyl (3R,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate (253 mg, 1.25 mmol) was dissolved in DMF (1 mL). TEA (211 mg, 2.08 mmol) and CDI (169 mg, 1.04 mmol) were added to the clear solution and stirred at room temperature. After 15 min, N-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamoyl)-3-chlorophenyl)-5-bromo-1-methyl-1H-imidazole-2-carboxamide hydrochloride (197.8 mg, 416 μmol) was added, and the resulting light brown reaction solution was stirred for 1.5 h. Water (7 mL) was added to the reaction mixture, but the product did not precipitate. The aqueous layer was extracted with EA (2 × 10 mL). The organic layers were washed with LiCl solution (5% in water) (10 mL for each organic layer) and saturated NaCl solution (1 × 10 mL), dried over Na2SO4, filtered off, and concentrated in vacuo at 40 °C. The crude product was purified by silica gel chromatography to give tert-butyl (3R,4R)-3-((1R,5S)-6-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzamido)-3-azabicyclo[3.1.0]hexane-3-carboxamido)-4-hydroxypyrrolidine-1-carboxylate (216 mg). [M+H] + :668.3.

[0194] The following intermediates were prepared similarly to intermediate D11. [Table 5]

[0195] Intermediate E1 and Intermediate E2 1-(2-Methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate E1) 1-(2-Methoxyethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate E2) [ka]

[0196] To a 25 mL microwave vial was added 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 9.61 mmol), 1-bromo-2-methoxyethane (1.74 g, 12.5 mmol), K2CO3 (1.73 g, 12.5 mmol), and potassium iodide (319 mg, 1.92 mmol) in DMF (15 mL). The vial was capped and heated in a microwave at 100 °C for 15 h. The reaction mixture was filtered through glass fiber paper. The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography to give 2 g of crude product. The crude product was purified by preparative HPLC to give 1-(2-methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (550 mg) (Intermediate E1) and 1-(2-methoxyethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (316 mg) (Intermediate E2). MS [M+H] + :267.1.

[0197] The following intermediates were prepared similarly to intermediate E1. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0198] Intermediate E18 5-Ethyl-1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole [ka]

[0199] A solution of 4-bromo-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole (0.47 g, 2.0 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.56 g, 3.0 mmol) was dissolved in THF (8.0 mL). The solution was cooled to -78 °C under an argon atmosphere. N-butyllithium (2.0 mL, 3.0 mol) was then added dropwise to the solution. The resulting solution was stirred at this temperature for 60 minutes, and then the temperature was gradually raised to room temperature. The reaction mixture was quenched with methanol at 0 °C, and the solvent was evaporated to give the crude product, which was purified by flash chromatography on silica gel to give 5-ethyl-1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (706 mg). MS [M+H] + :281.1.

[0200] Intermediate E19 tert-Butyl-dimethyl-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]butoxy]silane [ka]

[0201] Step 1: 2-[(4-bromopyrazol-1-yl)methoxy]ethyl-trimethyl-silane

[0202] 4-Bromo-1H-pyrazole (7.35 g, 50 mmol) and DIPEA (13.0 g, 100 mmol) were dissolved in anhydrous CHCl (50 mL). The solution was cooled to 0° C., and then (2-(chloromethoxy)ethyl)trimethylsilane (10 g, 60 mmol) was added dropwise. The mixture was allowed to warm to room temperature and then stirred for 12.0 hours. The mixture was poured into water, and the aqueous solution was extracted with EtOAc (2×150 mL). The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a red oil, which was purified by flash chromatography on silica gel to give 2-[(4-bromopyrazol-1-yl)methoxy]ethyl-trimethyl-silane (8.6 g). MS [M+H] + :277.1.

[0203] Step 2: 2-[[4-bromo-5-[4-[tert-butyl(dimethyl)silyl]oxybutyl]pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0204] To a solution of 2-[(4-bromopyrazol-1-yl)methoxy]ethyl-trimethyl-silane (1.4 g, 5.0 mmol) in anhydrous THF (15 mL) was added LDA (2.0 M in THF) (5.0 mmol) dropwise under argon at −78° C. The resulting mixture was stirred at −78° C. for 1.0 h, and tert-butyl-(4-iodobutoxy)-dimethyl-silane (2.4 g, 7.5 mmol) was added. The reaction was stirred at −78° C. for 30 min. The reaction was allowed to warm to room temperature with stirring. The reaction was quenched with a saturated aqueous solution of ammonium chloride, followed by extraction with EtOAc (2×50 mL). The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 2-[[4-bromo-5-[4-[tert-butyl(dimethyl)silyl]oxybutyl]pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (1.2 g). MS [M+H] + :463.3.

[0205] Step 3: tert-butyl-dimethyl-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]butoxy]silane

[0206] To a solution of 2-[[4-bromo-5-[4-[tert-butyl(dimethyl)silyl]oxybutyl]pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (0.46 g, 1.0 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.28 g, 1.5 mmol) in anhydrous THF (15 mL) was added n-BuLi (1.6 M in THF) (1.3 mL, 2.0 mmol) dropwise at −78° C. under argon. The resulting mixture was stirred at −78° C. for 1.0 h, then the reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with a saturated aqueous solution of ammonium chloride followed by extraction with EtOAc (2×50 mL). The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give the title compound tert-butyl-dimethyl-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]butoxy]silane (400.0 mg). MS [M+H] + :511.0.

[0207] Intermediate E20 1-(2-Methoxyethyl)-5-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole [ka]

[0208] Step 1: 4-Bromo-1-(2-methoxyethyl)pyrazole

[0209] To a solution of 4-bromo-1H-pyrazole (5.88 g, 40 mmol) in anhydrous DMF (25 ml) was added NaH (2.4 g, 60 mmol), and the mixture was stirred at 0° C. for 1 hour. 1-Bromo-2-methoxyethane (8.34 g, 60 mmol) was added in batches to the mixture, which was then stirred at room temperature for an additional 2.0 hours. The reaction mixture was quenched with water at 0° C. and then acidified to pH 7-8 with 1N HCl. The aqueous solution was extracted with EtOAc, and the combined extracts were concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 4-bromo-1-(2-methoxyethyl)pyrazole (7.2 g).

[0210] Step 2: 4-Bromo-2-(2-methoxyethyl)pyrazole-3-carbaldehyde

[0211] To a solution of 4-bromo-1-(2-methoxyethyl)pyrazole (3.1 g, 15 mmol) in anhydrous THF (20 mL) was added LDA (22.5 mmol) dropwise under argon at −78° C. The resulting mixture was stirred at −78° C. for 1.0 h, then DMF (1.65 g, 22.5 mmol) was added dropwise to the mixture and stirred at room temperature for an additional 8.0 h. The reaction mixture was quenched with water at 0° C. and then acidified to pH=7-8 with 1N HCl. The aqueous solution was extracted with EtOAc, and the combined extracts were concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 4-bromo-2-(2-methoxyethyl)pyrazole-3-carbaldehyde (3.0 g). MS [M+H] + :232.9.

[0212] Step 3: [4-bromo-2-(2-methoxyethyl)pyrazol-3-yl]methanol

[0213] To a solution of 4-bromo-2-(2-methoxyethyl)pyrazole-3-carbaldehyde (3.5 g, 15 mmol) in anhydrous THF (65 mL) was added borane (1.0 M in THF) (22.5 mmol) dropwise under argon at −78° C. The resulting mixture was stirred at −78° C. for 2.0 hours and then at room temperature for an additional 5.0 hours. The reaction mixture was quenched with water at 0° C. and then extracted with EtOAc (75 mL×3), and the combined extracts were concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give [4-bromo-2-(2-methoxyethyl)pyrazol-3-yl]methanol (2.8 g). MS [M+H] + :235.0.

[0214] Step 4: 4-Bromo-1-(2-methoxyethyl)-5-(methoxymethyl)pyrazole

[0215] To a solution of [4-bromo-2-(2-methoxyethyl)pyrazol-3-yl]methanol (1.2 g, 5.0 mmol) in anhydrous THF (25 mL) was added NaH (300 mg, 7.5 mmol) at 0° C., and the suspension was then stirred for 1 h. Iodomethane (1.1 g, 7.5 mmol) was added to the mixture, and the mixture was stirred at room temperature for an additional 2.0 h. The mixture was quenched with water and then poured into water (50 mL), and the aqueous solution was extracted with EtOAc (100 mL × 2). The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a red oil. The residue was purified by flash chromatography on silica gel to give 4-bromo-1-(2-methoxyethyl)-5-(methoxymethyl)pyrazole (0.86 g). MS [M+H] + :249.0.

[0216] Step 5: 1-(2-methoxyethyl)-5-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

[0217] A solution of 4-bromo-1-(2-methoxyethyl)-5-(methoxymethyl)pyrazole (2.5 g, 10 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.3 g, 12 mmol) was dissolved in THF (20 mL). The solution was cooled to −78° C. under an argon atmosphere, and n-butyllithium (7.5 mL, 12 mmol) was added dropwise to the solution. The resulting solution was stirred at this temperature for 1.0 hour, and then the temperature was allowed to rise to room temperature. The reaction mixture was quenched with methanol at 0° C. Evaporation of the solvent gave the crude product, which was purified by flash chromatography on silica gel to give 1-(2-methoxyethyl)-5-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.0 g). MS [M+H] + :297.1.

[0218] Intermediate F1 and Intermediate F2 4-(4-Bromo-2,3-difluoro-phenyl)-1-(2,2-difluoroethyl)-3-methyl-pyrazole (Intermediate F1) 4-(4-Bromo-2,3-difluoro-phenyl)-1-(2,2-difluoroethyl)-3-methyl-pyrazole (Intermediate F2) [ka]

[0219] Step 1: 4-(4-bromo-2,3-difluoro-phenyl)-3-methyl-1H-pyrazole

[0220] To a 25 mL microwave vial was added 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.7 g, 8.15 mmol), 1-bromo-2,3-difluoro-4-iodobenzene (2 g, 6.27 mmol), NaCO (1.99 g, 18.8 mmol), and PdCl(dppf)-CHCl adduct (459 mg, 627 μmol) in dioxane (50 mL) / water (5 mL). The vial was capped and heated at 100° C. in a microwave under N for 15 hours. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography to give 4-(4-bromo-2,3-difluorophenyl)-3-methyl-1H-pyrazole (1.7 g). MS [M+H] + :275.0.

[0221] Step 2: 4-(4-Bromo-2,3-difluoro-phenyl)-1-(2,2-difluoroethyl)-3-methyl-pyrazole and 4-(4-bromo-2,3-difluoro-phenyl)-1-(2,2-difluoroethyl)-3-methyl-pyrazole

[0222] In a 50 mL round-bottom flask, 4-(4-bromo-2,3-difluorophenyl)-3-methyl-1H-pyrazole (1 g, 3.66 mmol), KCO (759 mg, 5.49 mmol), and 1,1-difluoro-2-iodoethane (914 mg, 4.76 mmol) were combined with DMF (10 mL) to give a pale yellow solution. The reaction mixture was heated to 100 °C and stirred for 15 h. The reaction mixture was filtered through glass fiber paper. The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography to give 400 mg of the product mixture. The mixture was purified by preparative chiral HPLC to give 4-(4-bromo-2,3-difluoro-phenyl)-1-(2,2-difluoroethyl)-3-methyl-pyrazole (96.7 mg) and 4-(4-bromo-2,3-difluoro-phenyl)-1-(2,2-difluoroethyl)-5-methyl-pyrazole (60 mg). MS [M+H] + :337.1.

[0223] Intermediate F3 4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)-1H-pyrazole [ka]

[0224] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (5 g, 19.1 mmol), 1-bromo-2,3-difluoro-4-iodobenzene (6.08 g, 19.1 mmol), sodium carbonate (6.07 g, 57.2 mmol), and PdCl(dppf)-CHCl adduct (1.56 g, 1.91 mmol) in dioxane (90 mL) and water (9 mL) was added. The resulting mixture was heated at 100 °C under N for 10 h. The crude reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography to give 4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)-1H-pyrazole (3.9 g). MS [M+H] + :327.0.

[0225] The following intermediates were prepared similarly to intermediate F3. [Table 7]

[0226] Intermediate G1 2-[[4-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane [ka]

[0227] Step 1: 2-[[4-(4-bromo-2,3-difluorophenyl)-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0228] In a 100 mL round-bottom flask, 4-(4-bromo-2,3-difluorophenyl)-3-methyl-1H-pyrazole (1.7 g, 6.23 mmol) and DIPEA (1.21 g, 9.34 mmol) were combined with THF (30 mL) to give a light brown solution. SEM-Cl (1.56 g, 1.66 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into 50 mL of HO and extracted with EtOAc (3 × 30 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 2-[[4-(4-bromo-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (1.51 g). MS [M+H]: 405.1.

[0229] Step 2: 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0230] In a 250 mL round-bottom flask, bis(pinacolato)diboron (1.44 g, 5.65 mmol), 2-[4-(4-bromo-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]ethoxymethyl-trimethyl-silane (1.52 g, 3.77 mmol), PdCl(dppf)-CHCl adduct (276 mg, 377 μmol), and potassium acetate (1.11 g, 11.3 mmol) were combined with dioxane (60 mL) to give a dark red solution. The reaction mixture was heated to 80 °C and stirred under N for 15 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 50 mL of HO and extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with saturated NaCl (1 × 50 mL), dried over NaSO, and concentrated in vacuo. The crude material was purified by flash chromatography to give 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (1 g).

[0231] Intermediate G2 4-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2-methoxyethyl)-3-methyl-pyrazole [ka]

[0232] Step 1: 4-(4-bromo-2,3-difluoro-phenyl)-1-(2-methoxyethyl)-3-methyl-pyrazole

[0233] In a 50 mL round-bottom flask, 1-(2-methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (459 mg, 1.72 mmol), 1-bromo-2,3-difluoro-4-iodobenzene (500 mg, 1.57 mmol), PdCl(dppf)-CHCl adduct (115 mg, 157 μmol), and NaCO (499 mg, 4.7 mmol) were combined with dioxane (10 mL) and water (1 mL) to give a dark red solution. The reaction mixture was heated to 100 °C and stirred under N for 15 h. The reaction mixture was filtered through glass fiber paper. The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography to give 4-(4-bromo-2,3-difluoro-phenyl)-1-(2-methoxyethyl)-3-methyl-pyrazole (310 mg). MS [M+H] + :333.1.

[0234] Step 2: 4-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2-methoxyethyl)-3-methyl-pyrazole

[0235] In a 50 mL round-bottom flask, 4-(4-bromo-2,3-difluorophenyl)-1-(2-methoxyethyl)-3-methyl-pyrazole (310 mg, 936 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (357 mg, 1.4 mmol), PdCl(dppf)-CHCl adduct (68.5 mg, 93.6 μmol), and potassium acetate (276 mg, 2.81 mmol) were combined with dioxane (10 mL) to give a dark red solution. The reaction mixture was heated to 100 °C and stirred under N for 15 h. The reaction mixture was filtered through glass fiber paper. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography to give 4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2-methoxyethyl)-3-methyl-pyrazole (350 mg). MS [M+H] + :379.1.

[0236] The following intermediates were prepared similarly to intermediate G2. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6]

[0237] Intermediate G33 1-[2-(Difluoromethoxy)ethyl]-4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazole intermediate [ka]

[0238] Step 1: 2-[4-(4-bromo-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]ethoxy-tert-butyl-dimethyl-silane

[0239] To a solution of 1-bromo-2,3-difluoro-4-iodobenzene (1000 mg, 3.14 mmol) in a mixed solvent of dioxane (10 mL) and water (2 mL) was added sodium carbonate (665 mg, 6.27 mmol), 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.15 g, 3.14 mmol), and PdCl(dppf)-CHCl adduct (256 mg, 314 μmol). The reaction was stirred at 130° C. under microwave irradiation and an argon atmosphere for 3 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give 2-[4-(4-bromo-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]ethoxy-tert-butyl-dimethyl-silane (1g). MS [M+H] + :431.1.

[0240] Step 2: 2-[4-(4-bromo-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]ethanol

[0241] To a solution of 4-(4-bromo-2,3-difluorophenyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-1H-pyrazole (1 g, 2.32 mmol) in THF (10 mL) was added TBAF (6.95 mL, 6.95 mmol) and the reaction was stirred at room temperature for 1 h. The reaction mixture was washed with brine (20 mL) and extracted with DCM (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to give 2-[4-(4-bromo-2,3-difluorophenyl)-3-methyl-pyrazol-1-yl]ethanol (500 mg). MS [M+H] + :317.0.

[0242] Step 3: 4-(4-bromo-2,3-difluoro-phenyl)-1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazole

[0243] To a solution of 2-(4-(4-bromo-2,3-difluorophenyl)-3-methyl-1H-pyrazol-1-yl)ethan-1-ol (450 mg, 1.42 mmol) in acetonitrile (5 mL) was added copper(I) iodide (54 mg, 284 μmol), the reaction was heated to 60° C., and then 2,2-difluoro-2-(fluorosulfonyl)acetic acid (505 mg, 2.84 mmol) in acetonitrile (5 mL) was added dropwise over 5 minutes. The reaction was stirred for an additional 30 minutes. The reaction was cooled to room temperature and the mixture was concentrated in vacuo. The residue was purified by column chromatography to give 4-(4-bromo-2,3-difluoro-phenyl)-1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazole (200 mg). MS [M+H] + :367.0.

[0244] Step 4: 1-[2-(difluoromethoxy)ethyl]-4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazole

[0245] To a solution of 4-(4-bromo-2,3-difluorophenyl)-1-(2-(difluoromethoxy)ethyl)-3-methyl-1H-pyrazole (200 mg, 545 μmol) in dioxane (3 mL) was added potassium acetate (107 mg, 1.09 mmol), PdCl(dppf)-CHCl adduct (44.5 mg, 54.5 μmol), and bis(pinacolato)diboron (138 mg, 545 μmol), and the reaction was stirred at 80° C. under an argon atmosphere for 15 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to give 1-[2-(difluoromethoxy)ethyl]-4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazole (150 mg). MS [M+H] + :415.2.

[0246] The following intermediates were prepared similarly to intermediate G33. [Table 9]

[0247] Intermediate G35 4-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-isopropyl-1-(2-methoxyethyl)pyrazole [ka]

[0248] Step 1: 4-Bromo-3-isopropyl-1-(2-methoxyethyl)pyrazole

[0249] To a solution of 4-bromo-3-isopropyl-1H-pyrazole (1000 mg, 5.29 mmol) in acetonitrile (10 mL) was added 1-bromo-2-methoxyethane (735.2 mg, 5.29 mmol) and cesium carbonate (3.45 g, 10.58 mmol), and the reaction was stirred at 100° C. for 8 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, and the residue was purified by chiral HPLC to give 4-bromo-3-isopropyl-1-(2-methoxyethyl)pyrazole (1.2 g). MS [M+H] + :247.0.

[0250] Step 2: 2,3-Difluoro-4-[3-isopropyl-1-(2-methoxyethyl)pyrazol-4-yl]phenol

[0251] To a mixed solvent solution of 4-bromo-3-isopropyl-1-(2-methoxyethyl)pyrazole (900 mg, 3.64 mmol) in 1,4-dioxane (12 mL) and water (2.4 mL) was added (2,3-difluoro-4-hydroxyphenyl)boronic acid (1.27 g, 7.28 mmol), tetrakis(triphenylphosphine)palladium (420.83 mg, 0.364 mmol), and sodium carbonate (1.16 g, 10.93 mmol), and the reaction was stirred at 100° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to give 2,3-difluoro-4-[3-isopropyl-1-(2-methoxyethyl)pyrazol-4-yl]phenol (210 mg). MS [M+H] + :297.1.

[0252] Step 3: [2,3-difluoro-4-[3-isopropyl-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]trifluoromethanesulfonate

[0253] To a solution of 2,3-difluoro-4-[3-isopropyl-1-(2-methoxyethyl)pyrazol-4-yl]phenol (100 mg, 0.337 mmol) in N,N-dimethylformamide (3 mL) was added 1,1,1-trifluoro-N-phenyl-N-triflyl-methanesulfonamide (144.68 mg, 0.405 mmol), triethylamine (68.3 mg, 675 mmol), and n-(4-pyridyl)dimethylamine (4.12 mg, 0.034 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography to give [2,3-difluoro-4-[3-isopropyl-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]trifluoromethanesulfonate (135 mg). MS [M+H] + :429.1.

[0254] Step 4: 4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-isopropyl-1-(2-methoxyethyl)pyrazole

[0255] To a solution of trifluoromethanesulfonic acid [2,3-difluoro-4-[3-isopropyl-1-(2-methoxyethyl)pyrazol-4-yl]phenyl] ester (80 mg, 0.187 mmol) in anhydrous 1,4-dioxane (3 mL) was added 4,4,4',4',5,5,5',5''-octamethyl-2,2'-bi(1,3,2 dioxaborolane) (47.42 mg, 0.187 mmol), potassium acetate (36.66 mg, 0.374 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(ii) dichloride dichloromethane adduct (15.25 mg, 0.019 mmol), and the reaction was stirred at 100°C under a nitrogen atmosphere for 5 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to give 4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-isopropyl-1-(2-methoxyethyl)pyrazole (60 mg). MS [M+H] + :407.2.

[0256] The following intermediates were prepared similarly to intermediate G35. [Table 10]

[0257] Intermediate G38 3-[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrazol-1-yl]propanamide [ka]

[0258] Step 1: 3-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazol-1-yl]propanamide

[0259] A mixture of 4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazole (500 mg, 1.53 mmol), 3-bromopropanamide (279 mg, 1.83 mmol), and potassium carbonate (634 mg, 4.59 mmol) in anhydrous acetonitrile (7.64 mL) was heated at 60 °C for 18 h. The mixture was cooled to room temperature, and 100-200 mesh silica gel was added to absorb the material. The loaded sample was purified by flash chromatography to give the final compound as a yellow oil (550 mg). MS [M+H] + :398.0.

[0260] Step 2: 3-[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrazol-1-yl]propanamide

[0261] To a solution of 3-(4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propanamide (590 mg, 1.48 mmol) in dioxane (14.8 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2 dioxaborolane) (452 ​​mg, 1.78 mmol), potassium acetate (436 mg, 4.45 mmol), and PdCl(dppf)-CHCl (122 mg, 148 μmol), and the reaction was stirred at 100° C. under an argon atmosphere for 18 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography to give the product as a yellow solid (390 mg). MS [M+H] + :446.2.

[0262] The following examples were prepared analogously to intermediate G38. [Table 11-1] [Table 11-2]

[0263] Intermediate G47 1-[4-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrazol-1-yl]propan-2-ol [ka]

[0264] Step 1: 1-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazol-1-yl]propan-2-one

[0265] 4-(4-Bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazole (110 mg, 336 μmol), 1-bromopropan-2-one (55.3 mg, 404 μmol), and potassium carbonate (139 mg, 1.01 mmol) in anhydrous acetonitrile (3.36 mL) were stirred at room temperature for 30 minutes. 100-200 mesh silica gel was added to absorb the material. The loaded sample was purified by flash chromatography to give the final compound as a pale yellow oil (120 mg). MS [M+H] + :383.0.

[0266] Step 2: 1-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazol-1-yl]propan-2-ol

[0267] 1-(4-(4-Bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-one (120 mg, 313 μmol) was dissolved in MeOH. The solution was cooled to 0°C. Sodium tetrahydroborate (11.8 mg, 313 μmol) was added to this solution, and the resulting mixture was stirred at the same temperature for 1 hour. 100-200 mesh silica gel was added to absorb the material. The loaded sample was then purified by flash chromatography to give the final compound as a pale yellow oil (110 mg). MS [M+H] + :385.0.

[0268] Step 3: 1-[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrazol-1-yl]propan-2-ol

[0269] To a solution of 1-(4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-ol (120 mg, 312 μmol) in dioxane (3.12 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2 dioxaborolane) (94.9 mg, 374 μmol), potassium acetate (91.7 mg, 935 μmol), and PdCl(dppf)-CHCl (25.5 mg, 31.2 μmol), and the reaction was stirred at 100° C. under an argon atmosphere for 18 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography to give the final compound as a light brown oil (90 mg). MS [M+H] + :433.2.

[0270] Intermediate G48 1-[2-(Difluoromethoxy)ethyl]-4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrazole [ka]

[0271] Step 1: 2-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazol-1-yl]ethanol

[0272] To a solution of 4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazole (600 mg, 1.83 mmol) in DMF (15 mL) was added 2-iodoethan-1-ol (315 mg, 1.83 mmol) and potassium carbonate (761 mg, 5.5 mmol), and the reaction was stirred at 90 °C for 3 h. The reaction mixture was cooled to room temperature, washed with brine, and extracted into DCM. The organic layer was dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by column chromatography to give 2-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazol-1-yl]ethanol (640 mg). MS [M+H] + :371.1.

[0273] Step 2: 4-(4-bromo-2,3-difluoro-phenyl)-1-[2-(difluoromethoxy)ethyl]-3-(trifluoromethyl)pyrazole

[0274] To a solution of 2-(4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-ol (500 mg, 1.35 mmol) in acetonitrile (5 mL) was added copper(I) iodide (51.3 mg, 269 μmol), the reaction was heated to 60° C., and then a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (480 mg, 2.69 mmol) in acetonitrile (5 mL) was added dropwise over 5 minutes. The reaction was stirred for an additional 30 minutes. The reaction was cooled to room temperature and the mixture was concentrated in vacuo. The residue was purified by column chromatography to give 4-(4-bromo-2,3-difluoro-phenyl)-1-[2-(difluoromethoxy)ethyl]-3-(trifluoromethyl)pyrazole (260 mg). MS [M+H] + :421.1.

[0275] Step 3: 1-[2-(difluoromethoxy)ethyl]-4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrazole

[0276] To a solution of 4-(4-bromo-2,3-difluorophenyl)-1-(2-(difluoromethoxy)ethyl)-3-(trifluoromethyl)-1H-pyrazole (260 mg, 617 μmol) in dioxane (3 mL) was added potassium acetate (121 mg, 1.23 mmol), PdCl(dppf)-CHCl (50.4 mg, 61.7 μmol), and bis(pinacolato)diboron (157 mg, 617 μmol), and the reaction was stirred at 80° C. under an argon atmosphere for 15 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to give 1-[2-(difluoromethoxy)ethyl]-4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrazole (205 mg). MS [M+H] + :469.1.

[0277] Intermediate G49 3-[4-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrazol-1-yl]-2-methyl-propan-1-ol [ka]

[0278] Step 1: 4-(4-bromo-2,3-difluoro-phenyl)-1-(2-methylallyl)-3-(trifluoromethyl)pyrazole

[0279] To a solution of 4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazole (600 mg, 1.83 mmol) in DMF (5 mL) was added 3-iodo-2-methylprop-1-ene (334 mg, 1.83 mmol) and potassium carbonate (761 mg, 5.5 mmol), and the reaction was stirred at 90 °C for 3 h. The reaction mixture was cooled to room temperature, washed with brine, and extracted into DCM. The organic layer was dried over anhydrous NaSO and concentrated in vacuo. The crude product was purified by column chromatography to give 4-(4-bromo-2,3-difluoro-phenyl)-1-(2-methylallyl)-3-(trifluoromethyl)pyrazole (400 mg). MS [M+H] + :381.1.

[0280] Step 2: 3-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazol-1-yl]-2-methyl-propan-1-ol

[0281] To a solution of 4-(4-bromo-2,3-difluorophenyl)-1-(2-methylallyl)-3-(trifluoromethyl)-1H-pyrazole (400 mg, 1.05 mmol) in THF (5 mL) was added dropwise a borane tetrahydrofuran complex solution (2.1 mL, 2.1 mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred for 4 hours, then water (0.5 mL) was added dropwise, followed by sodium hydroxide (2.1 mL, 3 mol / L) and hydrogen peroxide (2.1 mL, 30%). The reaction was stirred for an additional 4 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography to give 3-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazol-1-yl]-2-methyl-propan-1-ol (320 mg). MS [M+H] + :399.1.

[0282] Step 3: 3-[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrazol-1-yl]-2-methyl-propan-1-ol

[0283] To a solution of 3-(4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol (400 mg, 1 mmol) in dioxane (5 mL) was added potassium acetate (197 mg, 2 mmol), PdCl(dppf)-CHCl (81.8 mg, 100 μmol), and bis(pinacolato)diboron (254 mg, 1 mmol), and the reaction was stirred at 80° C. under an argon atmosphere for 15 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to give 3-[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrazol-1-yl]-2-methyl-propan-1-ol (260 mg). MS [M+H] + :447.1.

[0284] Intermediate G50 [4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]boronic acid [ka]

[0285] Step 1: 1-(4-benzyloxy-2,3-difluoro-phenyl)butan-2-one

[0286] To a solution of 2-(4-benzyloxy-2,3-difluorophenyl)-N-methoxy-N-methyl-acetamide (6.7 g, 20.85 mmol) in THF (50.0 mL) was slowly added ethylmagnesium bromide in EtO (3 M) (10.43 mL, 31.28 mmol) at −40° C. under N. The reaction mixture was stirred at −10° C. for 2 h. The reaction was quenched with NH4Cl (50.0 mL) and extracted with EtOAc (50.0 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 8:1) to give 1-(4-benzyloxy-2,3-difluorophenyl) butan-2-one (1.4 g) as a yellow solid.

[0287] Step 2: 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-ethyl-1-(2-methoxyethyl)pyrazole

[0288] To a mixture of 1-(4-benzyloxy-2,3-difluorophenyl)butan-2-one (700.0 mg, 2.41 mmol) and molecular sieves 4A (500.0 mg) in toluene (8.0 mL) was added 2-methoxyethylhydrazine (521.53 mg, 5.79 mmol) in one portion. The reaction mixture was stirred at 100 °C for 3 h. The mixture was filtered and concentrated under reduced pressure to give a residue. A mixture of the residue and N,N-dimethylformamide dimethyl acetal (7.07 mL, 86.81 mmol) was stirred at 100 °C for 16 h. The reaction was quenched with H2O (10.0 mL) and extracted with EtOAc (10.0 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 5: 1) to give 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-ethyl-1-(2-methoxyethyl)pyrazole (630.0 mg) as a yellow oil. MS [M+H] + :373.2.

[0289] Step 3: 4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenol

[0290] To a solution of 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-ethyl-1-(2-methoxyethyl)pyrazole (630.0 mg, 1.69 mmol) in methanol (6 mL) was added palladium on carbon (180.03 mg) in one portion under N2. The mixture was degassed and purged with N2 three times. H2 (15 psi) was then introduced into the system. The reaction mixture was stirred under H2 atmosphere at 20 °C for 16 h. The mixture was filtered and concentrated under reduced pressure to give the crude product 4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenol (470.0 mg) as a black oil. MS [M+H] + :283.2.

[0291] Step 4: [4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]trifluoromethanesulfonate

[0292] A mixture of 4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenol (220.0 mg, 0.78 mmol) and pyridine (0.09 mL, 1.17 mmol) in DCM (5 mL) was degassed and purged with N2 three times. Trifluoromethanesulfonic anhydride (0.15 mL, 0.94 mmol) was then added dropwise to the mixture at 0 °C. The reaction mixture was stirred at 20 °C under a N2 atmosphere for 2 hours. The reaction was quenched with NaHCO3 (10 mL) and extracted with DCM (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product [4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]trifluoromethanesulfonate (390.0 mg) as a red oil. MS [M+H] + :415.1.

[0293] Step 5: [4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]boronic acid

[0294] A mixture of bis(pinacolato)diboron (478.03 mg, 1.88 mmol), [4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluorophenyl]trifluoromethanesulfonate (390.0 mg, 0.94 mmol), potassium acetate (0.15 mL, 2.35 mmol), and X-PHOS (44.87 mg, 0.09 mmol) in 1,4-dioxane (5 mL) was degassed and purged with N three times. Tris(dibenzylideneacetone)dipalladium(0) (43.1 mg, 0.05 mmol) was then added to the mixture. The reaction mixture was stirred at 100 °C under a N atmosphere for 2 hours. The reaction mixture was extracted with EtOAc (10 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 (TFA) to give [4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]boronic acid (150.0 mg, 0.480 mmol, 49.46% yield) as a brown oil. MS [M+H] + :311.2.

[0295] Intermediate G51 [4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]boronic acid [ka]

[0296] Step 1: Methyl 4-bromo-1-(2-methoxyethyl)pyrazole-3-carboxylate

[0297] A mixture of methyl 4-bromo-1H-pyrazole-3-carboxylate (2.5 g, 12.19 mmol) and potassium carbonate (2.53 g, 18.29 mmol) in ACN (10 mL) was degassed and purged with N2 three times. 1-Bromo-2-methoxyethane (3.44 mL, 36.58 mmol) was then added to the mixture. The reaction mixture was stirred at 80 °C under a N2 atmosphere for 2 hours. The mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product (5 batches) was purified by preparative HPLC to give methyl 4-bromo-1-(2-methoxyethyl)pyrazole-3-carboxylate (8.0 g). MS [M+H] + :263.0.

[0298] Step 2: [4-bromo-1-(2-methoxyethyl)pyrazol-3-yl]methanol

[0299] To a solution of methyl 4-bromo-1-(2-methoxyethyl)pyrazole-3-carboxylate (2.0 g, 7.6 mmol) in THF (20.0 mL) was added lithium borohydride (5.7 mL, 11.4 mmol) slowly at -40 °C under N. The reaction mixture was stirred at 20 °C for 16 h. The reaction was quenched with HCl (1 M, 20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over NaSO and concentrated to give the crude product [4-bromo-1-(2-methoxyethyl)pyrazol-3-yl]methanol (1.6 g). MS [M+H] + :235.0.

[0300] Step 3: [4-Bromo-1-(2-methoxyethyl)pyrazol-3-yl]methoxy-tert-butyl-dimethyl-silane

[0301] To a solution of [4-bromo-1-(2-methoxyethyl)pyrazol-3-yl]methanol (1.2 g, 5.1 mmol) in DMF (10.0 mL) was added imidazole (0.48 mL, 7.15 mmol) and tert-butyldimethylchlorosilane (1.08 g, 7.15 mmol) in one portion. The reaction mixture was stirred at 20 °C for 16 h. The reaction was quenched with brine (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over NaSO and concentrated to give the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 5:1) to give [4-bromo-1-(2-methoxyethyl)pyrazol-3-yl]methoxy-tert-butyl-dimethyl-silane (1.36 g). MS [M+H] + :349.1.

[0302] Step 4: [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]methoxy-tert-butyl-dimethyl-silane

[0303] A mixture of 2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.31 g, 3.78 mmol), [4-bromo-1-(2-methoxyethyl)pyrazol-3-yl]methoxy-tert-butyl-dimethyl-silane (1.36 g, 3.78 mmol), and potassium carbonate (1.04 g, 7.55 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was degassed and purged with N three times. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (276.36 mg, 0.38 mmol) was 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 silica gel chromatography (PE: EtOAc = 5: 1) to give [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl) pyrazol-3-yl] methoxy-tert-butyl-dimethyl-silane (1.17 g). MS [M + H]+ :489.2.

[0304] Step 5: 4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenol

[0305] To a solution of [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]methoxy-tert-butyl-dimethyl-silane (1.0 g, 2.05 mmol) in methanol (10 mL) was added palladium on carbon (217.79 mg) in one portion under N2. The mixture was degassed and purged with N2 three times. H2 (15 psi) was then introduced into the system. The reaction mixture was stirred under H2 atmosphere at 20 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 2:1) to give 4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenol (480.0 mg). MS [M+H] + :399.2.

[0306] Step 6: [4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]trifluoromethanesulfonate

[0307] A mixture of 4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluorophenol (250.0 mg, 0.63 mmol) and pyridine (0.08 mL, 0.94 mmol) in DCM (5 mL) was degassed and purged with N three times. Trifluoromethanesulfonic anhydride (0.12 mL, 0.75 mmol) was then added dropwise to the mixture at 0 °C. The reaction mixture was stirred at 20 °C under a N atmosphere for 2 h. The reaction was quenched with NaHCO (10 mL) and extracted with DCM (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product [4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]trifluoromethanesulfonate (370.0 mg). MS [M+H] + :531.2.

[0308] Step 7: [4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]boronic acid

[0309] A mixture of [4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluorophenyl]trifluoromethanesulfonate (330.0 mg, 0.62 mmol), bis(pinacolato)diboron (315.88 mg, 1.24 mmol), potassium acetate (0.1 mL, 1.55 mmol), and X-PHOS (29.65 mg, 0.06 mmol) in 1,4-dioxane (8 mL) was degassed and purged with N three times. Then, tris(dibenzylideneacetone)dipalladium(0) (28.48 mg, 0.03 mmol) was added to the mixture. The reaction mixture was stirred at 100 °C under a N atmosphere for 3 hours. The reaction mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative HPLC (TFA) to give [4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]boronic acid (210.0 mg). MS [M+H] + :427.3.

[0310] Intermediate G52 [2,3-Difluoro-4-[1-(2-methoxyethyl)-3-(methylamino)pyrazol-4-yl]phenyl]boronic acid [ka]

[0311] Step 1: 4-Bromo-1-(2-methoxyethyl)pyrazole-3-carboxylic acid

[0312] To a solution of methyl 4-bromo-1-(2-methoxyethyl)pyrazole-3-carboxylate (1.0 g, 3.8 mmol) in THF (10.0 mL), methanol (10.0 mL), and water (2.5 mL) was added lithium hydroxide monohydrate (638.0 mg, 15.2 mmol) in one portion. The reaction mixture was stirred at 25° C. for 4 hours. HCl (1 M) was added to the mixture to pH < 3. The mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give 4-bromo-1-(2-methoxyethyl)pyrazole-3-carboxylic acid (900.0 mg). The crude product was used directly in the next step without further purification. MS [M+H] + :249.0.

[0313] Step 2: tert-butyl N-[4-bromo-1-(2-methoxyethyl)pyrazol-3-yl]carbamate

[0314] To a solution of 4-bromo-1-(2-methoxyethyl)pyrazole-3-carboxylic acid (900.0 mg, 3.61 mmol) and triethylamine (1.01 mL, 7.23 mmol) in tert-butanol (20 mL) was added diphenylphosphonic acid azide (1.56 mL, 7.23 mmol) in one portion. The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was concentrated to give a residue. The residue was diluted with EtOAc (30 mL) and washed with saturated aqueous Na2CO3 (5 mL x 2). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel chromatography (PE:EtOAc = 1:1 to 1:2) to give tert-butyl N-[4-bromo-1-(2-methoxyethyl)pyrazol-3-yl]carbamate (1.0 g). MS [M+H] + :320.0.

[0315] Step 3: tert-butyl N-[4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]carbamate

[0316] To a solution of tert-butyl N-[4-bromo-1-(2-methoxyethyl)pyrazol-3-yl]carbamate (1.0 g, 3.12 mmol), 2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.08 g, 3.12 mmol), and potassium carbonate (0.86 g, 6.25 mmol) in 1,4-dioxane (20 mL) and water (2 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (228.53 mg, 0.31 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 (50 mL) and washed with brine (10 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 (PE: EtOAc = 5:1 to 1:1) to give tert-butyl N-[4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]carbamate (1.1 g). MS [M+H] + :460.1.

[0317] Step 4: tert-butyl N-[4-(2,3-difluoro-4-hydroxy-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]carbamate

[0318] To a solution of tert-butyl N-[4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]carbamate (800.0 mg, 1.74 mmol) in methanol (10 mL) was added palladium on carbon (185.28 mg) in one portion under N2. H2 (15 psi) was then introduced into the system. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to give tert-butyl N-[4-(2,3-difluoro-4-hydroxy-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]carbamate (600.0 mg). The crude product was used directly in the next step without further purification. MS [M+H]+ :370.0.

[0319] Step 5: [4-[3-(tert-butoxycarbonylamino)-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]trifluoromethanesulfonate

[0320] To a solution of tert-butyl N-[4-(2,3-difluoro-4-hydroxy-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]carbamate (600.0 mg, 1.62 mmol) and pyridine (0.2 mL, 2.44 mmol) in DCM (10 mL) was added trifluoromethanesulfonic anhydride (0.32 mL, 1.95 mmol) in one portion at 0 °C. The reaction mixture was then warmed to 25 °C and stirred for 1 h. The reaction was quenched with saturated aqueous NaHCO (10 mL) and extracted with DCM (10 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated to give [4-[3-(tert-butoxycarbonylamino)-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]trifluoromethanesulfonate (800.0 mg), MS [M+H] + :502.0.

[0321] Step 6: [4-[3-(tert-butoxycarbonylamino)-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]boronic acid

[0322] To a solution of bis(pinacolato)diboron (607.73 mg, 2.39 mmol), [4-[3-(tert-butoxycarbonylamino)-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluorophenyl]trifluoromethanesulfonate (800.0 mg, 1.6 mmol), and potassium acetate (313.17 mg, 3.19 mmol) in 1,4-dioxane (10.0 mL), tris(dibenzylideneacetone)dipalladium(0) (146.1 mg, 0.16 mmol) and X-PHOS (76.06 mg, 0.16 mmol) were added in one portion under N. The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (TFA) to give [4-[3-(tert-butoxycarbonylamino)-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]boronic acid (190.0 mg). MS [M+H] + :342.1.

[0323] Intermediate G53 2-[[4-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-phenyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane [ka]

[0324] Step 1: 3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0325] To a solution of 3-phenyl-1H-pyrazole (1.0 g, 6.94 mmol) in DMF (20 mL) was added sodium hydride (416.2 mg, 10.4 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. 2-(Trimethylsilyl)ethoxymethyl chloride (1.6 mL, 9.02 mmol) was then added, and the mixture was stirred at 0 °C for 12 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The organics were washed with water (50 mL × 2) followed by saturated brine solution (50 mL × 1). The organics were then separated and dried (MgSO4) before being concentrated to dryness. The crude product was then purified by flash column chromatography and lyophilized to dryness to give trimethyl-[2-[(3-phenylpyrazol-1-yl)methoxy]ethyl]silane (1.85 g). MS [M+H] + :275.4.

[0326] Step 2: 4-Bromo-3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0327] To a solution of trimethyl-[2-[(3-phenylpyrazol-1-yl)methoxy]ethyl]silane (500.0 mg, 1.82 mmol) in DMF (10 mL) was added N-bromosuccinimide (0.45 mL, 2.37 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h. The reaction was dissolved in EtOAc (50 mL), and the organics were washed with water (50 mL × 2) followed by saturated brine solution (50 mL × 1). The organics were then separated and dried (MgSO4) before being concentrated to dryness to give 2-[(4-bromo-3-phenyl-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane (300 mg). MS [M+H] + :353.1.

[0328] Step 3: 4-(4-(benzyloxy)-2,3-difluorophenyl)-3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0329] To a solution of 2-[(4-bromo-3-phenyl-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane (1.0 g, 2.83 mmol) and 2-(4-benzyloxy-2,3-difluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 g, 3.11 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was added potassium carbonate (782.3 mg, 5.66 mmol) and Pd(dppf)Cl (206.9 mg, 0.28 mmol) under argon in a glove box. The mixture was stirred at 90 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by flash column and dried by lyophilization to give 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-3-phenyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (1 g). MS [M+H] + :493.2.

[0330] Step 4: 4-(4-(benzyloxy)-2,3-difluorophenyl)-3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0331] To a solution of 2-[[4-(4-benzyloxy-2,3-difluorophenyl)-3-phenyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (1.0 g, 2.03 mmol) in methanol (20.0 mL) was added Pd / C (1.0 g) under nitrogen. The mixture was then stirred under hydrogen at 20° C. for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 2,3-difluoro-4-[3-phenyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenol (800.0 mg). MS [M+H] + 403.1.

[0332] Step 5: 2,3-difluoro-4-(3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl trifluoromethanesulfonate

[0333] To a solution of 2,3-difluoro-4-[3-phenyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenol (350.0 mg, 0.87 mmol) in pyridine (10.0 mL) was added trifluoromethanesulfonic anhydride (490.7 mg, 1.74 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was dissolved in EtOAc (50 mL), and the organics were washed with water (50 mL × 2) followed by saturated brine solution (50 mL × 1). The organics were then separated and dried (MgSO4) before being concentrated to dryness to give [2,3-difluoro-4-[3-phenyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]trifluoromethanesulfonate (400 mg). MS [M+H] + :535.1.

[0334] Step 6: 4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0335] To a solution of [2,3-difluoro-4-[3-phenyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]trifluoromethanesulfonate (400.0 mg, 0.75 mmol) and bis(pinacolato)diboron (228.0 mg, 0.90 mmol) in 1,4-dioxane (10 mL), Pd(dppf)Cl (54.7 mg, 0.07 mmol) and potassium acetate (110.1 mg, 1.12 mmol) were added under argon in a glove box. The mixture was stirred at 100 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was purified by flash column chromatography and lyophilized to dryness to give 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-phenyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (250.0 mg, 0.49 mmol, 65.2% yield) as a yellow solid. MS [M+H] +:513.2.

[0336] Intermediate G54 3-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole [ka]

[0337] Step 1: 3-Bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

[0338] To a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (500.0 mg, 4.62 mmol) in DCM (5.0 mL) was added N-bromosuccinimide (905.2 mg, 5.09 mmol). The mixture was stirred under N at 20 °C for 12 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried (NaSO), and concentrated to give crude product 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (850.0 mg). MS [M+H] + :187.0.

[0339] Step 2: 3-(4-benzyloxy-2,3-difluoro-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

[0340] A mixture of 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (0.8 g, 4.28 mmol), 2-(4-benzyloxy-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.6 g, 4.70 mmol), KCO (1.2 g, 8.55 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (349.0 mg, 0.43 mmol) was placed in a flask. The flask was degassed and purged with N gas four times. 1,4-Dioxane (5 mL) and water (1 mL) were added to the mixture via syringe. 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 crude product was purified by flash chromatography and concentrated to give 3-(4-benzyloxy-2,3-difluoro-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (900.0 mg). MS [M+H] + :327.1.

[0341] Step 3: 4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluoro-phenol

[0342] To a solution of 3-(4-benzyloxy-2,3-difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (900.0 mg, 2.76 mmol) in THF (20 mL) was added Pd / C (500.0 mg, 2.76 mmol) under N. The suspension was degassed under vacuum and purged several times with H at 20 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluorophenol (600.0 mg) as an orange oil. MS [M+H] + :237.0.

[0343] Step 4: [4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluoro-phenyl]trifluoromethanesulfonate

[0344] To a solution of 4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluoro-phenol (600.0 mg, 2.54 mmol) in pyridine (6.0 mL) was added trifluoromethanesulfonic anhydride (1.3 mL, 5.08 mmol) at 0 °C, and the reaction was stirred at 20 °C for 1 hour. Water (20 mL) was added to the reaction and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried (Na SO ), and concentrated to give the crude product [4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluoro-phenyl]trifluoromethanesulfonate (900.0 mg). MS [M+H] + :369.0.

[0345] Step 5: [4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluoro-phenyl]boronic acid

[0346] A mixture of bis(pinacolato)diboron (703.3 mg, 2.77 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (188.3 mg, 0.23 mmol), [4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluorophenyl]trifluoromethanesulfonate (850.0 mg, 2.31 mmol), and potassium acetate (453.0 mg, 4.62 mmol) was placed in a flask. 1,4-Dioxane (8 mL) was added to the mixture via syringe. The flask was degassed and purged with N gas four times. The mixture was stirred under a N atmosphere at 100 °C for 2 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the product was purified by reverse phase chromatography (FA) to give [4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluoro-phenyl]boronic acid (210.0 mg). MS [M+H] + :265.0.

[0347] Intermediate G55 [2,3-Difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]boronic acid [ka]

[0348] Step 1: [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]methoxy-tert-butyl-dimethyl-silane

[0349] To a solution of 4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluorophenol (200.0 mg, 0.5 mmol) in DMF (5 mL) was added potassium carbonate (138.7 mg, 1.0 mmol) and benzyl bromide (0.07 mL, 0.6 mmol). The reaction mixture was stirred at 20 °C for 4 h. The mixture was filtered and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na SO , and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (PE: EtOAc = 3:1) to give [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]methoxy-tert-butyl-dimethyl-silane (220.0 mg). MS [M+H] + :489.2.

[0350] Step 2: [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]methanol

[0351] To a solution of the compound [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]methoxy-tert-butyl-dimethyl-silane (220.0 mg, 0.45 mmol) in DCM (5 mL) was added hydrochloric acid (1.8 mL, 7.2 mmol) in MeOH (4 M). The reaction mixture was stirred at 20 °C for 2 hours. The mixture was concentrated under reduced pressure to give the crude product [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]methanol (170.0 mg). MS [M+H] + :375.2.

[0352] Step 3: 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-(fluoromethyl)-1-(2-methoxyethyl)pyrazole

[0353] To a solution of [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyrazol-3-yl]methanol (150.0 mg, 0.4 mmol) in DCM (5 mL) was added diethylaminosulfur trifluoride (0.21 mL, 1.6 mmol) slowly at −60° C. under N. The reaction mixture was stirred at −60° C. for 1 hour. The reaction was quenched with NaHCO (20 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over NaSO and concentrated to give the crude product. The crude product was purified by TLC (PE: EtOAc = 1:1) to give 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-(fluoromethyl)-1-(2-methoxyethyl)pyrazole (130.0 mg). MS [M+H] + :377.1.

[0354] Step 4: 2,3-Difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl]phenol

[0355] To a solution of 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-(fluoromethyl)-1-(2-methoxyethyl)pyrazole (130.0 mg, 0.35 mmol) in methanol (10 mL) was added palladium on carbon (0.04 mL, 0.03 mmol) in one portion under N2. The mixture was degassed and purged with N2 three times. H2 (15 psi) was then introduced into the system. The reaction mixture was stirred under H2 atmosphere at 20 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (PE: EtOAc = 1:1) to give 2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl] phenol (90.0 mg). MS [M+H] + :287.1.

[0356] Step 5: [2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]trifluoromethanesulfonate

[0357] A mixture of 2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl]phenol (90.0 mg, 0.31 mmol) and pyridine (0.05 mL, 0.63 mmol) in DCM (5.0 mL) was degassed and purged with N2 three times. Trifluoromethanesulfonic anhydride (0.07 mL, 0.44 mmol) was then added to the mixture at 0 °C. The reaction mixture was stirred at 20 °C under a N2 atmosphere for 2 hours. The reaction was quenched with NaHCO3 (10 mL) and extracted with DCM (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product [2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]trifluoromethanesulfonate (130.0 mg). MS [M+H] + :419.1.

[0358] Step 6: [2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]boronic acid

[0359] A mixture of [2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]trifluoromethanesulfonate (130.0 mg, 0.31 mmol), bis(pinacolato)diboron (157.8 mg, 0.62 mmol), potassium acetate (76.3 mg, 0.78 mmol), and X-PHOS (14.8 mg, 0.03 mmol) in 1,4-dioxane (5.0 mL) was degassed and purged with N three times. Tris(dibenzylideneacetone)dipalladium (28.46 mg, 0.03 mmol) was then added to the mixture. The reaction mixture was stirred at 100 °C under a N atmosphere for 2 hours. The reaction was filtered and concentrated to give the crude product. The crude product was purified by TLC (PE: EtOAc = 3:1) to give [2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]boronic acid (70.0 mg). MS [M+H] + :315.1.

[0360] Intermediate G56 [4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]boronic acid [ka]

[0361] Step 1: 3-chloro-1-(2-methoxyethyl)pyrazole

[0362] A mixture of 3-chloro-1H-pyrazole (4.5 g, 43.89 mmol) and potassium carbonate (9.1 g, 65.84 mmol) in ACN (100 mL) was degassed and purged with N2 three times. Then, 1-bromo-2-methoxyethane (12.37 mL, 131.68 mmol) was added to the mixture. The reaction mixture was stirred at 80 °C under N2 atmosphere for 16 hours. The mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography to give 3-chloro-1-(2-methoxyethyl)pyrazole (6.5 g) as a yellow oil. MS [M+H] + :161.1.

[0363] Step 2: 4-Bromo-3-chloro-1-(2-methoxyethyl)pyrazole

[0364] To a solution of 3-chloro-1-(2-methoxyethyl)pyrazole (1.0 g, 6.23 mmol) in ACN (10 mL) was added N-bromosuccinimide (1.22 g, 6.85 mmol). The reaction mixture was stirred at 20 °C for 6 h. The reaction was quenched with Na2SO3 (40 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give crude product 4-bromo-3-chloro-1-(2-methoxyethyl)pyrazole (1.8 g). MS ([M+H] + / [M+2+H] + ):239.0 / 241.0.

[0365] Step 3: 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-chloro-1-(2-methoxyethyl)pyrazole

[0366] A mixture of 4-bromo-3-chloro-1-(2-methoxyethyl)pyrazole (1.8 g, 7.52 mmol), 2-(4-benzyloxy-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.9 g, 11.27 mmol), and potassium carbonate (2.08 g, 15.03 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was degassed and purged with N three times. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (274.97 mg, 0.38 mmol) was added dropwise to the mixture. The reaction mixture was stirred at 80 °C under a N atmosphere for 9 hours. The mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 10: 1 to 2: 1) to give 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-chloro-1-(2-methoxyethyl)pyrazole (1.7 g). MS [M+H] + :379.1.

[0367] Step 4: 4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenol

[0368] To a solution of 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-chloro-1-(2-methoxyethyl)pyrazole (3.4 g, 8.98 mmol) in methanol (30 mL) was added platinum(IV) oxide (101.91 mg, 0.45 mmol) in one portion under Ar. The mixture was degassed and purged with Ar three times. H (15 psi) was then introduced into the system. The reaction mixture was stirred under an H atmosphere at 20 °C for 6 h. The reaction was carefully filtered and concentrated to give the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 4:1 to 1:1) to give 4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenol (2.4 g). MS [M+H] + :289.1.

[0369] Step 5: [4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]trifluoromethanesulfonate

[0370] A mixture of 4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenol (500.0 mg, 1.73 mmol) and pyridine (0.28 mL, 3.46 mmol) in DCM (5 mL) was degassed and purged with N2 three times. Trifluoromethanesulfonic anhydride (0.4 mL, 2.42 mmol) was then added to the mixture at 0 °C. The reaction mixture was stirred at 20 °C under a N2 atmosphere for 2 hours. The reaction was quenched with NaHCO3 (10 mL) and extracted with DCM (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product [4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]trifluoromethanesulfonate (750.0 mg). MS [M+H] + :421.0.

[0371] Step 6: [4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]boronic acid

[0372] A mixture of [4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluorophenyl]trifluoromethanesulfonate (900.0 mg, 2.14 mmol), bis(pinacolato)diboron (1.09 g, 4.28 mmol), potassium acetate (524.84 mg, 5.35 mmol), and X-PHOS (50.99 mg, 0.11 mmol) in 1,4-dioxane (5 mL) was degassed and purged with N three times. Tris(dibenzylideneacetone)dipalladium(0) (97.94 mg, 0.11 mmol) was then added to the mixture. The reaction mixture was stirred at 90 °C under a N atmosphere for 2 hours. The reaction was filtered and concentrated to give the crude product. The crude product was purified by TLC (PE:EA=3:1) to give [4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]boronic acid (450.0 mg). MS [M+H] + :317.0.

[0373] The following examples were prepared analogously to intermediate G54. [Table 12]

[0374] Intermediate G58 [2,3-Difluoro-4-[5-(2-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]boronic acid [ka]

[0375] Step 1: 2-(4-bromo-1H-pyrazol-5-yl)pyridine

[0376] To a solution of 2-(1H-pyrazol-5-yl)pyridine (3.0 g, 20.7 mmol) in acetic acid (20 mL) was added bromine (3.6 g, 22.7 mmol), and the mixture was stirred at 20° C. for 0.5 h. The mixture was concentrated, the residue was diluted with 20 mL of water, and the solution was added to aqueous NaOH (30 mL, 1 M). The precipitate was filtered off and dried in vacuo to give 2-(4-bromo-1H-pyrazol-5-yl)pyridine (4.6 g). MS [M+H] + :223.9.

[0377] Step 2: 2-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridine

[0378] To a solution of 2-(4-bromo-1H-pyrazol-5-yl)pyridine (4.5 g, 20.08 mmol) in ACN (50.0 mL) was added cesium carbonate (13.1 g, 40.17 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (4.27 mL, 24.1 mmol), and the mixture was stirred at 70° C. for 1 h. The mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC to give 2-[[4-bromo-5-(2-pyridyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (3.82 g). MS [M+H] + :354.0.

[0379] Step 3: 2-(4-(4-(benzyloxy)-2,3-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridine

[0380] To a solution of 2-[[4-bromo-5-(2-pyridyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (1.0 g, 2.82 mmol) in 1,4-dioxane (10 mL), 2-(4-benzyloxy-2,3-difluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 3.39 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (206.5 mg, 0.28 mmol), potassium carbonate (780.2 mg, 5.64 mmol) and dioxane (10 mL) / water (1 mL) were added in a glove box and the mixture was stirred at 100 °C under Ar for 16 h. The mixture was diluted with 10 mL of ethyl acetate, filtered, the filtrate was concentrated, and the residue was purified by flash HPLC to give 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-5-(2-pyridyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (520 mg). MS [M+H] + :494.2.

[0381] Step 4: 2,3-Difluoro-4-(5-(pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenol

[0382] To a solution of 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-5-(2-pyridyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (470.0 mg, 0.95 mmol) in methanol (10 mL) was added Pd / C (80.0 mg) under N2, and the mixture was then flushed with H2 and stirred at 20 °C for 2 h using a H2 balloon. The mixture was filtered, and the filtrate was concentrated to give 2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenol (290.0 mg). MS [M+H] + :404.1.

[0383] Step 5: 2,3-difluoro-4-(5-(pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl trifluoromethanesulfonate

[0384] To a solution of 2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenol (290.0 mg, 0.72 mmol) in pyridine (4.0 mL) was added trifluoromethanesulfonic anhydride (405.5 mg, 1.44 mmol) under N at 0° C. The mixture was stirred at 20° C. for 0.5 h. The mixture was diluted with 50 mL of ethyl acetate and washed with 20 mL of water and 20 mL of brine. The organic layer was dried over NaSO and concentrated to give [2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]trifluoromethanesulfonate (384.0 mg). MS [M+H] + :536.1.

[0385] Step 6: (2,3-Difluoro-4-(5-(pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)boronic acid

[0386] To a solution of [2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]trifluoromethanesulfonate (350.0 mg, 0.65 mmol) in 1,4-dioxane (2.0 mL), potassium acetate (0.08 mL, 1.31 mmol), bis(pinacolato)diboron (331.9 mg, 1.31 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (47.8 mg, 0.07 mmol) were added in a glove box. The mixture was stirred at 100 °C for 8 h. The mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC to give [2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]boronic acid (500.0 mg). MS [M+H] + :432.1.

[0387] Intermediate G59 2-[[4-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(4-methoxyphenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane [ka]

[0388] Step 1: 2-[(4-bromopyrazol-1-yl)methoxy]ethyl-trimethyl-silane

[0389] To a solution of 4-bromo-1H-pyrazole (20.0 g, 136.08 mmol) in THF (500 mL) was slowly added 60% sodium hydride in oil (6.5 g, 163.3 mmol) at 0 °C. After the addition, the reaction mixture was stirred at 0 °C for 1 hour. Then, 2-(trimethylsilyl)ethoxymethyl chloride (36.1 mL, 204.12 mmol) was slowly added to the mixture at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 15 hours. The reaction was quenched with saturated aqueous NH Cl (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na SO and concentrated to give 2-[(4-bromopyrazol-1-yl)methoxy]ethyl-trimethyl-silane (32.0 g). Step 2: 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0390] To a solution of 2-(4-benzyloxy-2,3-difluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.5 g, 36.07 mmol), 2-[(4-bromopyrazol-1-yl)methoxy]ethyl-trimethyl-silane (10.0 g, 36.07 mmol), and potassium carbonate (7.5 g, 54.11 mmol) in 1,4-dioxane (200 mL) and water (20 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.3 g, 1.8 mmol) was added in one portion under N . The reaction mixture was stirred at 100 °C for 4 h, and the filtrate was concentrated to give a residue. The residue was diluted with EtOAc (200 mL) and washed with brine (50 mL × 2). The organic layer was dried over Na SO and concentrated to give the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 5: 1 to 1: 1) to give 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl) pyrazol-1-yl] methoxy] ethyl-trimethyl-silane (10.0 g). MS [M+H] + :417.2.

[0391] Step 3: 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-5-bromo-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0392] To a solution of 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (9.0 g, 21.61 mmol) in DMF (100 mL) was added N-bromosuccinimide (4.6 g, 25.93 mmol) in one portion. The reaction mixture was stirred at 80 °C for 16 h. The reaction was quenched with saturated aqueous NaSO (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over NaSO and concentrated to give the crude product. The crude product was purified by Prep-HPLC to give 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-5-bromo-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (3.0 g). MS [M+H] + :496.9.

[0393] Step 4: 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-5-(4-methoxyphenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0394] To a solution of 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-5-bromo-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (184.0 mg, 1.21 mmol), compound 5 (400.0 mg, 0.81 mmol), and potassium carbonate (223.2 mg, 1.61 mmol) in 1,4-dioxane (10 mL) and water (1 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (59.1 mg, 0.08 mmol) was added in one portion under N2. The reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was filtered, and the filtrate was concentrated to give a residue. The residue was diluted with EtOAc (50 mL) and washed with brine (10 mL × 2). The organic phase was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel chromatography to give 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-5-(4-methoxyphenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (330.0 mg). MS [M+H] + :523.2.

[0395] Step 5: 2,3-Difluoro-4-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenol

[0396] To a solution of 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-5-(4-methoxyphenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (280.0 mg, 0.54 mmol) in methanol (20 mL) was added palladium on carbon (10%, 57.0 mg) in one portion under N2. H2 (15 psi) was then introduced into the system. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to give 2,3-difluoro-4-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenol (230.0 mg, 0.53 mmol), which was used directly in the next step without further purification. MS [M+H] + :433.2.

[0397] Step 6: [2,3-difluoro-4-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]trifluoromethanesulfonate

[0398] To a solution of 2,3-difluoro-4-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenol (230.0 mg, 0.53 mmol) and pyridine (0.06 mL, 0.8 mmol) in DCM (10 mL) was added trifluoromethanesulfonic anhydride (0.11 mL, 0.64 mmol) in one portion at 0 °C. The reaction mixture was then warmed to 20 °C and stirred for 2 h. The reaction was quenched with saturated aqueous NaCO (10 mL) and extracted with DCM (10 mL × 2). The combined organic layers were dried over NaSO and concentrated to give [2,3-difluoro-4-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]trifluoromethanesulfonate (320.0 mg). MS [M+H] + :565.0.

[0399] Step 7: 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(4-methoxyphenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0400] To a solution of [2,3-difluoro-4-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]trifluoromethanesulfonate (320.0 mg, 0.57 mmol), bis(pinacolato)diboron (287.8 mg, 1.13 mmol), and potassium acetate (139.06 mg, 1.42 mmol) in 1,4-dioxane (10 mL), X-PHOS (27.0 mg, 0.06 mmol) and tris(dibenzylideneacetone)dipalladium(0) (51.9 mg, 0.06 mmol) were added in one portion under N. 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 silica gel chromatography to give 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(4-methoxyphenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (250.0 mg, 0.46 mmol). MS [M+H] + :543.3.

[0401] The following examples were prepared similarly to intermediate G59. [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4]

[0402] Intermediate G70 tert-Butyl N-[6-[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]carbamate [ka]

[0403] Step 1: 2-(4-bromo-3-methyl-1H-pyrazol-1-yl)-5-nitropyridine

[0404] To a solution of 4-bromo-3-methyl-1H-pyrazole (2.5 g, 15.53 mmol) in DMF (100 mL) was added sodium hydride (750.0 mg, 18.75 mmol) in portions at 0° C. under N. After the addition was complete, the mixture was stirred at 0° C. for 0.5 h. 2-Chloro-5-nitropyridine (2.5 g, 15.77 mmol) was then added to the above mixture at 0° C., and the resulting mixture was gradually warmed to 20° C. and stirred for 11.5 h. The mixture was then quenched with saturated NH4Cl (800 mL), filtered, and the filter cake was washed with ACN (50 mL) and dried under vacuum to give 2-(4-bromo-3-methyl-pyrazol-1-yl)-5-nitro-pyridine (3.8 g). MS [M+H] + :283.0.

[0405] Step 2: 6-(4-bromo-3-methyl-1H-pyrazol-1-yl)pyridin-3-amine

[0406] To a solution of 2-(4-bromo-3-methyl-pyrazol-1-yl)-5-nitro-pyridine (3.8 g, 13.42 mmol) and ammonium chloride (8.6 g, 161.09 mmol) in ethanol (70 mL) and water (20 mL), Fe powder (2.5 g, 44.29 mmol) was added under N at 20 °C, and the resulting mixture was stirred at 80 °C under N for 3 h. TLC (PE:EA = 1:1) showed the formation of the desired product. After the reaction mixture was cooled to 20 °C, saturated NaHCO (60 mL) was added to the mixture, which was then extracted with brine (150 mL) and EtOAc (120 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give 6-(4-bromo-3-methyl-pyrazol-1-yl)pyridin-3-amine (3.2 g).

[0407] Step 3: tert-butyl (6-(4-bromo-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)carbamate (4)

[0408] To the resulting solution of 6-(4-bromo-3-methyl-pyrazol-1-yl)pyridin-3-amine (3.2 g, 12.64 mmol) and BocO (5.5 g, 25.30 mmol) in methanol (50 mL) was added triethylamine (3.5 mL, 25.29 mmol), and the resulting mixture was stirred at 20° C. for 14 hours. The mixture was then concentrated in vacuo to give a residue that was purified by HPLC and evaporated in vacuo to give tert-butyl N-[6-(4-bromo-3-methyl-pyrazol-1-yl)-3-pyridyl]carbamate (2.8 g). MS [M+H] + :353.0.

[0409] Step 4: tert-butyl (6-(4-(4-(benzyloxy)-2,3-difluorophenyl)-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)carbamate

[0410] To a solution of tert-butyl N-[6-(4-bromo-3-methyl-pyrazol-1-yl)-3-pyridyl]carbamate (1.0 g, 2.83 mmol), 2-(4-benzyloxy-2,3-difluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 4.33 mmol), and potassium carbonate (800.0 mg, 5.79 mmol) in 1,4-dioxane (25 mL) and water (5.0 mL), Pd(dppf)Cl (207.0 mg, 0.28 mmol) was added under N at 20 °C, and the mixture was then stirred at 85 °C under N for 15 h. After cooling to 20 °C, the mixture was filtered through Celite, and the filtrate was extracted with brine (200 mL) and EtOAc (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by HPLC and evaporated under reduced pressure to give tert-butyl N-[6-[4-(4-benzyloxy-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]-3-pyridyl]carbamate (1.1 g) as a yellow solid. MS [M+H] + :493.1.

[0411] Step 5: tert-butyl (6-(4-(2,3-difluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)carbamate

[0412] To a solution of tert-butyl N-[6-[4-(4-benzyloxy-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]-3-pyridyl]carbamate (500.0 mg, 1.02 mmol) in methanol (15 mL) and ethyl acetate (15 mL) was added Pd / C (500.0 mg) under H2 at 20 °C, and the resulting mixture was stirred under a balloon of H2 at 20 °C for 12 hours. The mixture was then filtered through celite, and the filtrate was concentrated in vacuo to give tert-butyl N-[6-[4-(2,3-difluoro-4-hydroxy-phenyl)-3-methyl-pyrazol-1-yl]-3-pyridyl]carbamate (325.0 mg). MS [M+H] +:403.1.

[0413] Step 6: 4-(1-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-3-methyl-1H-pyrazol-4-yl)-2,3-difluorophenyl trifluoromethanesulfonate

[0414] To a solution of tert-butyl N-[6-[4-(2,3-difluoro-4-hydroxy-phenyl)-3-methyl-pyrazol-1-yl]-3-pyridyl]carbamate (325.0 mg, 0.81 mmol) and pyridine (0.4 mL, 4.95 mmol) in DCM (15 mL) was added trifluoromethanesulfonic anhydride (290.0 mg, 1.03 mmol) at 20 °C, and the resulting mixture was stirred at 20 °C for 2 hours. The mixture was then extracted with saturated NH Cl (70.0 mL) and EtOAc (60 mL × 3). The combined organic layers were dried over Na SO , filtered, and concentrated in vacuo to give [4-[1-[5-(tert-butoxycarbonylamino)-2-pyridyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]trifluoromethanesulfonate (390.0 mg). MS[M+H] + :534.9.

[0415] Step 7: tert-butyl (6-(4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)carbamate

[0416] To a solution of [4-[1-[5-(tert-butoxycarbonylamino)-2-pyridyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]trifluoromethanesulfonate (300.0 mg, 0.56 mmol), bis(pinacolato)diboron (280.0 mg, 1.10 mmol) and potassium acetate (0.07 mL, 1.12 mmol) in 1,4-dioxane (8.0 mL) was added Pd(dppf)Cl (42.0 mg, 0.06 mmol) under N at 20 °C, and the resulting mixture was stirred at 100 °C under N for 14 h. The mixture was cooled and filtered through celite, after which the filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (FA) and concentrated in vacuo to give tert-butyl N-[6-[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]carbamate (160.0 mg). MS [M+H] + :513.2.

[0417] The following examples were prepared similarly to intermediate G70. [Table 14-1] [Table 14-2]

[0418] Intermediate G75 2-[[4-[6-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-3-(4-methoxyphenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane [ka]

[0419] Step 1: 6-Bromo-2-fluoropyridin-3-ol

[0420] To a solution of 2-fluoropyridin-3-ol (2.0 g, 17.69 mmol) in acetic acid (20.0 mL), sodium acetate (1.3 mL, 17.69 mmol) was added to dissolve the solid, and then bromine (2.8 g, 17.69 mmol) was added dropwise at 0° C. The mixture was stirred at 20° C. for 3 hours. 1 g of sodium sulfite was added to the reaction mixture, and the mixture was concentrated. The residue was diluted with 20 mL of water, neutralized with 2 M NaOH solution, and the solid was filtered off and dried in vacuo to give 6-bromo-2-fluoro-pyridin-3-ol (1.8 g). MS [M+H] + :191.9.

[0421] Step 2: 3-(benzyloxy)-6-bromo-2-fluoropyridine

[0422] To a solution of 6-bromo-2-fluoro-pyridin-3-ol (1.5 g, 7.81 mmol) in DMF (20.0 mL) was added NaH (375.0 mg, 9.38 mmol) at 0 ° C. The mixture was stirred at 0 ° C. for 0.5 h, then benzyl bromide (0.9 mL, 7.81 mmol) was added, and the mixture was stirred at 20 ° C. for 16 h. The mixture was quenched with 30 mL of aqueous NH4Cl solution at 0 ° C. The mixture was then extracted with ethyl acetate (30 mL × 3), the organic layer was concentrated, and the residue was purified by preparative HPLC to give 3-benzyloxy-6-bromo-2-fluoro-pyridine (1.7 g). MS [M+H] + :281.9.

[0423] Step 3: 3-(benzyloxy)-2-fluoro-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridine

[0424] To a solution of 3-benzyloxy-6-bromo-2-fluoro-pyridine (1.5 g, 5.32 mmol) in 1,4-dioxane (60.0 mL) and water (6.0 mL) was added trimethyl-[2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methoxy]ethyl]silane (3.8 g, 5.85 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (389.1 mg, 0.53 mmol), KCO (1.1 g, 10.63 mmol) in a glove box, and the mixture was stirred at 60 °C under Ar for 16 h. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column to give 2-[[4-(5-benzyloxy-6-fluoro-2-pyridyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (1.55 g) as a yellow solid. MS [M+H] + :400.1.

[0425] Step 4: 3-(benzyloxy)-6-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-2-fluoropyridine

[0426] To a solution of 2-[[4-(5-benzyloxy-6-fluoro-2-pyridyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (1.5 g, 3.75 mmol) in DMF (15 mL) was added NBS (1.34 g, 7.51 mmol) and the mixture was stirred at 60 °C for 16 hours. The mixture was purified by preparative HPLC to give 2-[[4-(5-benzyloxy-6-fluoro-2-pyridyl)-5-bromo-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (800.0 mg). MS [M+H] + :478.1.

[0427] Step 5: 3-(benzyloxy)-2-fluoro-6-(5-(4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridine

[0428] To a solution of (4-methoxyphenyl)boronic acid (297.3 mg, 1.96 mmol) in 1,4-dioxane (1.0 mL) and water (0.1 mL) were added 2-[[4-(5-benzyloxy-6-fluoro-2-pyridyl)-5-bromo-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (780.0 mg, 1.63 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (119.3 mg, 0.16 mmol), KCO (518.4 mg, 4.89 mmol) in a glove box, and the mixture was stirred at 60 °C under Ar for 4 h. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column to give 2-[[4-(5-benzyloxy-6-fluoro-2-pyridyl)-5-(4-methoxyphenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (550.0 mg). MS [M+H] + :506.2.

[0429] Step 6: 2-fluoro-6-(5-(4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-3-ol

[0430] To a mixture of 2-[[4-(5-benzyloxy-6-fluoro-2-pyridyl)-5-(4-methoxyphenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (550.0 mg, 1.09 mmol) in methanol (100 mL) was added Pd / C (50.0 mg) under N2, and then the mixture was flushed with H2 and stirred with a H2 balloon at 15 °C for 6 hours. The mixture was filtered, and the filtrate was concentrated to give 2-fluoro-6-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]pyridin-3-ol (450.0 mg). MS[M+H] + :416.1.

[0431] Step 7: tert-butyl 2-fluoro-6-(5-(4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-3-yl trifluoromethanesulfonate

[0432] To a mixture of 2-fluoro-6-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]pyridin-3-ol (450.0 mg, 1.08 mmol) in pyridine (15 mL) was added trifluoromethanesulfonic anhydride (611.1 mg, 2.17 mmol) at 0 °C, and the mixture was then stirred at 15 °C for 1 hour. The mixture was diluted with 50 mL of ethyl acetate and washed with 30 mL of water and 30 mL of brine. The organic layer was dried over Na SO and concentrated to give [2-fluoro-6-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-3-pyridyl]trifluoromethanesulfonate (580.0 mg). MS [M+H] + :548.1.

[0433] Step 8: 2-fluoro-6-(5-(4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0434] To a solution of [2-fluoro-6-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-3-pyridyl]trifluoromethanesulfonate (560.0 mg, 1.02 mmol) in 1,4-dioxane (1.0 mL), bis(pinacolato)diboron (389.5 mg, 1.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (74.8 mg, 0.10 mmol), and potassium acetate (300.9 mg, 3.07 mmol) were added in a glove box, and the mixture was stirred at 90°C for 16 hours. The mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC to give 2-[[4-[6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-5-(4-methoxyphenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (530.0 mg). MS [M+H] + :526.3.

[0435] Intermediate G76 2-[2-[4-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]ethyl]-6-methoxy-pyridine [ka]

[0436] Step 1: 2-Methoxy-6-vinylpyridine

[0437] A mixture of 2-bromo-6-methoxy-pyridine (6.5 mL, 53.19 mmol) and potassium trifluoro(vinyl)boranide (8.6 g, 63.82 mmol) in 1,4-dioxane (120 mL) was added to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.8 g, 1.06 mmol), potassium carbonate (20.6 g, 149.31 mmol), and water (12 mL) in a glovebox. The mixture was stirred at 100 °C under Ar for 16 h. The mixture was distilled in vacuo, the collector cooled with dry ice, and 20 mL of HCl / 1,4-dioxane (4 M) was added to the distillate and stirred at 60 °C for 2 h. The mixture was then concentrated to give 2-methoxy-6-vinyl-pyridine hydrochloride (2.6 g) as a yellow gum. MS [M+H] + :136.1.

[0438] Step 2: 2-(2-(4-bromo-3-methyl-1H-pyrazol-1-yl)ethyl)-6-methoxypyridine

[0439] To a mixture of 2-methoxy-6-vinyl-pyridine hydrochloride (2.5 g, 18.5 mmol) in DMSO (20.0 mL) was added potassium carbonate (5.1 g, 36.99 mmol) and 4-bromo-3-methylpyrazole (3.6 g, 22.20 mmol), and the mixture was stirred at 80 °C for 12 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC (TFA as an additive) to give 2-[2-(4-bromo-3-methyl-pyrazol-1-yl)ethyl]-6-methoxy-pyridine (2.0 g) as a yellow oil. MS [M+H] + :296.0.

[0440] Step 3: 2-(2-(4-(4-(benzyloxy)-2,3-difluorophenyl)-3-methyl-1H-pyrazol-1-yl)ethyl)-6-methoxypyridine

[0441] A solution of 2-[2-(4-bromo-3-methyl-pyrazol-1-yl)ethyl]-6-methoxy-pyridine (2.2 g, 6.36 mmol), Pd(dppf)Cl (0.9 g, 0.70 mmol), 2-(4-benzyloxy-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.8 g, 6.08 mmol) and KCO (1.8 g, 13.02 mmol) in 1,4-dioxane (10 mL) and water (3 mL) was stirred at 80 °C for 12 h. The reaction mixture was dried in vacuo, and the residue was purified by column and dried in vacuo to give 2-[2-[4-(4-benzyloxy-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]ethyl]-6-methoxy-pyridine (1.7 g, 3.81 mmol, 62.6% yield) as an off-white solid. MS [M+H] + :435.9.

[0442] Step 4: 2,3-Difluoro-4-(1-(2-(6-methoxypyridin-2-yl)ethyl)-3-methyl-1H-pyrazol-4-yl)phenol

[0443] A solution of 2-[2-[4-(4-benzyloxy-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]ethyl]-6-methoxy-pyridine (2.1 g, 4.82 mmol) and Pd / C (200.0 mg) in methanol (0.2 mL) was stirred at 25° C. for 2 hours. It was filtered and dried under vacuum to give 2,3-difluoro-4-[1-[2-(6-methoxy-2-pyridyl)ethyl]-3-methyl-pyrazol-4-yl]phenol (560.0 mg) as an off-white solid. MS [M+H] + :345.8.

[0444] Step 5: 2,3-difluoro-4-(1-(2-(6-methoxypyridin-2-yl)ethyl)-3-methyl-1H-pyrazol-4-yl)phenyl trifluoromethanesulfonate

[0445] To a mixture of 2,3-difluoro-4-[1-[2-(6-methoxy-2-pyridyl)ethyl]-3-methyl-pyrazol-4-yl]phenol (500.0 mg, 1.45 mmol) and pyridine (0.5 mL) in DCM (2.0 mL) was added trifluoromethanesulfonic anhydride (408.5 mg, 1.45 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into ice water (50 mL), extracted with EA (50 mL), dried over Na SO , and the organic phase was concentrated under reduced pressure to give [2,3-difluoro-4-[1-[2-(6-methoxy-2-pyridyl)ethyl]-3-methyl-pyrazol-4-yl]phenyl]trifluoromethanesulfonate (803.0 mg, 1.68 mmol, 116.2% yield) as a pale yellow gum. MS [M+H] + :478.1.

[0446] Step 6: 2-(2-(4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-1H-pyrazol-1-yl)ethyl)-6-methoxypyridine

[0447] A mixture of [2,3-difluoro-4-[1-[2-(6-methoxy-2-pyridyl)ethyl]-3-methyl-pyrazol-4-yl]phenyl]trifluoromethanesulfonate (600.0 mg, 2.36 mmol), bis(pinacolato)diboron (800.0 mg, 1.68 mmol), Pd(dppf)Cl (200.0 mg, 0.25 mmol) and AcOK (400.0 mg, 4.08 mmol) in 1,4-dioxane (0.3 mL) was stirred at 80 °C for 2 h. The reaction mixture was subjected to preparative HPLC (FA) to give 2-[2-[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]ethyl]-6-methoxy-pyridine (402.0 mg). MS [M+H] + :373.9.

[0448] Intermediate G78 2-[[4-[[4-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]methyl]triazol-1-yl]methoxy]ethyl-trimethyl-silane [ka]

[0449] Step 1: 4-Bromo-3-methyl-1-prop-2-ynyl-pyrazole

[0450] To a mixture of propargyl bromide (11.1 g, 93.17 mmol) in NMP (100.0 mL) was added 4-bromo-3-methyl-1H-pyrazole (10.0 g, 62.11 mmol) and potassium carbonate (17.2 g, 124.22 mmol), and the mixture was stirred at 100° C. for 16 h. The reaction mixture was poured into water (300 mL) and EtOAc (200 mL) and washed with brine (200 mL×2). The organic layer was dried over NaSO and concentrated to give the crude product, which was further purified by preparative HPLC (FA) to give a mixture of 4-bromo-3-methyl-1-prop-2-ynyl-pyrazole (2) (8.0 g). MS [M+H] + :198.7.

[0451] Step 2: 4-[(4-bromo-3-methyl-pyrazol-1-yl)methyl]-1H-triazole

[0452] A mixture of 4-bromo-3-methyl-1-prop-2-ynyl-pyrazole (5.0 g, 25.12 mmol) in azidotrimethylsilane (33.3 mL, 251.19 mmol) was stirred at 100 °C for 16 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous Na2CO3 (200 mL x 2). The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was further purified by preparative HPLC (FA) to give a mixture of isomers, which was further purified by chiral separation to give 4-[(4-bromo-3-methyl-pyrazol-1-yl)methyl]-1H-triazole (1.7 g). MS [M+H] + :242.0.

[0453] Step 3: 2-[[4-[(4-bromo-3-methyl-pyrazol-1-yl)methyl]triazol-1-yl]methoxy]ethyl-trimethyl-silane To a solution of 4-[(4-bromo-3-methyl-pyrazol-1-yl)methyl]-1H-triazole (1.6 g, 6.61 mmol) in DMF (20 mL) was added NaH (396.6 mg, 9.91 mmol) and 2-(trimethylsilyl)

[0454] Ethoxymethyl chloride (1.2 mL, 6.94 mmol) was added at 0 °C. The mixture was stirred at 25 °C under N for 12 h. The reaction mixture was quenched with (30 mL) NH4Cl (aq), extracted with EtOAc (80 mL x 3), and the organic phase was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated in vacuo to give 2-[[4-[(4-bromo-3-methyl-pyrazol-1-yl)methyl]triazol-1-yl]methoxy]ethyl-trimethyl-silane (2200.0 mg). MS [M+H] + :372.0.

[0455] Step 4: 2-[[4-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]methyl]triazol-1-yl]methoxy]ethyl-trimethyl-silane

[0456] A mixture of 2-[[4-[(4-bromo-3-methyl-pyrazol-1-yl)methyl]triazol-1-yl]methoxy]ethyl-trimethyl-silane (1300.0 mg, 3.49 mmol), 2-(4-benzyloxy-2,3-difluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1208.7 mg, 3.49 mmol), NaCO (740.1 mg, 6.98 mmol), and Pd(dppf)Cl (307.6 mg, 0.35 mmol) was placed in a flask. The flask was degassed and purged with N gas four times. 1,4-Dioxane (15.0 mL) and water (2.0 mL) were added to the mixture via syringe. The mixture was stirred under N at 80 °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 flash chromatography (petroleum / Et0Ac=20 / 1 to 1 / 1) and concentrated to give 2-[[4-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]methyl]triazol-1-yl]methoxy]ethyl-trimethyl-silane (1.7 g). MS [M+H] + :512.2.

[0457] Step 5: 2,3-Difluoro-4-[3-methyl-1-[[1-(2-trimethylsilylethoxymethyl)triazol-4-yl]methyl]pyrazol-4-yl]phenol

[0458] To a solution of 2-[[4-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]methyl]triazol-1-yl]methoxy]ethyl-trimethyl-silane (1.65 g, 3.22 mmol) in methanol (20.0 mL) was added Pd / C (300.0 mg) under N2. The suspension was degassed under vacuum and purged several times with H2 at 20 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2,3-difluoro-4-[3-methyl-1-[[1-(2-trimethylsilylethoxymethyl)triazol-4-yl]methyl]pyrazol-4-yl]phenol (1.35 g). MS [M+H] +:422.1.

[0459] Step 6: [2,3-difluoro-4-[3-methyl-1-[[1-(2-trimethylsilylethoxymethyl)triazol-4-yl]methyl]pyrazol-4-yl]phenyl]trifluoromethanesulfonate

[0460] To a solution of 2,3-difluoro-4-[3-methyl-1-[[1-(2-trimethylsilylethoxymethyl)triazol-4-yl]methyl]pyrazol-4-yl]phenol (1.3 g, 3.08 mmol) in pyridine (15.0 mL) was added trifluoromethanesulfonic anhydride (1.0 mL, 6.17 mmol) at 0 °C, and the reaction was stirred at 20 °C for 2 hours. The mixture was poured into ice water (20 mL) and extracted with EtOAc (50 mL × 2). The mixture was combined and washed with brine (20 mL). The organic layer was dried and concentrated in vacuo to give [2,3-difluoro-4-[3-methyl-1-[[1-(2-trimethylsilylethoxymethyl)triazol-4-yl]methyl]pyrazol-4-yl]phenyl]trifluoromethanesulfonate (1700.0 mg). MS [M+H] + :554.0.

[0461] Step 7: 2-[[4-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]methyl]triazol-1-yl]methoxy]ethyl-trimethyl-silane

[0462] A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (908.3 mg, 3.58 mmol), Pd(dppf)Cl (243.2 mg, 0.30 mmol), [2,3-difluoro-4-[3-methyl-1-[[1-(2-trimethylsilylethoxymethyl)triazol-4-yl]methyl]pyrazol-4-yl]phenyl]trifluoromethanesulfonate (1650.0 mg, 2.98 mmol), and potassium acetate (585.1 mg, 5.96 mmol) was placed in a flask. 1,4-Dioxane (20 mL) was added to the mixture via syringe. The flask was degassed and purged with N gas four times. The mixture was stirred under a N atmosphere at 80 °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 (FA as an additive) to give 2-[[4-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]methyl]triazol-1-yl]methoxy]ethyl-trimethyl-silane (800.0 mg). MS [M+H] + :532.3.

[0463] Intermediate G79 [2-Fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-3-pyridyl]boronic acid [ka]

[0464] Step 1: 6-Bromo-2-fluoropyridin-3-ol

[0465] To a solution of 2-fluoropyridin-3-ol (2.5 g, 22.11 mmol) in acetic acid (25 mL) was added sodium acetate (1.67 mL, 22.11 mmol). After dissolving the solid, bromine (3.5 g, 22.11 mmol) was added dropwise at 0 °C, and the mixture was then stirred at 20 °C for 3 hours. The reaction mixture was poured into ice water and extracted with EtOAc (2 × 200 mL). The reaction mixture was washed with 100 mL of aqueous sodium sulfite solution, and the organic layer was then dried in vacuo to give 6-bromo-2-fluoro-pyridin-3-ol (3.15 g). MS [M+H] + :191.6.

[0466] Step 2: 3-(benzyloxy)-6-bromo-2-fluoropyridine

[0467] A solution of 6-bromo-2-fluoro-pyridin-3-ol (3.1 g, 16.15 mmol, 1.0 equiv.), benzyl bromide (1.95 mL, 16.37 mmol, 1.0 equiv.), and K2CO3 (3.1 g, 22.43 mmol, 1.39 equiv.) in ACN (30 mL) was stirred at 25 °C for 12 h. The reaction mixture was filtered and washed with EtOAc (100 mL), and the filter was then washed with brine (2 x 200 mL), which was dried under vacuum to give 3-benzyloxy-6-bromo-2-fluoro-pyridine (4.1 g). MS [M+H] + :281.6.

[0468] Step 3: 3-(benzyloxy)-2-fluoro-6-(1-(2-methoxyethyl)-5-methyl-1H-pyrazol-4-yl)pyridine

[0469] To 3-benzyloxy-6-bromo-2-fluoro-pyridine (1.0 g, 3.54 mmol), 1-(2-methoxyethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.0 g, 3.76 mmol) in 1,4-dioxane (10 mL) and water (3 mL) was added Pd(dppf)Cl (300.0 mg, 0.37 mmol) and NaCO (0.8 g, 7.55 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was purified by pre-HPLC (FA as an additive) and dried under vacuum to give 3-benzyloxy-2-fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]pyridine (340 mg). MS [M+H] + :342.1.

[0470] Step 4: 2-fluoro-6-(1-(2-methoxyethyl)-5-methyl-1H-pyrazol-4-yl)pyridin-3-ol

[0471] A solution of 3-benzyloxy-2-fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]pyridine (320.0 mg, 0.94 mmol) and Pd / C (100.0 mg) in methanol (0.5 mL) was stirred under a H balloon at 25° C. for 12 hours. The reaction mixture was filtered and dried under vacuum to give 2-fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]pyridin-3-ol (236.0 mg). MS [M+H] + :251.8.

[0472] Step 5: 2-fluoro-6-(1-(2-methoxyethyl)-5-methyl-1H-pyrazol-4-yl)pyridin-3-yl trifluoromethanesulfonate

[0473] To a mixture of 2-fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]pyridin-3-ol (300.0 mg, 1.19 mmol) in pyridine (1.0 mL) was added trifluoromethanesulfonic anhydride (336.8 mg, 1.19 mmol) at 0 ° C., and the reaction mixture was stirred at 0 ° C. for 2 hours. The reaction mixture was poured into ice water (50 mL), extracted with EA (50 mL), and the organic layer was dried over Na SO , filtered, and evaporated to give [2-fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-3-pyridyl]trifluoromethanesulfonate (320.0 mg). MS [M+H] + :383.8.

[0474] Step 6: [2-Fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-3-pyridyl]boronic acid

[0475] A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (260.0 mg, 1.02 mmol), [2-fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-3-pyridyl]trifluoromethanesulfonate (320.0 mg, 0.83 mmol), Pd(dppf)Cl (96.0 mg, 0.12 mmol) and KOAc (200.0 mg, 2.06 mmol) in 1,4-dioxane (5 mL) was stirred at 80 °C for 2 h. The reaction product was purified by Pre-HPLC (FA) and dried in vacuo to give [2-fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-3-pyridyl]boronic acid (126.0 mg). MS[M+H] + :279.8.

[0476] The following examples were prepared analogously to intermediate G79. [Table 15]

[0477] Intermediate G86 [ka]

[0478] Step 1: (6-Bromo-3-pyridyl)-[3-[tert-butyl(dimethyl)silyl]oxypropyl]amine

[0479] (6-Bromo-3-pyridyl)amine (2.45 g, 14.16 mmol), 3-[tert-butyl(dimethyl)silyl]oxypropionaldehyde (2.67 g, 14.16 mmol), and acetic acid (170.07 mg, 2.83 mmol) were dissolved in dichloromethane (50 mL). Sodium triacetoxyborohydride (3.6 g, 16.99 mmol) was added in portions to this solution. 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 × 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 (silica gel; EtOAc:PE = 0:1 to 1:1) to give (6-bromo-3-pyridyl)-[3-[tert-butyl(dimethyl)silyl]oxypropyl]amine (3 g). MS[M+H] + :345.6.

[0480] Step 2: N-(6-bromo-3-pyridyl)-N-(3-hydroxypropyl)carbamic acid 9H-fluoren-9-ylmethyl ester

[0481] (6-Bromo-3-pyridyl)-[3-[tert-butyl(dimethyl)silyl]oxypropyl]amine (3.00 g, 8.69 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 (2.25 g, 8.69 mmol) in anhydrous toluene (ultra-dry, 20 mL) at 0 °C. After the addition, the mixture was stirred at 0 °C for 1 h and then at room temperature for an additional 1 h, during which a yellow precipitate formed. The mixture was stirred overnight. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica gel; EtOAc:PE = 0:1 to 1:0) to give N-(6-bromo-3-pyridyl)-N-(3-hydroxypropyl)carbamic acid 9H-fluoren-9-ylmethyl ester (2 g). MS [M+H] + :453.1.

[0482] Step 3: 3-[(6-bromo-3-pyridyl)-(9H-fluoren-9-ylmethoxycarbonyl)amino]propionic acid

[0483] Iodobenzene diacetate (703.41 mg, 2.18 mmol), TEMPO (62.44 mg, 0.397 mmol), and N-(6-bromo-3-pyridyl)-N-(3-hydroxypropyl)carbamic acid 9H-fluoren-9-ylmethyl ester (900 mg, 1.99 mmol) were combined in a reaction vessel, and acetonitrile (10.99 mL) and water (5.99 mL) were added to the mixture. The reaction mixture was stirred for 3 h, after which another batch of iodobenzene diacetate (703.41 mg, 2.18 mmol) was added. Stirring was continued for 18 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica gel; EtOAc:PE = 0:1 to 1:0) to give 3-[(6-bromo-3-pyridyl)-(9H-fluoren-9-ylmethoxycarbonyl)amino]propionic acid (778 mg). MS[M+H] + :467.1.

[0484] Step 4: N-(3-amino-3-keto-propyl)-N-(6-bromo-3-pyridyl)carbamic acid 9H-fluoren-9-ylmethyl ester

[0485] 3-[(6-Bromo-3-pyridyl)-(9H-fluoren-9-ylmethoxycarbonyl)amino]propionic acid (770 mg, 1.65 mmol), ammonium chloride (176.27 mg, 3.3 mmol), and DIEA (1.06 g, 8.24 mmol) were stirred in N,N-dimethylacetamide (27.11 mL) for 1 minute. HATU (751.82 mg, 1.98 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 × 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 (silica gel; EtOAc:PE = 0:1 to 1:0) to give N-(3-amino-3-keto-propyl)-N-(6-bromo-3-pyridyl)carbamic acid 9H-fluoren-9-ylmethyl ester (725 mg). MS [M+H] + :466.2.

[0486] Step 5: N-(3-amino-3-keto-propyl)-N-[6-(2,3-difluoro-4-hydroxy-phenyl)-3-pyridyl]carbamic acid 9H-fluoren-9-ylmethyl ester

[0487] A microwave tube was charged with N-(3-amino-3-keto-propyl)-N-(6-bromo-3-pyridyl)carbamic acid 9H-fluoren-9-ylmethyl ester (400 mg, 0.858 mmol), palladium tetrakis (99.12 mg, 0.086 mmol), NaCO (272.74 mg, 2.57 mmol), and (2,3-difluoro-4-hydroxyphenyl)boronic acid (223.76 mg, 1.29 mmol) in water (0.351 mL) and 1,4-dioxane (3.51 mL). The vial was sealed with a rubber septum and evacuated and filled with nitrogen five times. The mixture was then heated at 100 °C for 0.5 h. The mixture was cooled to room temperature, and 100-200 mesh silica gel was added to absorb the material. The loaded sample was purified by flash chromatography (silica gel; MeOH:DCM=0:1 to 1:10) to give N-(3-amino-3-keto-propyl)-N-[6-(2,3-difluoro-4-hydroxy-phenyl)-3-pyridyl]carbamic acid 9H-fluoren-9-ylmethyl ester (166 mg). MS [M+H] + :516.8. Step 6: Trifluoromethanesulfonic acid [4-[5-[(3-amino-3-keto-propyl)-(9H-fluoren-9-ylmethoxycarbonyl)amino]-2-pyridyl]-2,3-difluoro-phenyl] ester

[0488] N-(3-amino-3-keto-propyl)-N-[6-(2,3-difluoro-4-hydroxy-phenyl)-3-pyridyl]carbamic acid 9H-fluoren-9-ylmethyl ester (165 mg, 0.320 mmol) and pyridine (75.95 mg, 0.960 mmol) were dissolved in anhydrous, ultra-dry dichloromethane (3.3 mL). TfO (108.37 mg, 0.384 mmol) was added dropwise at 0 °C. The solution was stirred at the same temperature for 1 h. 100-200 mesh silica gel was added to absorb the material. The loaded sample was purified by flash chromatography (silica gel; EtOAc:PE = 0:1 to 1:0) to give trifluoromethanesulfonic acid [4-[5-[(3-amino-3-keto-propyl)-(9H-fluoren-9-ylmethoxycarbonyl)amino]-2-pyridyl]-2,3-difluoro-phenyl] ester (168 mg). MS [M+H] + :648.3.

[0489] Step 7: N-(3-amino-3-keto-propyl)-N-[6-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-pyridyl]carbamic acid 9H-fluoren-9-ylmethyl ester

[0490] Trifluoromethanesulfonic acid [4-[5-[(3-amino-3-keto-propyl)-(9H-fluoren-9-ylmethoxycarbonyl)amino]-2-pyridyl]-2,3-difluorophenyl] ester (165 mg, 0.255 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (21.06 mg, 0.025 mmol), bis(pinacolato)diboron (77.64 mg, 0.306 mmol), and potassium acetate (75.02 mg, 0.764 mmol) were placed in ultra-dry 1,4-dioxane (3.61 mL) in a microwave tube. The tube was sealed with a rubber septum and evacuated and backfilled with nitrogen five times. The mixture was heated at 100 °C for 1 h. The mixture was cooled to room temperature and absorbed onto 100-200 mesh silica gel. The loaded sample was purified by flash chromatography (silica gel; MeOH:DCM = 0:1 to 1:10) to give N-(3-amino-3-keto-propyl)-N-[6-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-pyridyl]carbamic acid 9H-fluoren-9-ylmethyl ester (90 mg). MS [M+H] + :648.3.

[0491] The following examples were prepared analogously to intermediate G86. [Table 16]

[0492] Intermediate H1 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide [ka]

[0493] Step 1: tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate

[0494] To a 25 mL microwave vial was added tert-butyl 4-[4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (180 mg, 282 μmol), 4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2-methoxyethyl)-3-methyl-pyrazole (160 mg, 423 μmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (18.4 mg, 28.2 μmol) and NaCO (89.7 mg, 846 μmol) in 1,4-dioxane (15 mL) / water (1.5 mL). The vial was capped and heated in a microwave at 100° C. for 3 hours under N2. The reaction mixture was filtered through glass fiber paper. The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography to give tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (150 mg). MS [M+H] + :809.5.

[0495] Step 2: N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide

[0496] In a 50 mL round-bottom flask, tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (150 mg, 185 μmol) was combined with THF (2 mL) to give a light brown solution. Aqueous HCl (1.24 mL, 14.8 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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide (131 mg). MS [M+H] + :709.3.

[0497] The following intermediates were prepared similarly to intermediate H1. [Table 17-1] [Table 17-2]

[0498] Intermediate I1 N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide [ka]

[0499] Step 1: tert-butyl 4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate

[0500] In a 100 mL round-bottom flask, tert-butyl 4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carboxylate (150 mg, 285 μmol), 4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(2-methoxyethyl)-5-methyl-1H-pyrazole (151 mg, 399 μmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (18.6 mg, 28.5 μmol), and NaCO (90.5 mg, 854 μmol) were combined with dioxane (10 mL) in water (1 mL) to give a dark red solution. The reaction mixture was heated to 100° C. and stirred under N for 15 h. The crude reaction mixture was concentrated in vacuo. The crude product was used directly in the next step to give tert-butyl 4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate (160 mg). MS [M+H] + :698.2.

[0501] Step 2: N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide In a 50 mL round-bottom flask, tert-butyl 4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate (160 mg, 229 μmol) was combined with THF (2 mL) to give a light brown solution. Aqueous HCl (1.15 mL, 13.8 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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide (137 mg). MS [M+H] + :598.1.

[0502] The following intermediates were prepared similarly to intermediate I1. [Table 18-1] [Table 18-2] [Table 18-3]

[0503] Intermediate J1 N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]imidazole-2-carboxamide [ka]

[0504] Under N protection, a solution of trimethyl-[2-[[3-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazol-1-yl]methoxy]ethyl]silane (323.9 mg, 0.782 mmol), 5-bromo-N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide (400 mg, 782 μmol), NaCO (249 mg, 2.34 mmol), and 1,1-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (25.5 mg, 39.1 μmol) in 1,4-dioxane (7 mL) and water (0.7 mL) was heated at 95 °C for 15 h. The mixture was then filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to give N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]imidazole-2-carboxamide (50 mg) as a yellow solid. MS[M+H] + :719.2.

[0505] The following examples were prepared similarly to Intermediate J1. [Table 19]

[0506] Intermediate K1 N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide [ka]

[0507] Step 1: tert-butyl (2S,4R)-2-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-hydroxy-pyrrolidine-1-carboxylate

[0508] A mixture of N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide (350 mg, 585 μmol), (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (176 mg, 761 μmol), HATU (334 mg, 878 μmol), and DIPEA (227 mg, 1.76 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The mixture was then poured into water. The aqueous layer was extracted with DCM. The combined organic layers were washed with water and concentrated in vacuo. The residue was purified by flash column to give tert-butyl (2S,4R)-2-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-hydroxy-pyrrolidine-1-carboxylate (310 mg) as a brown solid. MS [M+H] + :811.2.

[0509] Step 2: N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide

[0510] A solution of tert-butyl (2S,4R)-2-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-hydroxy-pyrrolidine-1-carboxylate (310 mg, 382 μmol) in DCM (10 mL) and TFA (5 mL) was stirred at room temperature for 1 h. The mixture was then concentrated in vacuo. The residue was basified to pH 8-9 with NH3.HO. The aqueous layer was extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give crude product N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide (240 mg) as a brown oil. MS [M+H] + :711.3.

[0511] The following examples were prepared analogously to intermediate K1. [Table 20-1] [Table 20-2] [Table 20-3]

[0512] Intermediate L1 2-Chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoic acid [ka]

[0513] Step 1: tert-butyl 2-chloro-4-[[5-[2,3-difluoro-4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoate

[0514] A round-bottom flask was charged with tert-butyl 4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoate (3.3 g, 7.96 mmol), 4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (4.29 g, 9.52 mmol), PdCl(dtbpf) (259 mg, 398 μmol), and potassium carbonate (3.3 g, 23.9 mmol). Water (7.23 mL) and dioxane (72.3 mL) were added, and the flask was evacuated and filled with argon five times. The mixture was heated at 100° C. for 18 hours. The reaction was cooled to room temperature and poured into 100 mL of water. The aqueous phase was extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography to give the product (2.46 g). MS [M+H] + :658.2.

[0515] Step 2: 2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoic acid

[0516] tert-Butyl 2-chloro-4-(5-(2,3-difluoro-4-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoate (2.45 g, 3.72 mmol) was stirred in TFA (3.72 mL) and CHCl (14.9 mL) for 5 h. The solvent was removed in vacuo and the residue was azeotroped with toluene (50 mL×3) to give the product, which was used in the next step without further purification (1.74 g). MS [M+H] + :472.2.

[0517] The following examples were prepared analogously to intermediate L1. [Table 21]

[0518] Intermediate M1 N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; hydrochloride [ka]

[0519] Step 1: tert-butyl 4-[2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate

[0520] 1-((Dimethylamino)(dimethylimino)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (V) (96.7 mg, 254 μmol) was added to a solution of N-ethyl-N-isopropylpropan-2-amine (137 mg, 1.06 mmol), 2-chloro-4-(5-(2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoic acid (100 mg, 212 μmol), and tert-butyl piperazine-1-carboxylate (47.4 mg, 254 μmol) in DMA (4.24 mL) and stirred at room temperature for 2 hours. The mixture was poured into 100 mL of water and extracted with EtOAc (50 mL × 4). The organic layer was washed with 50 mL of brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography to give the product (105 mg). MS [M+H] + :640.2.

[0521] Step 2: N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; hydrochloride

[0522] tert-Butyl 4-(2-chloro-4-(5-(2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (1.38 g, 2.16 mmol) was dissolved in 4 M HCl / MeOH (10.8 mL) solution. The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo, and the residue was azeotroped with toluene (50 mL x 3) to give the product, which was used in the next step without purification (1.17 g). MS [M+H] + :540.2.

[0523] The following examples were prepared similarly to intermediate M1. [Table 22]

[0524] Intermediate N1 and Intermediate N2 tert-Butyl (1R,5S)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate N1) and tert-butyl (1R,5S)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate N2) [ka]

[0525] Step 1: tert-butyl (1S,5R)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0526] In a 100 mL round-bottom flask, (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (248 mg, 1.09 mmol), N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide (491 mg, 909 μmol), HATU (415 mg, 1.09 mmol), and DIPEA (235 mg, 1.82 mmol) were combined with DMF (6 mL) to give a light brown 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 (3 × 25 mL). The organic layers were combined and washed with saturated NaCl (1×25 mL), and the organic layer was dried over NaSO and concentrated in vacuo. The crude material was purified by flash chromatography to give tert-butyl (1S,5R)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (520 mg). MS [M+H] + :749.3.

[0527] Step 2: tert-Butyl (1R,5S)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate N1) and tert-butyl (1R,5S)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate N2)

[0528] To a 5 mL microwave vial was added tert-butyl (1S,5R)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (330 mg, 440 μmol), 1-bromo-2-methoxyethane (91.8 mg, 661 μmol), and KCO (122 mg, 881 μmol) in DMF (3 mL). The vial was capped and heated in a microwave at 70 °C for 1 h. The reaction mixture was poured into 50 mL of HO and extracted with EtOAc (3 × 25 mL). The organic layers were combined and washed with saturated NaCl (1 x 25 mL), the organic layer was dried over NaSO and concentrated in vacuo. The crude material was purified by flash chromatography to give 220 mg of crude product. The crude product was purified by preparative chiral HPLC to give tert-butyl (1R,5S)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxyle ester (60 mg) and tert-butyl (1R,5S)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (36 mg). MS [M+H] + :807.4.

[0529] Intermediate O1 2-[4-[4-[2-[[4-[4-(1-tert-butoxycarbonylpiperidine-4-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluoro-phenyl]-3-methyl-pyrazol-1-yl]acetic acid [ka]

[0530] Step 1: tert-butyl 4-[4-[2-chloro-4-[[5-[4-[1-(2-ethoxy-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate

[0531] A mixture of tert-butyl 4-[4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (4554.2 mg, 7.14 mmol), ethyl 2-[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]acetate (2900.0 mg, 7.14 mmol), NaCO (1513.3 mg, 14.28 mmol) and [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (943.4 mg, 1.07 mmol) in a flask. The flask was degassed and purged with N gas four times. 1,4-Dioxane (30 mL) and water (6 mL) were added to the mixture via syringe. The mixture was stirred under N at 90 °C for 2 hours. 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 and lyophilized to dryness to give tert-butyl 4-[4-[2-chloro-4-[[5-[4-[1-(2-ethoxy-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (2750.0 mg). MS [M+H] + :837.3.

[0532] 2-[4-[4-[2-[[4-[4-(1-tert-butoxycarbonylpiperidine-4-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluoro-phenyl]-3-methyl-pyrazol-1-yl]acetic acid

[0533] To a solution of tert-butyl 4-[4-[2-chloro-4-[[5-[4-[1-(2-ethoxy-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (2740.0 mg, 3.27 mmol) in methanol (30.0 mL) and water (10.0 mL) was added LiOH (235.1 mg, 9.82 mmol). The mixture was stirred under N at 20 °C for 12 hours. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (100 × 3 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), and concentrated to give 2-[4-[4-[2-[[4-[4-(1-tert-butoxycarbonylpiperidine-4-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluoro-phenyl]-3-methyl-pyrazol-1-yl]acetic acid (2500.0 mg). MS [M+H] + :809.3.

[0534] The following examples were prepared analogously to intermediate O1. [Table 23]

[0535] Intermediate P1 N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-bromo-1-methyl-imidazole-2-carboxamide [ka]

[0536] Step 1: 5-Bromo-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide

[0537] To a solution of tert-butyl 4-(4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamide)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (1.9 g, 3.0 mmol) in DCM (25 mL) was added TFA (5 mL), and the resulting mixture was stirred at room temperature for 1.0 h. The mixture was basified with aqueous ammonia to pH=9-10, and then poured into water (50 mL). The mixture was then extracted with dichloromethane / isopropanol (100 / 10 mL), and the organic layer was concentrated in vacuo to give 5-bromo-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide (1.2 g), which was used in the next step without purification. MS[M+H] + :537.3

[0538] Step 2: N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-bromo-1-methyl-imidazole-2-carboxamide

[0539] To a solution of 5-bromo-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide (2.15 g, 4.0 mmol), DIPEA (1.55 g, 12 mmol) in acetonitrile (25 ml) was added 2-iodoacetamide (888 mg, 4.8 mmol) at room temperature and stirred overnight.

[0540] The mixture was poured into water (50 mL) and then extracted with dichloromethane / isopropanol (100 / 10 mL), and the organic layer was concentrated to give a red oil, which was purified by flash chromatography on silica gel to give N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-bromo-1-methyl-imidazole-2-carboxamide (1.8 g). MS [M+H]+ :594.2. Intermediate Q1 tert-Butyl 4-[4-[4-[[5-[4-[1-(2-aminoethyl)-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate [ka]

[0541] Step 1: tert-butyl 4-[4-[4-[[5-[4-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate

[0542] 4-[4-[4-[(5-Bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 2.35 mmol) was dissolved in 1,4-dioxane (15 mL) and water (1.5 mL). tert-Butyl-[2-[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-pyrazol-1-yl]ethoxy]-dimethyl-silane (1.46 g, 3.06 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (153.24 mg, 0.235 mmol), and Na2CO3 (747.64 mg, 7.05 mmol) were added at room temperature. The mixture was stirred at 100 °C under N2 for 15 hours. The reaction was filtered, and the filtrate was concentrated in vacuo. The crude compound was purified by flash chromatography on silica gel to give 4-[4-[4-[[5-[4-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (1.2 g). MS [M+H] + :910.1.

[0543] Step 2: tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-hydroxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate

[0544] tert-Butyl 4-[4-[4-[[5-[4-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (1.2 g, 1.32 mmol) was dissolved in N,N-dimethylformamide (20 mL) and water (5 mL), and ammonium fluoride ((NH)F) (977.37 mg, 26.39 mmol) was added at room temperature. The reaction was stirred at 60 °C for 1 hour. The reaction mixture was diluted with water (80 mL) and extracted twice with EtOAc (40 mL). The organic layer was washed with brine (30 mL), dried over NaSO, and concentrated to dryness. The crude product was used directly in the next step to give tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-hydroxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (1.04 g). MS [M+H] + :795.9.

[0545] Step 3: tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[5-methyl-1-(2-methylsulfonyloxyethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate

[0546] Tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-hydroxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (1 g, 1.26 mmol) was dissolved in dichloromethane (30 mL), and methanesulfonic anhydride (328.57 mg, 1.89 mmol) and DIEA (325.02 mg, 2.51 mmol) were added at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[5-methyl-1-(2-methylsulfonyloxyethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (580 mg). MS [M+H] + :873.8.

[0547] Step 4: tert-butyl 4-[4-[4-[[5-[4-[1-(2-aminoethyl)-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate

[0548] Tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[5-methyl-1-(2-methylsulfonyloxyethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (580 mg, 0.664 mmol) was dissolved in methanol (10 mL), and 7 M ammonia (3.73 g, 33.21 mmol) was added at room temperature. The mixture was stirred at 80 °C for 15 hours. The reaction was concentrated in vacuo and the crude product was used directly in the next step to give tert-butyl 4-[4-[4-[[5-[4-[1-(2-aminoethyl)-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (527 mg). MS [M+H] + :794.8.

[0549] The following examples were prepared analogously to intermediate Q1. [Table 24]

[0550] Intermediate R1 O1-tert-butyl O2-methyl(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxypyrrolidine-1,2-dicarboxylate [ka]

[0551] 1-(tert-butyl) 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (500 mg, 2.04 mmol), tert-butylchlorodiphenylsilane (672 mg, 2.45 mmol), 1H-imidazole (278 mg, 4.08 mmol), and N,N-dimethylpyridin-4-amine (24.9 mg, 204 μmol) were stirred in CHCl (10.2 mL) for 18 h. The reaction mixture was quenched with saturated aqueous NaCO until pH = 10. The aqueous layer was extracted with CHCl, and the combined organic phases were dried over NaSO and filtered. The solvent was removed in vacuo to give an oil, which was purified by flash column chromatography on silica gel to give the product (902 mg). MS [M+H] + :484.2.

[0552] Intermediate R2 (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidine-2-carboxylic acid [ka]

[0553] Step 1: Methyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxypyrrolidine-2-carboxylate

[0554] O1-tert-butyl O2-methyl(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxypyrrolidine-1,2-dicarboxylate (700 mg, 1.45 mmol) was dissolved in 5 mL of 20% TFA / DCM solution and stirred at room temperature for 1 hour. The solvent was removed in vacuo. The residue was neutralized with 100 mL of saturated K2CO3, extracted with MeOH / DCM (50 mL x 4, v / v = 1:10), dried over sodium sulfate, and concentrated in vacuo to give the product (545 mg). MS [M+H] + :384.2.

[0555] Step 2: Methyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidine-2-carboxylate

[0556] Methyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-2-carboxylate (270 mg, 704 μmol) and formaldehyde (85.7 mg, 1.06 mmol) (37% aqueous solution) were dissolved in 1,2-dichloroethane (3.52 mL) and stirred at room temperature for 30 minutes, after which NaBHCN (66.4 mg, 1.06 mmol) was added. The mixture was then continued for 3 hours. The mixture was poured into 100 mL of water and extracted with DCM (50 mL × 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 product (230 mg) as a colorless oil. MS [M+H] + :398.2.

[0557] Step 3: (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidine-2-carboxylic acid

[0558] Methyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidine-2-carboxylate (230 mg) was dissolved in 5 mL of MeOH and 1 mL of water. To this solution, 100 mg of LiOH was added. The resulting mixture was stirred at room temperature for 48 hours. The solution was poured into 100 mL of 1N HCl and extracted with DCM (50 mL x 4). The organic layers were combined, washed with 50 mL of brine, dried over sodium sulfate, and concentrated in vacuo. The crude product (200 mg) was used in the next step without purification. MS [M+H] + :384.2.

[0559] Intermediate R3 (2S,4R)-1-tert-butoxycarbonyl-4-[tert-butyl(diphenyl)silyl]oxy-pyrrolidine-2-carboxylic acid [ka]

[0560] 1-(tert-butyl) 2-methyl(2S,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (200 mg, 413 μmol) and lithium hydroxide (99 mg, 4.13 mmol) were stirred in water (345 μL) and MeOH (1.72 mL) for 18 hours. After completion, the mixture was poured into 100 mL of 1 M HCl. The aqueous phase was extracted with DCM (50 mL x 3). The organic layers were combined, washed with 50 mL of brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was used in the next step without purification. MS [M+H] + :470.3.

[0561] Intermediate R4 5-(Difluoromethyl)-4-iodo-1-(2-methoxyethyl)pyrazole [ka]

[0562] To a solution of 4-iodo-2-(2-methoxyethyl)pyrazole-3-carbaldehyde (1000 mg, 3.57 mmol) in dichloromethane (10 mL) was slowly added dast (748.22 mg, 613.3 uL, 4.64 mmol) at 0 °C, and the reaction was gradually warmed to room temperature and stirred for 18 hours. The reaction was quenched with water. 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 purified by column chromatography to give 5-(difluoromethyl)-4-iodo-1-(2-methoxyethyl)pyrazole (800 mg). MS [M+H]+: 303.0.

[0563] Intermediate R5 4-Methyl-1-(4-piperidylmethyl)piperazin-2-one [ka]

[0564] Step 1: tert-butyl 4-[(4-methyl-2-oxo-piperazin-1-yl)methyl]piperidine-1-carboxylate

[0565] Sodium hydride (275 mg, 6.84 mmol) in anhydrous DMF (15 ml) was added to a solution of 4-methylpiperazin-2-one (650 mg, 5.7 mmol). After 30 minutes, tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (1.60 g, 5.7 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The mixture was poured into water (80 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to give tert-butyl 4-[(4-methyl-2-oxo-piperazin-1-yl)methyl]piperidine-1-carboxylate (1.2 g), which was used directly in the next step without further purification. MS [M+H] + :312.2.

[0566] Step 2: 4-Methyl-1-(4-piperidylmethyl)piperazin-2-one

[0567] To a solution of tert-butyl 4-((4-methyl-2-oxopiperazin-1-yl)methyl)piperidine-1-carboxylate (1.2 g, 3.8 mmol) in DCM (10 mL) was added TFA (3 mL), and the resulting mixture was stirred at room temperature for 1.0 h. The solvent was concentrated under reduced pressure to give 4-methyl-1-(4-piperidylmethyl)piperazin-2-one (600 mg). MS [M+H] + :212.2.

[0568] Intermediate R6 rac-(2S)-1-tert-butoxycarbonyl-4-(hydroxymethyl)pyrrolidine-2-carboxylic acid [ka]

[0569] Step 1: O1-tert-butyl O2-methyl rac-(2S)-4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate

[0570] To a solution of O1-tert-butyl O2-methyl(2S)-4-methylenepyrrolidine-1,2-dicarboxylate (1.0 g, 4.14 mmol) in THF (20.0 mL) was slowly added 9-borabicyclo[3.3.1]nonane (0.5 M in THF) (9.95 mL, 4.97 mmol) at 0 °C under N2. After the addition, the reaction mixture was warmed to 20 °C and stirred for 4 h. Sodium hydroxide (2 M) (5.18 mL, 10.36 mmol) and hydrogen peroxide (1.46 g, 12.85 mmol) were then slowly added to the mixture at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was then warmed to 20 °C and stirred for an additional 2 h. The reaction was quenched with saturated aqueous Na2SO3 (50 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product, which was purified by silica gel chromatography (PE: EtOAc = 1:1) to give O1-tert-butyl O2-methyl rac-(2S)-4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (500.0 mg) as a colorless oil. MS [M+H] + :260.2.

[0571] Step 2: rac-(2S)-1-tert-butoxycarbonyl-4-(hydroxymethyl)pyrrolidine-2-carboxylic acid

[0572] To a solution of rac-(2S)-4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (400.0 mg, 1.54 mmol) in methanol (5.0 mL), THF (5 mL), and water (1 mL) was added lithium hydroxide monohydrate (97.1 mg, 2.31 mmol) in one portion. The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated to give the crude product. The crude product was purified by preparative HPLC (FA) to give rac-(2S)-1-tert-butoxycarbonyl-4-(hydroxymethyl)pyrrolidine-2-carboxylic acid (160.0 mg, 0.65 mmol, 34.34% yield) as a yellow oil. MS [M+H] + :146.0.

[0573] Intermediate R7 2-[4-Hydroxy-4-(hydroxymethyl)-1-piperidyl]-1-piperazin-1-yl-ethanone;2,2,2-Trifluoroacetic acid [ka]

[0574] Step 1: tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate

[0575] To a solution of tert-butyl piperazine-1-carboxylate (500.0 mg, 2.68 mmol) in DCM (10.0 mL) was added 2-bromoacetyl chloride (464.78 mg, 2.95 mmol) slowly at 0 °C. After the addition, the reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with saturated aqueous NaHCO (20 mL) and extracted with DCM (10 mL × 2). The combined organic layers were dried over NaSO and concentrated to give tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (800.0 mg), and the crude product was used directly in the next step without further purification. MS [M+H-C4H8] + :251.0.

[0576] Step 2: tert-butyl 4-[2-[4-hydroxy-4-(hydroxymethyl)-1-piperidyl]acetyl]piperazine-1-carboxylate

[0577] To a solution of 4-(hydroxymethyl)piperidin-4-ol (100.0 mg, 0.76 mmol) and potassium carbonate (210.73 mg, 1.52 mmol) in ACN (5.0 mL) was added tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (100.0 mg, 0.76 mmol) and potassium carbonate (351.28 mg, 1.14 mmol) in one portion. The reaction was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (FA). A solution of the desired product in ACN / HO was lyophilized to give tert-butyl 4-[2-[4-hydroxy-4-(hydroxymethyl)-1-piperidyl]acetyl]piperazine-1-carboxylate (180.0 mg). MS [M+H] + :358.1.

[0578] Step 3: 2-[4-hydroxy-4-(hydroxymethyl)-1-piperidyl]-1-piperazin-1-yl-ethanone; 2,2,2-trifluoroacetic acid

[0579] To a solution of tert-butyl 4-[2-[4-hydroxy-4-(hydroxymethyl)-1-piperidyl]acetyl]piperazine-1-carboxylate (180.0 mg, 0.5 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.5 mL, 6.49 mmol) in one portion. The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated to give 2-[4-hydroxy-4-(hydroxymethyl)-1-piperidyl]-1-piperazin-1-yl-ethanone; 2,2,2-trifluoroacetic acid (190.0 mg), and the crude product was used directly in the next step without further purification. MS [M+H] + :258.1.

[0580] Intermediate R8 Tetrahydropyran-3-amine [ka]

[0581] Step 1: Tetrahydropyran-3-one oxime

[0582] To a solution of tetrahydropyran-3-one (400.0 mg, 4.0 mmol) and potassium carbonate (828.2 mg, 5.99 mmol) in ACN (5 mL) was added hydroxylamine hydrochloride (555.3 mg, 7.99 mmol). The reaction mixture was stirred at 15° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography to give tetrahydropyran-3-one oxime (400.0 mg).

[0583] Step 2: Tetrahydropyran-3-amine

[0584] To a solution of tetrahydropyran-3-one oxime (350.0 mg, 3.04 mmol) in methanol (5.0 mL) was added palladium on carbon (161.7 mg) in one portion under N. The mixture was degassed and purged with N three times. H (15 psi) was then introduced into the system. The reaction mixture was stirred under an H atmosphere at 30 °C for 6 h. The reaction was carefully filtered and concentrated to give the crude product tetrahydropyran-3-amine (150.0 mg).

[0585] Intermediate R9 4-Methyl-N-(tetrahydropyran-4-ylideneamino)benzenesulfonamide [ka]

[0586] To a solution of tetrahydropyran-4-one (2.0 g, 19.98 mmol) in methanol (30.0 mL) was added 4-methylbenzenesulfonhydrazide (3.7 g, 19.98 mmol), and the mixture was stirred at 20 °C for 3 hours. The mixture was concentrated to give 4-methyl-N-(tetrahydropyran-4-ylideneamino)benzenesulfonamide (5.3 g, 19.75 mmol) as a white solid. MS [M+H] + :269.0.

[0587] Intermediate R10 4-(tert-Butoxycarbonylamino)-1,1-dimethyl-piperidin-1-ium-4-carboxylic acid; chloride [ka]

[0588] To a solution of 4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylic acid (300 mg, 1.23 mmol) in MeOH (5 mL) was added sodium hydroxide (147 mg, 3.68 mmol) and methyl iodide (872 mg, 6.14 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction mixture was acidified with 3N HCl and concentrated in vacuo to give 4-(tert-butoxycarbonylamino)-1,1-dimethyl-piperidin-1-ium-4-carboxylic acid; chloride, which was used directly in the next step without further purification. MS [M] + :273.2

[0589] Intermediate R11 (2-tert-butoxy-2-oxo-ethyl)-(3-carboxypropyl)-bis[3-(methylamino)propyl]ammonium bromide [ka]

[0590] Step 1: Benzyl 4-[bis[3-(tert-butoxycarbonylamino)propyl]amino]butanoate

[0591] To a solution of 3-(BOC-amino)propyl bromide (4.56 g, 19.16 mmol) in ACN (30 mL) was added benzyl 4-aminobutanoate hydrochloride (2.0 g, 8.71 mmol) at 10° C., and the mixture was then stirred at 70° C. for 16 hours. The solution was concentrated, and the residue was purified by reverse-phase HPLC (FA) to give benzyl 4-[bis[3-(tert-butoxycarbonylamino)propyl]amino]butanoate (2.2 g). MS [M+H] + :508.4.

[0592] Step 2: (4-benzyloxy-4-oxo-butyl)-bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)ammonium; bromide

[0593] To a solution of tert-butyl bromoacetate (1.27 mL, 7.88 mmol) in ACN (20 mL) was added benzyl 4-[bis[3-(tert-butoxycarbonylamino)propyl]amino]butanoate (2.0 g, 3.94 mmol) at 10° C., and the mixture was then stirred at 80° C. for 16 hours. The solution was concentrated, and the residue was purified by reverse-phase HPLC (TFA) to give (4-benzyloxy-4-oxo-butyl)-bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)ammonium bromide (1 g) as a colorless oil. MS [M] + :622.5.

[0594] Step 3: Bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)-(3-carboxypropyl)ammonium; bromide

[0595] To a solution of palladium on activated carbon (151.44 mg, 0.140 mmol) in methanol (10 mL) was added (4-benzyloxy-4-oxo-butyl)-bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)ammonium bromide (1.0 g, 1.42 mmol) under N2, and the mixture was then stirred under H2 at 10 °C for 16 h. The starting material was consumed to completion. The mixture was filtered and concentrated to give bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)-(3-carboxypropyl)ammonium bromide (700 mg). MS [M] + :532.4.

[0596] The following examples were prepared analogously to intermediate R11. [Table 25]

[0597] Intermediate R13 [(2S,4R)-4-Hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-yl]-piperazin-1-yl-methanone [ka]

[0598] Step 1: Benzyl 4-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carbonyl]piperazine-1-carboxylate

[0599] To a mixture of 1-CBZ-piperazine (5.0 g, 22.7 mmol) in THF (25 mL) and DMF (25 mL) were added N,N-diisopropylethylamine (17.57 g, 136.2 mmol) and BOC-HYP-OH (5.25 g, 22.7 mmol). To the mixture was then added propylphosphonic anhydride (18.78 g, 29.51 mmol) after 10 min. The reaction mixture was stirred at 25° C. for 16 h. The solution was extracted with water (50 mL) and EA (100 mL), washed with saturated aqueous NaCl (50 mL), and dried over anhydrous NaSO. The crude material was purified by preparative HPLC (FA) to give the title compound (9.8 g). MS [M+H] + :434.5.

[0600] Step 2: Benzyl 4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carboxylate

[0601] To a mixture of benzyl 4-[rac-(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carbonyl]piperazine-1-carboxylate (9.84 g, 22.7 mmol) in methanol (20 mL) was added HCl / dioxane (20 mL). The reaction mixture was stirred at 25° C. for 16 hours. The solution was used directly in the next step without purification to give the title compound (7.56 g). MS [M+H] + :334.5.

[0602] Step 3: Benzyl 4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carboxylate

[0603] To a mixture of benzyl 4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carboxylate (7.56 g, 22.68 mmol) in MeCN (70 mL) and water (7 mL) was added iodomethane (32.19 g, 226.77 mmol) and triethylamine (63.21 mL, 453.54 mmol). The reaction mixture was stirred at 25° C. for 16 hours. The mixture was concentrated to remove the solvent and purified by preparative HPLC (0.1% FA) to give the title compound (4 g). MS [M] + :362.4.

[0604] Step 4: Piperazin-1-yl-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-yl]methanone

[0605] To a mixture of benzyl 4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carboxylate (1600.0 mg, 4.41 mmol) in methanol (20 mL) was added ammonium hydroxide (2.0 mL, 4.41 mmol) and wet palladium 10% on activated carbon (0.140 mmol, 0.030 equiv.). The reaction mixture was stirred under hydrogen at 15 psi at 25° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated to remove the solvent to give the title compound (1 g). MS [M] + :228.2.

[0606] Intermediate R14 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-oxo-ethyl)piperidin-1-ium-4-carboxylate [ka]

[0607] Step 1: Benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]piperidine-4-carboxylate

[0608] To a solution of benzylpiperidine-4-carboxylate hydrochloride (500.0 mg, 1.96 mmol) and potassium carbonate (811 mg, 5.87 mmol) in DMF (10 mL) was added 1-BOC-3-(bromomethyl)azetidine (587 mg, 2.35 mmol). The mixture was stirred at 25° C. for 16 hours. The mixture was then stirred at 50° C. for an additional 16 hours. The mixture was diluted with EtOAc (100 mL) and then washed with brine (30 mL × 3). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (PE:EA = 2:1 to 0:1) to give the title compound (710 mg, 1.83 mmol, 74.17% yield) as a pale yellow gum. MS [M+H] + :389.1.

[0609] Step 2: Benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-oxo-ethyl)piperidin-1-ium-4-carboxylate formate

[0610] To a solution of benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]piperidine-4-carboxylate (4.7 g, 12.1 mmol) and sodium iodide (181 mg, 1.21 mmol) in DMF (50 mL) was added tert-butyl bromoacetate (4.72 g, 24.2 mmol) and N,N-diisopropylethylamine (6.32 mL, 36.29 mmol). The mixture was stirred at 60 °C for 16 h. The mixture was concentrated in vacuo. The residue was purified twice by preparative HPLC (FA conditions) to give the title compound (5 g, 9.93 mmol, 82.06% yield) as a yellow solid. MS [M] + :503.2.

[0611] Step 3: 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-oxo-ethyl)piperidin-1-ium-4-carboxylate

[0612] To a solution of benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-oxo-ethyl)piperidin-1-ium-4-carboxylate formate (4.7 g, 8.57 mmol) in methanol (150 mL) was added palladium on carbon (400 mg, 10% purity) and palladium hydroxide on carbon (400.0 mg, 10% by weight) under a nitrogen atmosphere. The mixture was degassed and then stirred under hydrogen (760 mmHg) at 15°C for 4 hours. The mixture was filtered through a Celit pad, and the solid was washed with MeOH (20 mL x 4). The combined filtrate was concentrated under reduced pressure. The solid was dissolved in water (100 mL) and then lyophilized to give 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-oxo-ethyl)piperidin-1-ium-4-carboxylate (3.5 g, 8.48 mmol, 93.86% yield) as a white solid. MS [M] + :413.2.

[0613] Intermediate R15 Tert-butyl 2-[1-[3-(tert-butoxycarbonylamino)propyl]piperazin-1-ium-1-yl]acetate formate [ka]

[0614] Step 1: Benzyl 4-[3-(tert-butoxycarbonylamino)propyl]piperazine-1-carboxylate

[0615] To a solution of 1-CBZ-piperazine (5.0 g, 22.7 mmol) in MeCN (100 mL) was added triethylamine (3.16 mL, 22.7 mmol) and 3-(BOC-amino)propyl bromide (5.68 g, 23.83 mmol), and the mixture was stirred at 25 °C for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE / EA = 100:1 to 1:2) to give the title compound (5.2 g, 13.78 mmol, 60.69% yield) as a light brown solid. MS [M+H] + :378.3.

[0616] Step 2: Benzyl 4-[3-(tert-butoxycarbonylamino)propyl]-4-(2-tert-butoxy-2-oxo-ethyl)piperazin-4-ium-1-carboxylate formate

[0617] To a solution of benzyl 4-[3-(tert-butoxycarbonylamino)propyl]piperazine-1-carboxylate (5.2 g, 13.78 mmol) in MeCN (100 mL) was added triethylamine (1.92 mL, 13.78 mmol) and tert-butyl bromoacetate (5.37 g, 27.55 mmol), and the mixture was then stirred at 50° C. for 16 h. The mixture was concentrated in vacuo and purified by preparative HPLC (0.1% FA)-MeOH to give the title compound (4 g, 59% yield) as a pale yellow solid. MS [M+H] + :492.4.

[0618] Step 3: tert-Butyl 2-[1-[3-(tert-butoxycarbonylamino)propyl]piperazin-1-ium-1-yl]acetate formate

[0619] To a solution of benzyl 4-[3-(tert-butoxycarbonylamino)propyl]-4-(2-tert-butoxy-2-oxo-ethyl)piperazin-4-ium-1-carboxylate formate (4.0 g, 8.12 mmol) in THF (40 mL) was added 10% palladium on charcoal (400 mg), and the reaction was stirred under a hydrogen atmosphere at 25 °C for 16 h. The mixture was concentrated in vacuo and purified by preparative HPLC (0.1% FA)-ACN to afford tert-butyl 2-[1-[3-(tert-butoxycarbonylamino)propyl]piperazin-1-ium-1-yl]acetate formate (1.5 g, 4.18 mmol, 51.53% yield) as a white solid. MS [M] + :358.3.

[0620] Example A1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide;Formate [ka]

[0621] In a 50 mL round-bottom flask, N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide (131 mg, 185 μmol), MeI (105 mg, 739 μmol), and DIPEA (95.5 mg, 739 μmol) were combined with MeCN (6 mL) to give a light brown solution. The reaction was stirred at room temperature for 15 hours. The crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to give N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; formate (80 mg). MS[M] + :737.3.

[0622] The following examples were prepared similarly to Example A1. [Table 26-1] [Table 26-2] [Table 26-3]

[0623] Example B1 N-[4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide;Formate [ka]

[0624] Step 1: N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide

[0625] In a 100 mL round-bottom flask, N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide (350 mg, 494 μmol), formaldehyde (74.1 mg, 2.47 mmol), and NaBHCN (155 mg, 2.47 mmol) were combined with MeOH (12 mL) to give a light brown solution. The reaction mixture was heated to 50 °C and stirred for 1 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 25 mL of saturated NaHCO and extracted with EtOAc (3 × 25 mL). The organic layers were combined and washed with saturated NaCl (1 x 25 mL), the organic layer was dried over NaSO and concentrated in vacuo to give N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide (357 mg). MS [M+H] + :723.4.

[0626] Step 2: N-[4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; formate

[0627] In a 50 mL round-bottom flask, N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide (89 mg, 123 μmol), 2-iodoacetamide (45.5 mg, 246 μmol), and DIPEA (79.5 mg, 615 μmol) were combined with MeCN (5 mL) to give a light brown solution. The reaction was stirred at room temperature for 15 hours. The crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to give N-[4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; formate (22.6 mg). MS[M] + :780.3.

[0628] Example B2 and Example B3 N-[4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; formate (Example B2). N-[4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; formate (Example B3). [ka]

[0629] N-[4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; the formate was purified by preparative chiral HPLC to give N-[4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]- 5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; formate (42.6 mg) and N-[4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; formate (38 mg) were obtained. MS [M] + :780.2.

[0630] The following examples were prepared similarly to Example B1. [Table 27-1] [Table 27-2] [Table 27-3] [Table 27-4]

[0631] Example B17 N-[3-chloro-4-[4-[1-(2-hydrazino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; Formic acid; Formate [ka]

[0632] Step 1: N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol...

Claims

1. Formula (I): 【Chemical 1】 (wherein X is N or C—R ５ wherein R １ and R ２ together with the nitrogen atom to which they are attached, form a group [Chemical 2] forms, or R １ is the base [Chemical Formula 3] and R ２ is hydrogen, R ３ is halogen or C １ ~C ６ -alkyl, R ４ is selected from hydrogen, halogen, C １ to C ６ -alkyl, and C １ to C ６ -alkoxy, R ５ is selected from hydrogen, halogen and C １ to C ６ -alkyl, R ６ is hydrogen, C １ ~C ６ -alkyl, carbamoyl-C １ ~C ６ -alkyl-NH-, amino, halogen, hydroxy-C １ ~C ６ -alkyl, halo-C １ ~C ６ -alkyl and group [Chemical Formula 4] is selected from R ７ is hydrogen, C １ ~C ６ -alkyl, C １ ~C ６ -alkoxy-C １ ~C ６ -alkyl-, hydroxy-C １ ~C ６ -alkyl, halo-C １ ~C ６ -alkyl, carbamoyl-C １ ~C ６ -alkyl, C １ ~C ６ -alkyl-NH-C(O)-C １ ~C ６ -alkyl-, C １ ~C ６ -alkyl-NH-C(O)-NH-C １ ~C ６ -alkyl-, cyano-C １ ~C ６ -alkyl, C １ ~C ６ -alkyl-SO ２ -C １ ~C ６ -alkyl-, halo-C １ ~C ６ -alkoxy-C １ ~C ６ -alkyl-, amino-C １ ~C ６ -alkoxy-C １ ~C ６ -alkyl-, and the group 【Chemical Formula 5】 selected from, and R ８ is hydrogen, halogen, C １ ~C ６ -alkyl, halo-C １ ~C ６ -alkyl, and C １ ~C ６ -alkoxy-C １ ~C ６ -alkyl, or R ７ and R ８ together with the atoms to which they are attached form a 3- to 14-membered heterocyclic ring, R ９ and R １０ are each independently hydrogen or halogen, R Ａ is hydrogen, (C １ ~C ６ -alkyl) ２ N-C １ ~C ６ -alkyl-C(O)-, (R Ａ６ ), ３ N ＋ -C １ ~C ６ -alkyl-C(O)-, and the group [Chemical Formula 6] is selected from R Ａ１ is hydrogen, hydroxy, amino, C １ to C ６ -alkyl, halo-C １ to C ６ -alkyl, hydroxy-C １ to C ６ -alkyl, amino-C １ to C ６ -alkyl, carbamoyl-C １ to C ６ -alkyl, C １ to C ６ -alkoxy-C １ to C ６ -alkyl, H ２ N-SO ２ -C １ to C ６ -alkyl-, H ２ N-NH-C(O)-C １ to C ６ -alkyl-, C １ to C ６ -alkoxy, oxo, carbamoyl and group 【Chemical Formula 7】 is selected from R Ａ２ is selected from hydrogen, hydroxy, amino, C １ to C ６ -alkyl, carboxy-C １ to C ６ -alkyl and carbamoyl-C １ to C ６ -alkyl, R Ａ３ 、 R Ａ４ 、 R Ａ５ 、 R Ｃ２ 、 and R Ｃ３ are each independently selected from hydrogen and C １ - C ６ - alkyl, Each R Ａ６ is independently C １ to C ６ -alkyl, amino-C １ to C ６ -alkyl, C １ to C ６ -alkyl-NH-C １ to C ６ -alkyl-, (C １ to C ６ -alkyl) ２ N-C １ to C ６ -alkyl-, carboxy-C １ to C ６ -alkyl, and (3- to 14-membered heterocyclyl)-C １ to C ６ -alkyl- and is selected from R Ａ７ is selected from hydrogen and C １ ~C ６ -alkyl, R Ｂ１ is selected from hydrogen, halogen, cyano, amino, oxo, C １ to C ６ -alkyl, C １ to C ６ -alkoxy, and 3- to 14-membered heterocyclyl, R Ｂ２ is selected from hydrogen, halogen and C １ to C ６ -alkyl, R Ｃ is hydrogen, (C １ ~C ６ -alkyl)- ２ N-C １ ~C ６ -alkyl-C(O)-, (C １ ~C ６ -alkyl)- ３ N ＋ -C １ ~C ６ -alkyl-C(O)- and the group [Chemical Formula 8] is selected from R Ｃ１ is hydroxy and R Ｅ is selected from C １ to C ６ -alkyl, C １ to C ６ -alkoxy and halogen, L Ａ is selected from -C １ ~C ６ -alkyldiyl-, carbonyl, -C(O)-NH-, -NH-C(O)-, -C(O)-N(C １ ~C ６ -alkyl)-, -N(C １ ~C ６ -alkyl)-C(O)-, -C １ ~C ６ -alkyldiyl-NH-C(O)-, -SO ２ -NH-, -NH-SO ２ -, -C １ ~C ６ -alkyldiyl-C(O)-, and -C(O)-C １ ~C ６ -alkyldiyl-C(O)-, L Ｂ is selected from a covalent bond, -C １ ~C ６ -alkyldiyl-, -NH-C(O)-C １ ~C ６ -alkyldiyl-, -C(O)-NH-C １ ~C ６ -alkyldiyl-, -NH-C(O)-NH-C １ ~C ６ -alkyldiyl-, -C(O)-C １ ~C ６ -alkyldiyl-, and -SO ２ -NH-C １ ~C ６ -alkyldiyl- L Ｃ and L Ｅ are each independently a covalent bond or -C １ ~C ６ -alkyldiyl- and L Ｃ１ is -NH-C(O)- or a carbonyl, A, C, and C1 are each independently a 3- to 14-membered heterocyclyl, A2 is selected from 3- to 14-membered heterocyclyl and C ６ -C １０ -aryl, A1 is selected from 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, and C ３ -C １０ -cycloalkyl, B is selected from 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, C ３ -C １０ -cycloalkyl, and C ６ -C １０ -aryl, and is selected from D is a 5- to 14-membered heteroaryl, E is selected from 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, and C ６ -C １０ -aryl, The wavy line represents the bonding point of each R group to the remainder of formula (I)) A compound of formula (I), or a pharmaceutically acceptable salt thereof.

2. R １ and R ２ together with the nitrogen atom to which they are attached, form a group 【Chemical Formula 9】 forms, R Ａ is (R Ａ６ ) ３ N ＋ -C １ -C ６ -alkyl-C(O)-, and the group 【Chemical 10】 is selected from R Ａ１ is hydroxy, C １ -C ６ -alkyl, carbamoyl-C １ -C ６ -alkyl, and the group 【Chemical 11】 is selected from R Ａ２ is selected from C １ ~C ６ -alkyl, carboxy-C １ ~C ６ -alkyl and carbamoyl-C １ ~C ６ -alkyl, and R Ａ３ is selected from hydrogen and C １ ~C ６ -alkyl, R Ａ４ and R Ａ５ are hydrogen, Each R Ａ６ is independently selected from amino-C １ to C ６ -alkyl and carboxy-C １ to C ６ -alkyl L Ａ is a carbonyl, A, A1, and A2 are each independently a 3- to 14-membered heterocyclyl, The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R １ and R ２ together with the nitrogen atom to which they are attached, form a group 【Chemical Formula 12】 or the group 【Chemical 13】 forms, R Ａ where R Ａ６ ) ３ N ＋ -(CH ２ ) ３ -C(O)- and the group 【Chemical Formula 14】 is selected from R Ａ１ is hydroxy, methyl, 2-amino-2-oxo-ethyl, and the group 【Chemical Formula 15】 is selected from R Ａ２ is selected from methyl, carboxymethyl, and 2-amino-2-oxo-ethyl, R Ａ３ is selected from hydrogen and methyl, R Ａ４ and R Ａ５ are hydrogen, Each R Ａ６ is independently selected from aminopropyl and carboxymethyl, L Ａ is a carbonyl, A1 is selected from pyrrolidinyl, piperazinyl, piperidinyl, and 3-azabicyclo[3.1.0]hexan-6-yl, A2 is azetidinyl, The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof.

4. R ３ The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R is halogen.

5. R ３ The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R is chloro.

6. X is C-R ５ and R ４ is selected from halogen and C １ ~C ６ -alkyl, R ５ is a halogen, and R ９ is hydrogen, The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

7. X is C-R ５ and R ４ is selected from methyl, fluoro and chloro, R ５ is fluoro and R ９ is hydrogen, The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof.

8. R ６ is hydrogen, C １ ~C ６ -alkyl, and a group 【Chemical Formula 16】 is selected from R ７ is hydrogen, C １ ~C ６ -alkoxy-C １ ~C ６ -alkyl-, and a group 【Chemical 17】 is selected from R ８ is selected from hydrogen, halogen, C １ ~C ６ -alkyl, and halo-C １ ~C ６ -alkyl, R Ｂ１ is selected from hydrogen and halogen, R Ｂ２ is hydrogen, and R Ｅ wherein R is a halogen, L Ｂ is selected from -C １ ~C ６ -alkyldiyl- and -NH-C(O)-C １ ~C ６ -alkyldiyl-, L Ｅ is a covalent bond, B and D are each independently a 5- to 14-membered heteroaryl, E is C ６ ~C １０ -aryl, The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

9. R ６ is hydrogen, methyl, and a group 【Chemical 18】 is selected from R ７ is hydrogen, 2-methoxyethyl, and a group 【Chemical 19】 is selected from R ８ is selected from hydrogen, chloro, methyl, and difluoromethyl, R Ｂ１ is selected from hydrogen and fluorine, R Ｂ２ is hydrogen, and R Ｅ is fluoro and L Ｂ is selected from -CH ２ - and -NH-C(O)-CH ２ -, and L Ｅ is a covalent bond, B is selected from pyridyl and pyridazinyl, D is pyrazolyl, E is phenyl, The compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt thereof.

10. R １０ The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

11. X is C-R ５ and R １ and R ２ together with the nitrogen atom to which they are attached form a group 【Chemical 20】 forms, R ３ , R ４ , R ５ and R Ｅ are each independently a halogen, R ６ is hydrogen, C １ ~C ６ -alkyl, and a group 【Chemical 21】 is selected from R ７ is hydrogen, C １ ~C ６ -alkoxy-C １ ~C ６ -alkyl-, and a group 【Chemical 22】 is selected from R ８ is selected from hydrogen, halogen, C １ ~C ６ -alkyl, and halo-C １ ~C ６ -alkyl, R ９ 、R １０ 、R Ａ４ 、R Ａ５ 、and R Ｂ２ are hydrogen, R Ａ is (R Ａ６ ) ３ N ＋ -C １ -C ６ -alkyl-C(O)-, and the group 【Chemical 23】 is selected from R Ａ１ is hydroxy, C １ -C ６ -alkyl, carbamoyl-C １ -C ６ -alkyl, and the group 【Chemical 24】 is selected from R Ａ２ is selected from C １ to C ６ -alkyl, carboxy-C １ to C ６ -alkyl and carbamoyl-C １ to C ６ -alkyl, R Ａ３ is selected from hydrogen and C １ ~C ６ -alkyl, and Each R Ａ６ is independently amino-C １ -C ６ -alkyl and carboxy-C １ -C ６ -alkyl selected from, R Ｂ１ is selected from hydrogen and halogen, L Ａ is a carbonyl, L Ｂ is selected from -C １ ~C ６ -alkyldiyl- and -NH-C(O)-C １ ~C ６ -alkyldiyl-, L Ｅ is a covalent bond, A, A1, and A2 are each independently a 3- to 14-membered heterocyclyl, B and D are each independently a 5- to 14-membered heteroaryl, E is C ６ ~C １０ -aryl, The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

12. X is C-R ５ and R １ and R ２ together with the nitrogen atom to which they are attached, form a group 【Chemical 25】 or the group 【Chemical 26】 forms, R ３ is chloro, and R ４ is fluoro or chloro, and R ５ and R Ｅ are fluoro, R ６ is hydrogen, methyl, and a group 【Chemical 27】 is selected from R ７ is hydrogen, 2-methoxyethyl, and a group 【Chemical 28】 is selected from R ８ is selected from hydrogen, chloro, methyl and difluoromethyl, R ９ 、R １０ 、R Ａ４ 、R Ａ５ 、and R Ｂ２ are hydrogen, R Ａ where R Ａ６ ) ３ N ＋ -(CH ２ ) ３ -C(O)- and a group 【Chemical Formula 29】 is selected from R Ａ１ is hydroxy, methyl, 2-amino-2-oxo-ethyl, and the group 【Chemical 30】 is selected from R Ａ２ is selected from methyl, carboxymethyl, and 2-amino-2-oxo-ethyl, R Ａ３ is selected from hydrogen and methyl, Each R Ａ６ is independently selected from aminopropyl and carboxymethyl, R Ｂ１ is selected from hydrogen and fluorine, L Ａ is a carbonyl, L Ｂ is selected from -CH ２ - and -NH-C(O)-CH ２ -, and L Ｅ is a covalent bond, A1 is selected from pyrrolidinyl, piperazinyl, piperidinyl, and 3-azabicyclo[3.1.0]hexan-6-yl, A2 is azetidinyl, B is selected from pyridyl and pyridazinyl, D is pyrazolyl, E is phenyl, The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

13. wherein the compound of formula (I) is N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-1,1-dimethylpyrrolidin-1-ium-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; [2-[4-[2-Chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]-trimethyl-ammonium; [2-[4-[[[2-Chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]methyl]-1-piperidyl]-2-oxo-ethyl]-trimethyl-ammonium; N-[3-Chloro-4-[4-(4,4-dimethylpiperazine-4-ium-1-carbonyl)piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S)-4-(hydroxymethyl)-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-methoxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[4-[1-(2,2-difluoroethyl)-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[1-(2-methoxyethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-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]-5-[4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 2-[4-[1-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]-1-methyl-piperazin-1-ium-1-yl]acetic acid; 2-[1-(2-amino-2-oxo-ethyl)-4-[1-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]piperazin-1-ium-1-yl]acetic acid; N-[4-[4-[4-(2-amino-2-oxo-ethyl)-4-methyl-piperazin-4-ium-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(2-amino-2-oxo-ethyl)-4-hydroxy-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydrazino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-ium-1-yl]acetic acid; N-[3-chloro-4-[4-[1-[(1,1-dimethylazetidin-1-ium-3-yl)methyl]-1-methyl-piperidine-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; diformate; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-ium-1-yl]acetic acid; N-[4-[4-[1-(azetidin-3-ylmethyl)-1-methyl-piperidine-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 2-[1-(azetidin-3-ylmethyl)-4-[1-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]piperazine-1-ium-1-yl]acetic acid; N-[4-[4-[4-(azetidin-3-ylmethyl)-4-methyl-piperazine-4-ium-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[4-(2-Amino-2-oxo-ethyl)-4-(azetidin-3-ylmethyl)piperazin-4-ium-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(1R,5S)-3,3-Dimethyl-3-azonia-bicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(1R,5S)-3,3-Dimethyl-3-azonia-bicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-Hydroxy-1-(3-hydroxypropyl)-1-methyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; Iodide; 2-[1-(Azetidin-3-ylmethyl)-4-[4-[2-Chloro-4-[[5-[3-chloro-2-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-ium-1-yl]acetic acid; 2-[1-(Azetidin-3-ylmethyl)-4-[4-[2-Chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-ium-1-yl]acetic acid; N-[3-Chloro-4-[4-[1-[(1,1-Dimethylazetidin-1-ium-3-yl)methyl]piperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[1-(2,2-Difluoroethyl)-1-methyl-piperidine-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[1-(2-Sulfamoylethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[1-Methyl-1-(2-sulfamoylethyl)piperidine-1-ium-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[1-(2-Hydroxyethyl)-1-methyl-pyrrolidine-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-Hydroxy-1-(2-hydroxyethyl)-1-methyl-pyrrolidine-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2-chloro-3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperazin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[5-chloro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(3-amino-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(3-Amino-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-[(3S,4S)-3-Amino-4-methoxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-[3-(Aminomethyl)-3-hydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(3-carbamoyl-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(3S)-3-Hydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(3R,4R)-3,4-Dihydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(3-Hydroxy-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(3R,4R)-3,4-Dihydroxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-[(3R,4R)-3-Amino-4-methoxy-1-methyl-pyrrolidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(1-Methylpyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-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]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(3-Hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(3-Hydroxy-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[3-(Hydroxymethyl)-4,4-dimethyl-piperazine-4-ium-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2R,4S)-4-Hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2R,4R)-4-Hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4S)-4-Hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[1-(3-methoxypropyl)-3-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[1-(3-methoxypropyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S)-4,4-Dimethylmorpholin-4-ium-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(3-methoxypropyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(4,4-dimethyl-2-oxo-piperazin-4-ium-1-yl)methyl]piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(1-methylpyrrolidin-1-ium-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(4-hydroxy-1,1-dimethyl-piperidin-1-ium-4-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[4-hydroxy-4-(hydroxymethyl)-1-methyl-piperidin-1-ium-1-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Amino-1,1-dimethyl-piperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(4,4-dimethyl-2-oxo-piperazin-4-ium-1-yl)methyl]piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2,3-Difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-N-[4-[4-(3-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]amino]piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(3-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S)-5-oxopyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(2-oxopiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(2-pyrrolidin-1-ylacetyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(pyrrolidine-2-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminobicyclo[1.1.1]pentane-1-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[[1-[2-(dimethylamino)acetyl]-4-piperidyl]methylcarbamoyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; [2-[4-[2-Chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]-trimethyl-ammonium; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(1,1-dimethylpiperidin-1-ium-4-yl)sulfonylamino]piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[[(1R,5S)-3-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidine-1-ium-2-carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[[(1S,5R)-3-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidine-1-ium-2-carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; Bis(3-aminopropyl)-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]ammonium; Bis(azetidin-3-ylmethyl)-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]ammonium; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-methoxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-(2,2-difluoroethyl)-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2-Chloro-3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-(difluoromethoxy)ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-(piperazine-1-carbonyl)phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2,3-Difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-N-[4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-(4-piperidylmethylcarbamoyl)phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[3-fluoro-4-[3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-(methoxymethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]-3-methyl-phenyl]-5-[4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-6-[5-(4-methoxyphenyl)-1H-pyrazol-4-yl]-3-pyridyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-6-(1H-pyrazol-4-yl)-3-pyridyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(1-methylpyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; (1S,5R)-6-[[2-Chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[4-(1H-pyrazol-4-yl)phenyl]imidazole-2-carboxamide; 5-[4-[1-(3-Amino-3-oxo-propyl)-3-(trifluoromethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2-chloro-3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-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-[2,3-difluoro-4-[1-(3-hydroxy-3-methyl-butyl)-5-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[3-methyl-1-[2-(methylamino)-2-oxo-ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-(difluoromethoxy)ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(3-hydroxy-2-methyl-propyl)-3-(trifluoromethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[(2S)-2,3-dihydroxypropyl]-3-(trifluoromethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[4-[1-[2-(Difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[4-[1-[2-(Difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2,3-Difluoro-4-[3-isopropyl-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]-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-[4-[5-(Difluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2,3-Difluoro-4-[1-(2-Methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-N-[4-[4-[(2S,4R)-4-Hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-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-[2,3-Difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[1-(3-hydroxypropyl)-3-methyl-pyrazol-4-yl]phenyl]-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-[2,3-difluoro-4-[1-(3-hydroxypropyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-Dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-Methoxy-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-Dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-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-[4-[5-Ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-Dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(4-hydroxybutyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-chloro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[3-fluoro-2-methoxy-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(4-hydroxy-1,1-dimethyl-piperidin-1-ium-4-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-(hydroxymethyl)-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[3-Amino-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2,3-difluoro-4-(3-phenyl-1H-pyrazol-4-yl) phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; Chloride; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[5-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methylsulfonylethyl)-3-(trifluoromethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-hydroxypropyl)-3-(trifluoromethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-(4-amino-4-oxo-butyl)-3-(trifluoromethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-(2-Amino-2-oxo-ethyl)-3-(trifluoromethyl)pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-(trifluoromethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-morpholinoethyl)-5-(trifluoromethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(3-methoxypropyl)-3-(trifluoromethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-(tetrahydropyran-4-ylmethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-(5-Amino-2-pyridyl)-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Chloride; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-(2-pyridylmethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-(1H-pyrazol-4-yl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-[(5-Amino-2-pyridyl)methyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; Chloride; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-(2-methylpyrazol-3-yl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-(3-fluorophenyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-(2-oxo-1-pyridyl)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-(1-methylpyrazol-4-yl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-(1H-pyrazol-4-yl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-phenyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-(2-pyridyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; [2-[4-[2-Chloro-4-[[1-methyl-5-[4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]-trimethyl-ammonium; [2-[4-[2-Chloro-4-[[5-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]-trimethyl-ammonium; 4-Chloro-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-(6-methoxypyridin-2-yl)ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[(6-methoxypyridin-2-yl)methyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-(1H-1,2,3-triazol-4-ylmethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-3-pyridyl]-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-[4-[1-(3-cyanopropyl)-3,5-dimethyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-6-[5-(4-methoxyphenyl)-1H-pyrazol-4-yl]-3-pyridyl]-1-methyl-imidazole-2-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; 5-[4-[5-[(3-amino-3-oxo-propyl)amino]-2-pyridyl]-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-(5-amino-3-methyl-2-pyridyl)-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-(5-amino-2-pyridyl)-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; (1S,5R)-6-[[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-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-[2-fluoro-6-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]-3-pyridyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-(isopropylamino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-[2-(tert-Butylamino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-[2-(1-bicyclo[1.1.1]pentylamino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[4-[1-[2-[(3-cyano-1-bicyclo[1.1.1]pentyl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-(2-Anilino-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2,3-difluoro-4-[1-[2-(2-fluoroanilino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-(2-methoxyanilino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-(4-fluoroanilino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-(cyclohexylamino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(thiazol-2-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(1H-pyrazol-4-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-[(1-methylpyrazol-4-yl)amino]-2-oxo-ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-(3-fluoroanilino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; Chloride; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(2-pyridylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-[(1-methylpyridin-1-ium-3-yl)amino]-2-oxo-ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; Diformate; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(pyrimidin-2-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(4-pyridylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; Chloride; 5-[4-[1-[2-(tert-butylamino)-2-oxo-ethyl]-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2,3-difluoro-4-[5-methyl-1-[2-oxo-2-(2-pyridylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(tetrahydrofuran-3-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(tetrahydropyran-2-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(tetrahydropyran-3-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(pyridazin-3-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-[(1,1-dimethylpiperidin-1-ium-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; diformate; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[5-methyl-1-[2-oxo-2-(pyridazin-3-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-[(4,4-difluorocyclohexyl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(3-pyridylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-[(5-methoxy-2-pyridyl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(1-piperidyl)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-[4-(4,4-dimethylpiperazine-4-ium-1-carbonyl)anilino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-[(6-fluoropyridazin-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-[[(1S,2S)-2-methoxycyclohexyl]amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(pyridazin-4-ylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-[(6-cyano-3-pyridyl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[2-[4-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluoro-phenyl]-5-methyl-pyrazol-1-yl]ethyl]pyridine-2-carboxamide; N-[2-[4-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluoro-phenyl]-3-methyl-pyrazol-1-yl]ethyl]pyridine-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-[(4-fluorophenyl)sulfonylamino]ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-[2-(tert-Butylcarbamoylamino)ethyl]-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-[2-(tert-Butylcarbamoylamino)ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[2,3-difluoro-4-[5-methyl-1-[2-(2-pyridylcarbamoylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-(2-pyridylcarbamoylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-(pyrrolidine-1-carbonylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(2-pyridyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(4-methoxyphenyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(3-methoxyphenyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(2-methoxyphenyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(5-thiazol-4-yl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(5-tetrahydropyran-4-yl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[5-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-[1-[2-(2-aminoethoxy)ethyl]-3,5-dimethyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-1λ ５ -azolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-(difluoromethoxy)ethyl]-3,5-dimethyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-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-[4-[1-[(2,2-difluorocyclopropyl)methyl]-3,5-dimethyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-benzyl-3-aza-6-azoniaspiro[5.5]undecane-9-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-[2-[(6-fluoropyridazin-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-[(6-methyl-3-pyridyl)carbamoylamino]ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-oxo-3-aza-6-azoniaspiro[5.5]undecane-9-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[3-fluoro-4-[1-[2-[(6-fluoropyridazin-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-[1-[2-[(6-fluoropyridazin-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; Bis(4-aminobutyl)-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-3-methyl-piperazino]-4-oxo-butyl]ammonium; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-[(6-methylpyridazin-3-yl)amino]-2-oxo-ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-[2-[(6-methoxypyridazin-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-[(6-morpholinopyridazin-3-yl)amino]-2-oxo-ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide; Cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; Cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[2-(3-aminopropyl)-4-[3-[[1-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]isonipecotoyl]amino]propyl]pyridin-1-ium-1-yl]acetic acid; Azetidin-3-ylmethyl-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[4-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-3-fluoro-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-yl]-4-oxo-butyl]-methyl-ammonium; Formic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[4-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-3-fluoro-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 3-Aminopropyl-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[4-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-3-fluoro-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-ammonium; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; Carboxymethyl-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-bis[2-(dimethylamino)ethyl]ammonium; Cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[4-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetate; Bis(3-aminopropyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-ammonium; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; 3-Aminopropyl-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazino]-4-oxo-butyl]-methyl-ammonium. 1:1 2,2,2-trifluoroacetic acid; Bis(4-aminobutyl)-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]ammonium; Cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; Trans 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[5-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazino]-5-oxo-pentanoyl]piperazin-1-ium-1-yl]acetic acid; 2-[1-(3-aminopropyl)-4-[5-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazino]-5-oxo-pentanoyl]piperazin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[(1S,5R)-6-[[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[[1-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-4-piperidyl]-methyl-carbamoyl]piperidin-1-ium-1-yl]acetic acid; azetidin-3-ylmethyl-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-ammonium; cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methylpyrazol-4-yl]phenyl]-1-methylimidazole-2-carbonyl]amino]-2-methylbenzoyl]piperazin-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazin-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; and cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[3-fluoro-4-[1-(2-methoxyethyl)-5-methylpyrazol-4-yl]-2-methylphenyl]-1-methylimidazole-2-carbonyl]amino]-2-methylbenzoyl]piperazin-1-carbonyl]piperidin-1-ium-1-yl]acetic acid The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from

14. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use as a therapeutic active substance.

15. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

16. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use as an antibiotic.

17. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of nosocomial infections and diseases resulting therefrom.

18. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections caused by Gram-negative bacteria and diseases resulting therefrom.

19. The compound for use according to claim 18, wherein the Gram-negative bacteria are selected from Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli.

20. The compound for use according to claim 19, wherein the Gram-negative bacteria are Acinetobacter baumannii.

21. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli (E. coli), or a combination thereof, and the resulting disease.

22. A method for the treatment or prevention of an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli (E. coli), or a combination thereof, and the resulting disease, the method comprising administering to a mammal a compound of formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

23. Use of a compound of formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an antibiotic.

24. Use of a compound of formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the treatment or prevention of an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, and the resulting diseases.

25. Use of a compound of formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the preparation of a medicament useful for the treatment or prevention of an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, and the resulting diseases.

26. The invention as described previously herein.

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