Field of the Invention

The present invention relates to novel heterocyclic compounds which exhibit antibacterial properties. The invention also relates to methods of using the compounds for the treatment or prevention of bacterial infections and resulting diseases, in particular for the treatment or prevention of infections with Acinetobacter baumannii and resulting diseases.

Background of the Invention

Acinetobacter baumannii is a Gram-negative, aerobic, nonfermenting bacterium recognized over the last decades as an emergining pathogen with very limited treatment options. A. baumannii is considered to be a serious threat by the US Centers for Disease Control and Prevention and belongs to the so called ‘ESKAPE’ pathogens (. Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species &E. coli ) that currently cause the majority of nosocomial infections and effectively “escape” the activity of antimicrobial agents. A. baumannii is most often encountered in intensive care units and surgical wards, where extensive antibiotic use has enabled selection for resistance against all known antimicrobials and where it causes infections that include bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection.

A. baumannii has an exceptional ability to upregulate and acquire resistance determinants and shows an environmental persistance that allows its survival and spread in the nosocomial setting, making this organism a frequent cause of outbreaks of infection and an endemic, health care- associated pathogen. Due to increasing antibiotic resistance to most if not all available therapeutic options, Muti-Drug Resistant (MDR) A. baumanniii infections, especially those caused by Carbapenem resistant A. baumannii, are extremely difficult or even impossible to treat with high mortality rate as well as increased morbidity and length of stay in intensive care unit. Acinetobacter baumannii has been defined and still remains “a prime example of a mismatch between unmet medical needs and the current antimicrobial research and development pipeline” according to the Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA). Thus, there is a high demand and need to identify compounds suitable for the treatment of diseases and infections caused by Acinetobacter baumannii. The present invention provides novel compounds which exhibit activity against drug-susceptible as well as drug-resistant strains of Acinetobacter baumannii. Summary of the Invention In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X, D, R ¹ to R ⁴ , and R ⁶ to R ¹⁰ are as defined herein. In one aspect, the present invention provides a process of manufacturing the compounds of formula (I) described herein, wherein said process is as described in any one of Schemes 1 to 6 herein. In a further aspect, the present invention provides a compound of formula (I) as described herein, when manufactured according to the processes described herein. 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 therapeutically active substance. 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. 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 antibiotic. 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 nosocomial infections and resulting diseases. 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. 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 Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination therof. Detailed Description of the Invention Definitions Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. The term “alkyl” refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“C ₁ -C ₆ -alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the 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, yet non-limiting examples of alkyl include methyl and ethyl. The term “alkyldiyl” as used herein refers to a saturated linear or branched-chain divalent hydrocarbon radical of about one to to six carbon atoms (C ₁ -C ₆ ) Examples of alkyldiyl groups include, but are not limited to, methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (- CH ₂ CH ₂ CH ₂ -), and the like. An alkyldiyl group may also be referred to as an “alkylene” group. The term “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“C ₁ -C ₆ -alkoxy”). In some preferred embodiments, the alkoxy group contains contains 1 to 4 carbon atoms. In still other embodiments, the 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, yet non-limiting example of alkoxy is methoxy. 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, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl). The term “cycloalkyl” as used herein refers to a saturated or partly unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C ₃ -C ₁₀ -cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon 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 to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 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. The term “aminoalkoxy” refers to an alkoxy group, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by an amino group. Preferably, “aminoalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by an amino group. Preferred, yet non-limiting examples of aminoalkoxy are aminomethoxy and 1- aminoethoxy. The term “heterocyclyl” refers to a saturated or partly unsaturated mono- 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 wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon. “Bicyclic heterocyclyl” refers to heterocyclic moieties consisting of two cycles 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 to spirocyclic moieties, i.e., the two rings are connected 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-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. The term “heterocyclylalkyl” refers to a heterocyclyl group that is bound to the parent moiety via an alkylene group. A preferred, yet non-limiting example of a heterocyclylalkyl group is azetidin-3-ylmethyl. The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members (“C ₆ -C ₁₀ -aryl”) and wherein at least one ring in the system is aromatic. A particularly preferred, yet non-limiting example of aryl is phenyl. The term "heteroaryl" refers to a mono- or multivalent, 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 in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, “heteroaryl” refers to a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, “heteroaryl” refers to a 5-10 membered heteroaryl comprising 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, 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. The term “hydroxy” refers to an –OH group. The term “carboxy” refers to a group –C(O) ₂ H, i.e. a carboxylic acid group. The term “oxo” refers to an oxygen atom that is bound to the parent moiety via a double bond (=O). The term “amino” refers to an –NH ₂ group. The term “cyano” refers to a –CN (nitrile) group. The term “carbamoyl” refers to a –C(O)NH ₂ group. The term "carbonyl" refers to a carbon radical having two of the four covalent bonds shared with an oxygen atom (C=O). The term “haloalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been 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, yet non-limiting example of haloalkyl is trifluoromethyl. The term “cyanoalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by cyano group. Preferably, “cyanoalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a cyano group. Most preferably, “cyanoalkyl” refers to an alkyl group wherein 1 hydrogen atom of the alkyl group has been replaced by a cyano group. A preferred, yet non-limiting example of cyanoalkyl is cyanomethyl. The term “alkoxyalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. Preferably, “alkoxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by an alkoxy group. Most preferably, “alkoxyalkyl” refers to an alkyl group wherein 1 hydrogen atom of the alkyl group has been replaced by an alkoxy group. A preferred, yet non-limiting example of alkoxyalkyl is 2-methoxyethyl. The term “haloalkoxy” refers to an alkoxy group, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non- limiting examples of haloalkoxy are fluoromethoxy (FCH ₂ O–), difluoromethoxy (F2CHO–), and trifluoromethoxy (F3CO–). The term “carbamoylalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a carbamoyl group. Preferably, “carbamoylalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a carbamoyl group. Most preferably, “carbamoylalkyl” refers to an alkyl group wherein 1 hydrogen atom of the alkyl group has been replaced by a carbamoyl group. A preferred, yet non- limiting example of a carbamoylalkyl group is 2-amino-2-oxo-ethyl. The term “carboxyalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a carboxy group. Preferably, “carboxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a carboxy group. Most preferably, “carboxyalkyl” refers to an alkyl group wherein 1 hydrogen atom of the alkyl group has been replaced by a carboxy group. A preferred, yet non-limiting example of a carboxyalkyl group is carboxymethyl. The term “hydroxyalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group. Preferably, “hydroxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the alkyl group have been replaced by a hydroxy group. Preferred, yet non-limiting examples of hydroxyalkyl are hydroxymethyl, hydroxyethyl (e.g.2-hydroxyethyl), and 3-hydroxy-3-methyl- butyl. The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular 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, N-acetylcystein and the like. In addition these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. 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 and the like. Particular pharmaceutically acceptable salts of compounds of formula (I) are hydrochlorides, fumarates, formates, lactates (in particular derived from L-(+)-lactic acid), tartrates (in particular derived from L-(+)-tartaric acid) and trifluoroacetates. The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. According to the Cahn-Ingold-Prelog Convention, the asymmetric carbon atom can be of the "R" or "S" configuration. The term “treatment” as used herein includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and/or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment. The term “mammal” as used herein includes both humans and non-humans and includes but is 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. The term “nosocomial infection” refers to a hospital-acquired infection (HAI), which is an infection that is acquired in a hospital or other health care facility. To emphasize both hospital and nonhospital settings, it is sometimes instead called a health care–associated infection (HAI or HCAI). Such an infection can be acquired in hospitals, nursing homes, rehabilitation facilities, outpatient clinics, or other clinical settings. Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: X is N or C-R ⁵ ; R ¹ and R ² , taken together with the nitrogen atom to which they are attached, form a group R ¹ is a group ; and R ² is hydrogen; R ³ is halogen or C ₁ -C ₆ -alkyl; R ⁴ is selected from hydrogen, halogen, C ₁ -C ₆ -alkyl, and C ₁ -C ₆ -alkoxy; R ⁵ is selected from hydrogen, halogen, and C ₁ -C ₆ -alkyl; R ⁶ is selected from 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 a group ; R ⁷ is selected from 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 a group selected from 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 , taken together with the atoms to which they are attached, form a 3- to 14- membered heterocycle; R ⁹ and R ¹⁰ are each independently hydrogen or halogen; R ^A is selected from hydrogen, (C ₁ -C ₆ -alkyl)2N-C ₁ -C ₆ -alkyl-C(O)-, (R ^A6 )3N ⁺ -C ₁ -C ₆ - alkyl-C(O)-, and a group R ^A1 is selected from hydrogen, hydroxy, amino, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, hydoxy- C ₁ -C ₆ -alkyl, amino-C ₁ -C ₆ -alkyl, carbamoyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, H ₂ N-SO ₂ -C ₁ -C ₆ -alkyl-, H ₂ N-NH-C(O)-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy, oxo, carbamoyl, and a group R ^A2 is selected from hydrogen, hydroxy, amino, C ₁ -C ₆ -alkyl, carboxy-C ₁ -C ₆ -alkyl, and carbamoyl-C ₁ -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 selected from C ₁ -C ₆ -alkyl, amino-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyl-NH- C ₁ -C ₆ -alkyl-, (C ₁ -C ₆ -alkyl) ₂ N- C ₁ -C ₆ -alkyl-, carboxy-C ₁ -C ₆ -alkyl, and (3- to 14- membered heterocyclyl)-C ₁ -C ₆ -alkyl-; R ^A7 is selected from hydrogen and C ₁ -C ₆ -alkyl; R ^B1 is selected from hydrogen, halogen, cyano, amino, oxo, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, and 3- to 14-membered heterocyclyl; R ^B2 is selected from hydrogen, halogen, and C ₁ -C ₆ -alkyl; R ^C is selected from hydrogen, (C ₁ -C ₆ -alkyl)2N-C ₁ -C ₆ -alkyl-C(O)–, (C ₁ -C ₆ -alkyl)3N ⁺ - C ₁ - C ₆ -alkyl-C(O)–, and a group R ^C1 is hydroxy; R ^E is selected from C ₁ -C ₆ -alkyl, C ₁ -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–; L ^C1 is –NH-C(O)– or carbonyl; A, C, and C ₁ are each independently a 3- to 14-membered heterocyclyl; A2 is selected from 3- to 14-membered heterocyclyl andC 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; 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; and a wavy line represents the point of attachment of the respective R group to the remainder of formula (I). In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: X is N or C-R ⁵ ; R ¹ and R ² , taken together with the nitrogen atom to which they are attached, form a group R ¹ is a group hydrogen; R ³ is halogen or C ₁ -C ₆ -alkyl; R ⁴ is selected from hydrogen, halogen, C ₁ -C ₆ -alkyl, and C ₁ -C ₆ -alkoxy; R ⁵ is selected from hydrogen, halogen, and C ₁ -C ₆ -alkyl; R ⁶ is selected from 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 a group _; R ⁷ is selected from 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 a group selected from 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 , taken together with the atoms to which they are attached, form a 3- to 14- membered heterocycle; R ⁹ and R ¹⁰ are each independently hydrogen or halogen; R ^A is selected from hydrogen, (C ₁ -C ₆ -alkyl)2N-C ₁ -C ₆ -alkyl-C(O)-, (R ^A6 )3N ⁺ -C ₁ -C ₆ - alkyl-C(O)-, and a group R ^A1 is selected from hydrogen, hydroxy, amino, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, hydoxy- C ₁ -C ₆ -alkyl, amino-C ₁ -C ₆ -alkyl, carbamoyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, H ₂ N-SO ₂ -C ₁ -C ₆ -alkyl-, H ₂ N-NH-C(O)-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy, oxo, carbamoyl, and a group R ^A2 is selected from hydrogen, hydroxy, amino, C ₁ -C ₆ -alkyl, carboxy-C ₁ -C ₆ -alkyl, and carbamoyl-C ₁ -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 selected from C ₁ -C ₆ -alkyl, amino-C ₁ -C ₆ -alkyl, carboxy-C ₁ -C ₆ - alkyl, and (3- to 14-membered heterocyclyl)-C ₁ -C ₆ -alkyl-; R ^B1 is selected from hydrogen, halogen, cyano, amino, oxo, C ₁ -C ₆ -alkyl, and C ₁ -C ₆ - alkoxy; R ^B2 is selected from hydrogen, halogen, and C ₁ -C ₆ -alkyl; R ^C is selected from 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 a group R ^C1 is hydroxy; R ^E is selected from C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, and halogen; L ^A is selected from –C ₁ -C ₆ -alkyldiyl–, carbonyl, –C(O)-NH–, and –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–; L ^C1 is –NH-C(O)– or carbonyl; A, A2, C, and C ₁ are each independently a 3- to 14-membered heterocyclyl; A1 is selected from 3- to 14-membered heterocyclyl and C3-C10-cycloalkyl; B is selected from 3- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, C3- C ₁₀ -cycloalkyl, and C ₆ -C ₁₀ -aryl; D is a 3- to 14-membered heteroaryl; E is selected from 3- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, and C ₆ -C ₁₀ -aryl; and a wavy line represents the point of attachment of the respective R group to the remainder of formula (I). In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ² , taken together with the nitrogen atom to which they are attached, form a group R ^A is selected from (R ^A6 ) ₃ N ⁺ -C ₁ -C ₆ -alkyl-C(O)-, and a group R ^A1 is selected from hydroxy, C ₁ -C ₆ -alkyl, carbamoyl-C ₁ -C ₆ -alkyl, and a group R ^A2 is selected from C ₁ -C ₆ -alkyl, carboxy-C ₁ -C ₆ -alkyl, and carbamoyl-C ₁ -C ₆ -alkyl; 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 -C ₆ -alkyl and carboxy-C ₁ -C ₆ -alkyl; L ^A is carbonyl; and A, A1 and A2 are each independently a 3- to 14-membered heterocyclyl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ² , taken together with the nitrogen atom to which they are attached, form a group or a group ; R ^A is selected from (R ^A6 )3N ⁺ -(CH ₂ )3-C(O)-, and a group R ^A1 is selected from hydroxy, methyl, 2-amino-2-oxo-ethyl, and a group 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 carbonyl; A1 is selected from pyrrolidinyl, piperazinyl, piperidinyl, and 3-azabicyclo[3.1.0]hexan- 6-yl; and A2 is azetidinyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² , taken together with the nitrogen atom to which they are attached, form a group or a group ; wherein R ^A is as defined herein. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein 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)–, –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)–. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L ^A is selected from –C ₁ - C ₆ -alkyldiyl–, carbonyl, –C(O)-NH–, –SO ₂ -NH–, and –C ₁ -C ₆ -alkyldiyl-C(O)–. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is a group R ² is hydrogen; R ^C is selected from 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 a group R ^C1 is hydroxy; R ^C2 and R ^C3 are each independently selected from hydrogen and C ₁ -C ₆ -alkyl; L ^C is a covalent bond or –C ₁ -C ₆ -alkyldiyl–; L ^C1 is –NH-C(O)– or carbonyl; and C and C ₁ are each independently a 3- to 14-membered heterocyclyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is a group ; R ² is hydrogen; R ^C is selected from 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 a group R ^C1 is hydroxy; R ^C2 and R ^C3 are each independently selected from hydrogen and C ₁ -C ₆ -alkyl; L ^C1 is –NH-C(O)– or carbonyl; and C ₁ is a 3- to 14-membered heterocyclyl. In a further preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² , taken together with the nitrogen atom to which they are attached, form a group wherein R ^A is as defined herein. In a further preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² , taken together with the nitrogen atom to which they are attached, form a group ; wherein R ^A is as defined herein. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is halogen. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is chloro or fluoro. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is chloro. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is C ₁ -C ₆ -alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is methyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: X is C-R ⁵ ; R ⁴ and R ⁵ are both halogen; and R ⁹ is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: X is C-R ⁵ ; R ⁴ is fluoro or chloro; R ⁵ is fluoro; and R ⁹ is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: X is C-R ⁵ ; R ⁴ is selected from halogen and C ₁ -C ₆ -alkyl; R ⁵ is halogen; and R ⁹ is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: X is C-R ⁵ ; R ⁴ is selected from methyl, fluoro and chloro; R ⁵ is fluoro; and R ⁹ is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ⁶ is selected from hydrogen, C ₁ -C ₆ -alkyl, and a group ; R ⁷ is selected from hydrogen, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, and a group 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; R ^E is 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 3- to 14-membered heteroaryl; and E is C ₆ -C10-aryl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ⁶ is selected from hydrogen, methyl, and a group ; R ⁷ is selected from hydrogen, 2-methoxyethyl, and a group R ⁸ is 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 ₂ – and –NH-C(O)-CH ₂ –; L ^E is a covalent bond; B is selected from pyridyl and pyridazinyl; D is pyrazolyl; and E is phenyl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group is a group . In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is C-R ⁵ ; R ¹ and R ² , taken together with the nitrogen atom to which they are attached, form a group R ³ , R ⁴ , R ⁵ and R ^E are each independently halogen; R ⁶ is selected from hydrogen, C ₁ -C ₆ -alkyl, and a group R ⁷ is selected from hydrogen, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, and a group 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 selected from (R ^A6 )3N ⁺ -C ₁ -C ₆ -alkyl-C(O)-, and a group R ^A1 is selected from hydroxy, C ₁ -C ₆ -alkyl, carbamoyl-C ₁ -C ₆ -alkyl, and a group R ^A2 is selected from C ₁ -C ₆ -alkyl, carboxy-C ₁ -C ₆ -alkyl, and carbamoyl-C ₁ -C ₆ -alkyl; R ^A3 is selected from hydrogen and C ₁ -C ₆ -alkyl; each R ^A6 is independently selected from amino-C ₁ -C ₆ -alkyl and carboxy-C ₁ -C ₆ -alkyl; R ^B1 is selected from hydrogen and halogen; L ^A is 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 3- to 14-membered heteroaryl; and E is C ₆ -C ₁₀ -aryl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is C-R ⁵ ; R ¹ and R ² , taken together with the nitrogen atom to which they are attached, form a group R ³ is chloro; R ⁴ is fluoro or chloro; R ⁵ and R ^E are fluoro; R ⁶ is selected from hydrogen, methyl, and a group ; R ⁷ is selected from hydrogen, 2-methoxyethyl, and a group 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 is selected from (R ^A6 ) ₃ N ⁺ -(CH ₂ ) ₃ -C(O)-, and a group R ^A1 is selected from hydroxy, methyl, 2-amino-2-oxo-ethyl, and a group 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 carbonyl; L ^B is selected from –CH ₂ – and –NH-C(O)-CH ₂ –; 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; and E is phenyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is C-R ⁵ ; R ¹ and R ² , taken together with the nitrogen atom to which they are attached, form a group ; R ³ , R ⁴ , and R ⁵ are each independently halogen; R ⁷ is C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-; R ⁸ is C ₁ -C ₆ -alkyl; R ⁶ , R ⁹ , R ¹⁰ , R ^A3 , R ^A4 , and R ^A5 are hydrogen; R ^A2 is carboxy-C ₁ -C ₆ -alkyl; L ^A is carbonyl; A, A1 and A2 are each independently a 3- to 14-membered heterocyclyl; and D is a 3- to 14-membered heteroaryl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is C-R ⁵ ; R ¹ and R ² , taken together with the nitrogen atom to which they are attached, form a group ; R ³ is chloro; R ⁴ and R ⁵ are both fluoro; R ⁷ is 2-methoxyethyl; R ⁸ is methyl; R ⁶ , R ⁹ , R ¹⁰ , R ^A3 , R ^A4 , and R ^A5 are hydrogen; R ^A is a group R ^A1 is a group R ^A2 is carboxymethyl; L ^A is carbonyl; A1 is piperidyl; A2 is azetidinyl; and D is a pyrazolyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is C-R ⁵ ; R ¹ and R ² , taken together with the nitrogen atom to which they are attached, form a group ; R ³ and R ⁵ are each independently halogen; R ⁴ is C ₁ -C ₆ -alkyl; R ⁷ is C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-; R ⁸ is C ₁ -C ₆ -alkyl; R ⁶ , R ⁹ , R ¹⁰ , R ^A3 , R ^A4 , and R ^A5 are hydrogen; R ^A is a group R ^A1 is a group R ^A2 is carboxy-C ₁ -C ₆ -alkyl; L ^A is carbonyl; A, A1 and A2 are each independently a 3- to 14-membered heterocyclyl; and D is a 3- to 14-membered heteroaryl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is C-R ⁵ ; R ¹ and R ² , taken together with the nitrogen atom to which they are attached, form a group ; 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 are hydrogen; R ^A is a group R ^A1 is a group R ^A2 is carboxymethyl; L ^A is carbonyl; A1 is piperidyl; A2 is azetidinyl; and D is a pyrazolyl. 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 a compound of formula (II):

wherein: X, D, R ³ , R ⁴ , and R ⁶ to R ¹⁰ are as defined herein; Y is CH or N, most preferably N; and R ^Y is selected from hydrogen,

wherein a wavy line indicates the point of attachment of R ^Y to Y. In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) or (II) is a compound of formula (III): wherein: X, R ¹ to R ⁴ , R ⁹ and R ¹⁰ are as defined herein; and R ^Z is selected from:

wherein a wavy line indicates the point of attachment of R ^Z to the remainder of formula (I). 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 selected from: N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]ph enyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-y l]phenyl]-1-methyl-imidazole- 2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5-[4- [1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-meth yl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]ph enyl]-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-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-hydroxy-1,1-dimethyl-piperidin-1-ium-4-c arbonyl)piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-c arbonyl)piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-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-pi peridyl]-2-oxo-ethyl]- trimethyl-ammonium; N-[3-chloro-4-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)pip eridine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]ph enyl]-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-d imethyl-pyrazol-4-yl]phenyl]- 1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S)-4-(hydroxymethyl)-1,1-dimethyl-pyrrol idin-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-c arbonyl)piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-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-met hyl-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-met hyl-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-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-piperidin-1-iu m-4-carbonyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-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-met hyl-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-met hyl-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-pyrazo l-4-yl]-2,3-difluoro-phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-piperidin-1-iu m-4-carbonyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-d imethyl-pyrazol-4-yl]phenyl]- 1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-piperidin-1-iu m-4-carbonyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-d imethyl-pyrazol-4-yl]phenyl]- 1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-methoxyethyl)-1-methyl-piperidin-1-iu m-4-carbonyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-d imethyl-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-pyraz ol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-piperidin-1-iu m-4-carbonyl]piperazine-1- carbonyl]phenyl]-5-[4-[1-(2-methoxyethyl)-3,5-dimethyl-pyraz ol-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-carbo nyl]-1-methyl-piperazin-1- ium-1-yl]acetic acid; 2-[1-(2-amino-2-oxo-ethyl)-4-[1-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2-methoxyethyl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]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-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[4-[4-[1-(2-amino-2-oxo-ethyl)-4-hydroxy-1-methyl-piperidi n-1-ium-4-carbonyl]piperazine- 1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxy ethyl)-3-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydrazino-2-oxo-ethyl)-1-methyl-piper idin-1-ium-4-carbonyl]piperazine- 1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-m ethyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2-methoxyethyl)-3-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]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;diform ate; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2-methoxyethyl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]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-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; 2-[1-(azetidin-3-ylmethyl)-4-[1-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2-methoxyethyl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]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-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[4-[4-[4-(2-amino-2-oxo-ethyl)-4-(azetidin-3-ylmethyl)pipe razin-4-ium-1- carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difl uoro-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-met hyl-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-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1-(3-hydroxypropyl)-1-me thyl-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]am ino]benzoyl]piperazine-1- carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2-methoxyethyl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]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-m ethyl-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-met hyl-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]ph enyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-[1-methyl-1-(2-sulfamoylethyl)piperidin-1-i um-4-carbonyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-pyrrolidin-1-i um-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-met hyl-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]am ino]benzoyl]piperazine-1- carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2-methoxyethyl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]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-y l)acetyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[4-[4-[2-(3-amino-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]pi perazine-1-carbonyl]-3-chloro- phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyraz ol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[4-[4-[2-(3-amino-1-methyl-pyrrolidin-1-ium-1-yl)acetyl]pi perazine-1-carbonyl]-3-chloro- phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyraz ol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-y l)acetyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-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-methoxyet hyl)-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-methoxyet hyl)-3-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(3-carbamoyl-1-methyl-pyrrolidin-1-ium-1-yl)acety l]piperazine-1-carbonyl]-3- chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methy l-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3R)-3-hydroxy-1-methyl-pyrrolidin-1-iu m-1-yl]acetyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-3-hydroxy-1-methyl-pyrrolidin-1-iu m-1-yl]acetyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3R,4R)-3,4-dihydroxy-1-methyl-pyrrolid in-1-ium-1-yl]acetyl]piperazine- 1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-m ethyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-y l)acetyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-d imethyl-pyrazol-4-yl]phenyl]- 1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3R,4R)-3,4-dihydroxy-1-methyl-pyrrolid in-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-methoxyet hyl)-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]pi perazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]ph enyl]-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-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-c arbonyl)piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-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-d imethyl-pyrazol-4-yl]phenyl]- 1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxy-1,1-dimethyl-piperidin-1-ium-4-c arbonyl)piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-d imethyl-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-met hyl-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-met hyl-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-met hyl-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-met hyl-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-met hyl-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-me thyl-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-me thyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S)-4,4-dimethylmorpholin-4-ium-3-carbony l]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(3-methoxypropyl)-3-me thyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(4,4-dimethyl-2-oxo-piperazin-4-ium-1-yl)m ethyl]piperidine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(1-methylpyrrolidin-1-ium-1-yl)acetyl]pi perazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-i midazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-i midazole-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-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[4-hydroxy-4-(hydroxymethyl)-1-methyl-pi peridin-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)pip erazine-1-carbonyl]-3-chloro- phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyraz ol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-[(4,4-dimethyl-2-oxo-piperazin-4-ium-1-yl)m ethyl]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]a mino]piperidine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-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]piperazin e-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-ca rbonyl]phenyl]-5-[2,3-difluoro-4- [1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-i midazole-2-carboxamide; N-[3-chloro-4-[4-(2-pyrrolidin-1-ylacetyl)piperazine-1-carbo nyl]phenyl]-5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide; N-[3-chloro-4-[4-(pyrrolidine-2-carbonyl)piperazine-1-carbon yl]phenyl]-5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-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]ph enyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]pi perazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]ph enyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbo nyl]phenyl]-5-[2,3-difluoro-4-[1- (2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imid azole-2-carboxamide; N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]-4-piperidyl]meth ylcarbamoyl]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-carbo nyl]phenyl]-5-[2,3-difluoro-4-(3- methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxam ide; [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]-trimethy l-ammonium; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]pi perazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-i midazole-2-carboxamide; N-[3-chloro-4-[4-[(1,1-dimethylpiperidin-1-ium-4-yl)sulfonyl amino]piperidine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[(1R,5S)-3-[(2S,4R)-4-hydroxy-1,1-dimethyl-py rrolidin-1-ium-2-carbonyl]-3- azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[2,3-difluor o-4-[1-(2-methoxyethyl)-3,5- dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxami de; N-[3-chloro-4-[[(1S,5R)-3-[(2S,4R)-4-hydroxy-1,1-dimethyl-py rrolidin-1-ium-2-carbonyl]-3- azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[2,3-difluor o-4-[1-(2-methoxyethyl)-3,5- dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxami de; 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]ben zoyl]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]ben zoyl]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-dif luoro-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-carbony l]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-carbony l]phenyl]-5-[2-fluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]-3-methyl-phenyl]-1-meth yl-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-methy l-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[3-fluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-meth yl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]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-methy l-phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]pi perazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]ph enyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-(4-piperidylmethylcarbamoyl)phenyl]-5-[2,3-dif luoro-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-carbony l]phenyl]-5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide; N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]pipera zine-1-carbonyl]-3-chloro- phenyl]-5-[3-fluoro-4-[3-(trifluoromethyl)-1H-pyrazol-4-yl]p henyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]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-me thyl-phenyl]-5-[4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbo nyl]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-carbo nyl]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-carbony l]phenyl]-5-[2-fluoro-6-[5-(4- methoxyphenyl)-1H-pyrazol-4-yl]-3-pyridyl]-1-methyl-imidazol e-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]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-carbony l]phenyl]-5-[2,3-difluoro-4-(3- methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxam ide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]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-carbony l]phenyl]-5-[2,3-difluoro-4-[1-(2- methoxyethyl)pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbo xamide; (1S,5R)-6-[[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethy l)-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-carbony l]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)piperazi ne-1-carbonyl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-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-bu tyl)-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-(methylami no)-2-oxo-ethyl]pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5-[4- [1-[2-(difluoromethoxy)ethyl]-3-(trifluoromethyl)pyrazol-4-y l]-2,3-difluoro-phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(3-hydroxy-2-methyl-propyl)-3-(trifluorom ethyl)pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5-[4- [1-[(2S)-2,3-dihydroxypropyl]-3-(trifluoromethyl)pyrazol-4-y l]-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-methoxy ethyl)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-met hyl-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-me thyl-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-me thyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-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-y l]-2,3-difluoro-phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-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)pip erazine-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-y l]-2,3-difluoro-phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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-p henyl]-N-[3-chloro-4-[4-(1,1- dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phe nyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-(3-phenyl-1H-pyrazol-4-yl)phenyl]-1-methyl-i midazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5-[4- (5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluoro-phe nyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-1-carbonyl]phenyl]-5-[4- [3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-pheny l]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5-[4- [5-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-pheny l]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-methylsulfonylethyl)-3-(trifluoromethy l)pyrazol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-hydroxypropyl)-3-(trifluoromethyl)pyra zol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; 5-[4-[1-(4-amino-4-oxo-butyl)-3-(trifluoromethyl)pyrazol-4-y l]-2,3-difluoro-phenyl]-N-[3- chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazi ne-1-carbonyl]phenyl]-1- methyl-imidazole-2-carboxamide; 5-[4-[1-(2-amino-2-oxo-ethyl)-3-(trifluoromethyl)pyrazol-4-y l]-2,3-difluoro-phenyl]-N-[3- chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazi ne-1-carbonyl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-methoxyethyl)-3-(trifluoromethyl)pyraz ol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-morpholinoethyl)-5-(trifluoromethyl)py razol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(3-methoxypropyl)-3-(trifluoromethyl)pyra zol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-(tetrahydropyran-4-ylmethyl)pyra zol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; 5-[4-[1-(5-amino-2-pyridyl)-3-methyl-pyrazol-4-yl]-2,3-diflu oro-phenyl]-N-[3-chloro-4-[4-(1,1- dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phe nyl]-1-methyl-imidazole-2- carboxamide;chloride; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-(2-pyridylmethyl)pyrazol-4-yl]ph enyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-(1H-pyrazol-4-yl)pyrazol-4-yl]ph enyl]-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-ca rbonyl]phenyl]-1-methyl- imidazole-2-carboxamide;chloride; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-(2-methylpyrazol-3-yl)-1H-pyrazol-4-yl]ph enyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-(2-oxo-1-pyridyl)ethyl]pyrazo l-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-(1-methylpyrazol-4-yl)-1H-pyrazol-4-yl]ph enyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-methoxyethyl)-3-phenyl-pyrazol-4-yl]ph enyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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]-trimethy l-ammonium; [2-[4-[2-chloro-4-[[5-[4-(3,5-dimethyl-1H-pyrazol-4-yl)pheny l]-1-methyl-imidazole-2- carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]-trimethy l-ammonium; 4-chloro-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-car bonyl)piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-[2-(6-methoxy-2-pyridyl)ethyl]-3-methyl-p yrazol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-[(6-methoxy-2-pyridyl)methyl]-3-methyl-py razol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-1-carbonyl]phenyl]-5-[2- fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-3-pyridy l]-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-pyrazo l-4-yl]-2,3-difluoro-phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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-methoxyethy l)-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]hexan e-3-carboxamide; 5-[4-[5-[(3-amino-3-oxo-propyl)amino]-2-pyridyl]-2,3-difluor o-phenyl]-N-[3-chloro-4-[4-(1,1- dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phe nyl]-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]phe nyl]-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-methoxyethy l)-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-carboxami de; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5-[2- fluoro-6-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]-3-py ridyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)piperazi ne-1-carbonyl]phenyl]-1- methyl-imidazole-2-carboxamide; 5-[4-[1-[2-(1-bicyclo[1.1.1]pentanylamino)-2-oxo-ethyl]-3-me thyl-pyrazol-4-yl]-2,3-difluoro- phenyl]-N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carb onyl)piperazine-1- carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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-d ifluoro-phenyl]-N-[3-chloro-4-[4- (1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbony l]phenyl]-1-methyl-imidazole- 2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-[2-(2-fluoroanilino)-2-oxo-ethyl]-3-methy l-pyrazol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-[2-(2-methoxyanilino)-2-oxo-ethyl]-3-meth yl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-[2-(4-fluoroanilino)-2-oxo-ethyl]-3-methy l-pyrazol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(thiazol-2-ylamino)ethy l]pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(1H-pyrazol-4-ylamino)e thyl]pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-[2-(3-fluoroanilino)-2-oxo-ethyl]-3-methy l-pyrazol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide;chloride; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(2-pyridylamino)ethyl]p yrazol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(pyrimidin-2-ylamino)et hyl]pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(4-pyridylamino)ethyl]p yrazol-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)piperazi ne-1-carbonyl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[5-methyl-1-[2-oxo-2-(2-pyridylamino)ethyl]p yrazol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(tetrahydrofuran-3-ylam ino)ethyl]pyrazol-4-yl]phenyl]- 1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(tetrahydropyran-2-ylam ino)ethyl]pyrazol-4-yl]phenyl]- 1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(tetrahydropyran-3-ylam ino)ethyl]pyrazol-4-yl]phenyl]- 1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(pyridazin-3-ylamino)et hyl]pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[5-methyl-1-[2-oxo-2-(pyridazin-3-ylamino)et hyl]pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(3-pyridylamino)ethyl]p yrazol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-[2-[(5-methoxy-2-pyridyl)amino]-2-oxo-eth yl]-3-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(1-piperidyl)ethyl]pyra zol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-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)pip erazine-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)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-oxo-2-(pyridazin-4-ylamino)et hyl]pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5-[4- [1-[2-[(6-cyano-3-pyridyl)amino]-2-oxo-ethyl]-3-methyl-pyraz ol-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-diflu oro-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-diflu oro-phenyl]-3-methyl-pyrazol- 1-yl]ethyl]pyridine-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)piperazi ne-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)piperazi ne-1-carbonyl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[5-methyl-1-[2-(2-pyridylcarbamoylamino)ethy l]pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-(2-pyridylcarbamoylamino)ethy l]pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[5-(2-pyridyl)-1H-pyrazol-4-yl]phenyl]-1-met hyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-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)pip erazine-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)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-(5-thiazol-4-yl-1H-pyrazol-4-yl)phenyl]-1-me thyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-(5-tetrahydropyran-4-yl-1H-pyrazol-4-yl)phen yl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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-carb onyl]piperazine-1- carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxy-1,1-dimethyl-1λ⁵-azol idine-2-carbonyl]piperazine-1- carbonyl]phenyl]-5-[4-[1-[2-(difluoromethoxy)ethyl]-3,5-dime thyl-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-carbony l)piperazine-1-carbonyl]-3- chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methy l-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-[2-[(6-fluoropyridazin-3- yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-methy l-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)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-[(6-methyl-3-pyridyl)carbamoy lamino]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-c arbonyl)piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-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]am ino]benzoyl]-3-methyl- piperazino]-4-keto-butyl]ammonium; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[3-methyl-1-[2-[(6-methylpyridazin-3-yl)amin o]-2-oxo-ethyl]pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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)pip erazine-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]ben zoyl]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-imid azole-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-a mmonium;formic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[4-[1-[2-(di fluoromethoxy)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-imid azole-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-a mmonium; 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]ben zoyl]piperazine-1- carbonyl]piperidin-1-ium-1-yl]acetic acid; carboxymethyl-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-me thoxyethyl)-5-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azin-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-(di fluoromethoxy)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]pip erazin-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-fluor o-4-[1-(2-methoxyethyl)-5- methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2- carbonyl]amino]benzoyl]piperazino]-4-keto-butyl]-methyl-ammo nium .1:12,2,2- 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]am ino]benzoyl]piperazin-1-yl]- 4-oxo-butyl]ammonium; cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2-methoxyethyl)-3- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]am ino]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-difluor o-4-[1-(2-methoxyethyl)-3- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]am ino]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-difl uoro-4-[1-(2-methoxyethyl)-5- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]am ino]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]ben zoyl]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]am ino]benzoyl]amino]-3- azabicyclo[3.1.0]hexane-3-carbonyl]piperidin-1-ium-1-yl]acet ic acid; 2-[1-(azetidin-3-ylmethyl)-4-[[1-[2-chloro-4-[[5-[2,3-difluo ro-4-[1-(2-methoxyethyl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]-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-methylben zoyl]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-met hoxyethyl)-3-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-ben zoyl]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-met hoxyethyl)-5-methylpyrazol-4- yl]-2-methylphenyl]-1-methylimidazole-2-carbonyl]amino]-2-me thylbenzoyl]piperazine-1- carbonyl]piperidin-1-ium-1-yl]acetic acid. 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 selected from: N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]ph enyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]ph enyl]-1-methyl-imidazole-2- carboxamide; N-[3-chloro-4-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)pip eridine-1-carbonyl]phenyl]-5- [2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]ph enyl]-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-met hyl-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-met hyl-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-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; N-[4-[4-[4-(2-amino-2-oxo-ethyl)-4-(azetidin-3-ylmethyl)pipe razin-4-ium-1- carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difl uoro-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-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2-methoxyethyl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]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-met hyl-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-met hyl-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]ben zoyl]piperazin-1-yl]-4-oxo- butyl]ammonium; N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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. In a particularly 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-[4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4- carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difl uoro-4-[1-(2-methoxyethyl)-3- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide . In a particularly 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 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-meth yl-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. In a particularly 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-[(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. In a particularly 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)pip erazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide. In a particularly 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 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium -1-yl]acetic acid. In a particularly 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-[(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. In one embodiment, the present invention provides pharmaceutically acceptable salts of the compounds of formula (I) as described herein, especially pharmaceutically acceptable salts selected from hydrochlorides, fumarates, lactates (in particular derived from L-(+)-lactic acid), tartrates (in particular derived from L-(+)-tartaric acid) and trifluoroacetates. In yet a further particular embodiment, the present invention provides compounds according to formula (I) as described herein (i.e., as “free bases” or “free acids”, respectively). In some embodiments, the 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 this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 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 I, respectively. 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 isotopes tritium, i.e. ³ H, and carbon-14, i.e., ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope. Substitution with heavier isotopes such as deuterium, i.e. ² H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, can be useful in Positron Emission Topography (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 as set out below using an appropriate isotopically-labeled reagent in place of the non- labeled reagent previously employed. Processes of Manufacturing The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes. The skills required for carrying out the reactions and purifications of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary. In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature 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). We find it convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux temperature. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art. All substituents, in particular, X, D, and R ¹ to R ⁹ are as defined above and in the claims, unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry. Scheme1 Wherein PG ³ is a protective group, such as Boc. Intermediate A can be prepared according to Scheme 1. Protection of substituted 4-nitrobenzoic acid A, e.g. with (Boc) ₂ O, gives compound B. Reduction of the nitro group of compound B, for example using the well-known ammonium chloride/iron system at room temperature, yields amine C. Coupling of carboxylic acid D and amine C in the presence of a condensing agent, such as HATU/DIPEA in a solvent, such as DMSO, affords Intermediate A. Scheme2 _{Intermediate A E} ^{Intermediate B, C, D} Wherein PG ¹ is a protective group, such as Boc, or PG ¹ is H (no protection); and PG ³ is a protective group, such as Boc. Intermediates B, C, D can be prepared according to Scheme 2. Hydrolysis the Intermediate A gives carboxylic acid E, which can be coupled with diverse amines in the presence of a condensing agent, such as HATU/DIPEA in a solvent, such as DMSO, to afford Intermediates B, C, and D. Scheme3 wherein: PG ² is a protective group, such as Boc, SEM, TBS; or PG ² H (no protection). Intermediate G can be prepared according to Scheme 3. Thus, Suzuki coupling of Intermediate E with boronic acid esters F, e.g. using palladium catalysts and phosphine ligands, affords Intermediate F. Intermediate F is further reacted with Bis(pinacolato)diboron using palladium catalysts and phosphine ligands to afford Intermediate G (in some cases, the bronic acid ester will directly hydrolyse to the bronic acid in the reaction system). Scheme4

D D Intermediate B, C, D Intermediate G Intermediate H-K, M-Q wherein: PG ¹ is a protective group, such as Boc, or PG ¹ is H (no protection); and PG ² is a protective group, such as Boc, SEM, TBS, or PG ² H (no protection). Intermediate H-K, and M-Q can be prepared according to Scheme 4. Thus, Suzuki coupling of Intermediate B, C, D with bronic acid ester Intermediate G in the presence of a palladium catalyst and a phosphine ligand affords Intermediate H-K, and M-Q. Scheme5

O R ³ O 3 O O R ^O _B NH R ⁴ O _O ^N R ¹⁰ X N NH + R ⁴ R ⁹ O ^{N 6} R ¹⁰ R D PG ² X N R ⁸ R ⁹ Br PG ² R ^{7 6 PG2} R D ^{2 8} PG Intermediate A Intermediate G R 2 P ^G _R ⁷ _PG ² G O R ³ O R ³ R ² H O PG ¹ N R ¹ NH PG ¹ NH O N 1 O N R ⁰ R ¹⁰ N ⁴ N R R ⁴ X X R ⁹ R ⁹ R ^{6 6 2} R PG ^{2 8} D ⁸ D PG R R 2 R ⁷ _PG ² 2 P ^{G PG} _R ⁷ _PG ² I _{ntermediate L} ^{Intermediate H-K, M-Q} wherein: PG ¹ is a protective group, such as Boc, or PG ¹ is H (no protection); and PG ² is a protective group, such as Boc, SEM, TBS, or or PG ² is H (no protection). In addition to the procedure outlined in Scheme 4, Intermediate H-K, and M-Q also can be prepared according to Scheme 5. Thus, Suzuki coupling of Intermediate A with boronic acid ester Intermediate G in the presence of a palladium catalyst and a phosphine ligand affords compound G. Hydrolysis of compound G yields carboxylic acid Intermediate L, which is subsequently coupled with diverse amines in the presence of a condensing agent, such as HATU/DIPEA in a solvent, such as DMSO, to afford Intermediate H-K, and M-Q. Scheme 6

wherein: PG ¹ is a protective group, such as Boc, or PG ¹ is H (no protection); and PG ² is a protective group, such as Boc, SEM, TBS, or PG ² is H (no protection). The Examples can be prepared according to Scheme 6. Thus, removal of PG ² (in case PG ² is not hydrogen) from Intermediates H-K, and M-Q affords compound H. Subsequent removal of PG ¹ (in case PG ¹ is not hydrogen) finally affords Examples. The order of deprotection steps can also be reversed, going via compound I. In some cases, the final Examples are achieved by alkylation of certain intermediates, e.g. methylation using MeI in the presence of DIPEA in acetonitrile at room temperature. The removal of the protective groups PG ¹ and PG ² can occur before or after the alkylation step, based on the requirements of the substitution pattern. In one aspect, the present invention provides a process of manufacturing the compounds of formula (I) described herein, wherein said process is as described in any one of Schemes 1 to 6 above. In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to the processes disclosed herein. Using the Compounds of the Invention As illustrated 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 resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly by Acinetobacter species, most particularly by Acinetobacter baumannii. 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, most particularly as pathogen-specific antibiotics against Acinetobacter baumannii. The compounds of formula (I) and their pharmaceutically acceptable salts can be used as antibiotics, i.e. as antibacterial pharmaceutical ingredients suitable in the treatment and prevention of bacterial infections, particularly in the treatment and prevention of bacterial infections caused by Acinetobacter species, more particularly in the treatment and prevention of bacterial infections caused by Acinetobacter baumannii. The compounds of the present invention can be used, either alone or in combination with other drugs, for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii. In one aspect, the present invention provides compounds of formula (I) or their pharmaceutically acceptable salts as described herein for use as therapeutically active substances. 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 antibiotic. 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 nosocomial infections and resulting diseases. In a particular embodiment, said nosocomial infections and resulting diseases are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection, or a combination thereof. 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. In a particular embodiment, said infections and resulting diseases caused by Gram-negative bacteria are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection, or a combination thereof. 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 Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination therof. 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 a combination therof, which method comprises administering a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, to a mammal. 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. In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination therof. 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 medicaments useful for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination therof. In a particular embodiment, said infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination therof, are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection, or a combination thereof. In a further aspect, the present invention provides compounds of formula (I) or their pharmaceutically acceptable salts as defined above for use in the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii. In a further aspect, the present invention provides a method for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii, which method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above to a mammal. In a further aspect, the present invention provides the use of compounds of formula (I) or their pharmaceutically acceptable salts as defined above for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii. In a further aspect, the present invention provides the use of compounds of formula (I) or their pharmaceutically acceptable salts as defined above for the preparation of medicaments for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii. Such medicaments comprise compounds of formula (I) or their pharmaceutically acceptable salts as defined above. Pharmaceutical Compositions and Administration In one aspect, the present invention provides pharmaceutical compositions comprising compounds of formula (I) or their pharmaceutically acceptable salts as defined above and one or more pharmaceutically acceptable excipients. Exemplary pharmaceutical compositions are described in Examples 1-4. In a further aspect, the present invention relates to pharmaceutical compositions comprising compounds of formula (I) or their pharmaceutically acceptable salts as defined above and one or more pharmaceutically acceptable excipients for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii. The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions or infusion solutions). The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such excipients for tablets, dragées and hard gelatin capsules. Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi- solid substances and liquid polyols, etc. Suitable excipients for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc. Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi- solid or liquid polyols, etc. Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity- increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated. Co-Administration of Compounds of Formula (I) and Other Agents The compounds of formula (I) or salts thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof may be employed alone or in combination with other agents for treatment. For example, the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound of formula (I) such that they do not adversely affect each other. The compounds may be administered together in a unitary pharmaceutical composition or separately. In one embodiment a compound or a pharmaceutically acceptable salt can be co-administered with an antibiotic, in particular with an antibiotic for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination therof. The term "co-administering" refers to either 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 a further active pharmaceutical ingredient or ingredients, including antibiotic agents. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered intravenously and another compound may be administered orally. Typically, any agent that has antimicrobial activity may be co-administered. Particular examples of such agents are Carbapenems (meropenem), Fluoroquinolone (Ciprofloxacin), Aminoglycoside (amikacin), Tetracyclines (tigecycline), Colistin, Sulbactam, Sulbactam+Durlobactam, Cefiderocol (Fetroja), macrocyclic peptides as exemplified e.g. in WO 2017072062 A1, WO 2019185572 A1 and WO 2019206853 A1, and Macrolides (erythromycin). In one aspect, the present invention provides a pharmaceutical composition described herein, further comprising an additional therapeutic agent. In one embodiment, said additional therapeutic agent is an antibiotic agent. In one embodiment, said additional therapeutic agent is an antibiotic agent that is useful for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination therof. In one embodiment, said additional therapeutic agent is an antibiotic agent selected from Carbapenems (meropenem), Fluoroquinolone (Ciprofloxacin), Aminoglycoside (amikacin), Tetracyclines (tigecycline), Colistin, Sulbactam, Sulbactam+Durlobactam, Cefiderocol (Fetroja), macrocyclic peptides as exemplified in WO 2017072062 A1, WO 2019185572 A1 and WO 2019206853 A1, and Macrolides (erythromycin). Examples The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples. In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization. All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise. 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) hour(s) HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri dinium 3-oxid hexafluorophosphate HPLC: high performance liquid chromatography HPLC-UV: high performance liquid chromatography with ultraviolet detector IC50 half maximal inhibitory concentration IC90 90% inhibitory concentration PE petroleum ether PdCl ₂ (DPPF) [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II ) Pd ₂ (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 saturated SEM 2-methoxyethyl(trimethyl)silane FA Formic acid TFA Trifluoroacetic Acid wt weight X-PHOS 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl Intermediate A1 tert-butyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-be nzoate Step 1 Step 2 Step 3 Intermediate A1 Step1: tert-butyl 2-chloro-4-nitro-benzoate 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 another 14 h. The mixture was concentrated. The residue was treated with EA (50 mL) and H ₂ O (50 mL). The mixture was extracted with EA. The combined organic layers were concentrated. The crude was then purified by flash column chromatography to afford tert-butyl 2-chloro-4-nitro-benzoate (18.8 g) as a colorless solid. Step2: tert-butyl 4-amino-2-chloro-benzoate 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 by Celite. The filtrate was concentrated to remove ethanol. The mixture was extracted with EA. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to afford tert-butyl 4-amino-2-chloro-benzoate (16.31 g) as a light yellow solid. MS [M+H] ⁺ : 228.1. Step3: tert-butyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-be nzoate 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. The mixture was added water (10 mL) and extracted with EA. The combined organic layers were concentrated. The crude was purified by FCC to afford 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. The following Intermediates were prepared in analogy to Intermediate A1 Intermediate B1 5-bromo-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methy l-imidazole-2-carboxamide Intermediate A1 Intermediate B1 Step 1: 4-(5-bromo-1-methyl-1h-imidazole-2-carboxamido)-2-chlorobenz oic acid In a 250 mL round-bottomed flask, tert-butyl 4-(5-bromo-1-methyl-1h-imidazole-2- carboxamido)-2-chlorobenzoate (5 g, 12.1 mmol) was combined with CH ₂ Cl ₂ (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 h. The crude reaction mixture was concentrated in vacuum to afford 4- (5-bromo-1-methyl-1h-imidazole-2-carboxamido)-2-chlorobenzoi c acid (4.32 g). MS [M+H] ⁺ : 359.8. Step 2: tert-butyl 4-(4-(5-bromo-1-methyl-1h-imidazole-2-carboxamido)-2- chlorobenzoyl)piperazine-1-carboxylate In a 100 mL round-bottomed 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 tempeature for 1 h. The reaction mixture was poured into 150 mL H ₂ O and extracted with EtOAc ( 3 x 75 mL ). The organic layers were combined, washed with sat. NaCl ( 1 x 75 mL ). The organic layers were dried over Na ₂ SO ₄ and concentrated in vacuum to afford tert- butyl 4-(4-(5-bromo-1-methyl-1h-imidazole-2-carboxamido)-2-chlorob enzoyl)piperazine-1- carboxylate (2.94 g). MS [M+H] ⁺ : 527.9. The following Intermediates were prepared in analogy to Intermediate B1

Intermediate C1 5-bromo-N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methy l-1h-imidazole-2- carboxamide Step 1 Intermediate B1 Intermediate C ₁ In a 100 mL round-bottomed flask, tert-butyl 4-(4-(5-bromo-1-methyl-1h-imidazole-2- carboxamido)-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 h. The crude reaction mixture was concentrated in vacuum. The crude product was directly used to the next step to afford 5-bromo- N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-1h-imi dazole-2-carboxamide (2.38 g). MS [M+H] ⁺ : 427.8. The following Intermediates were prepared in analogy to Intermediate C1

Intermediate D1 tert-butyl 4-(4-(4-(5-bromo-1-methyl-1h-imidazole-2-carboxamido)-2- chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate I ^{ntermediate C1} Intermediate D1 In a 100 mL round-bottomed 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 h. The reaction mixture was poured into 150 mL H ₂ O and extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with sat NaCl (1 x 75 mL). The organic layers were dried over Na ₂ SO ₄ and concentrated in vacuum to afford tert-butyl 4-(4-(4-(5-bromo-1-methyl-1h- imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbon yl)piperidine-1-carboxylate (3.56 g). MS [M+H] ⁺ : 638.9. The following intermediates were prepared in analogy to Intermediate D1 Intermediate D10 tert-butyl 4-[4-[4-[(5-bromo-4-chloro-1-methyl-imidazole-2-carbonyl)ami no]-2-chloro- benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate intermediate D10 Step 1: 5-bromo-4-chloro-1-methyl-imidazole 4-chloro-1-methyl-imidazole (466 mg, 4. mmol) was dissolved in N,N-dimethylformamide (8 mL), NBS (498.13 mg, 2.8 mmol) was added at rt. The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with sat. NaHCO ₃ -solution (20 mL) and extracted two times with EtOAc (30 mL). The organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The crude product was directly used to the next step, to afford 5-bromo-4-chloro-1-methyl-imidazole (284 mg, 36.34%) as light brown solid. MS [M+H] ⁺ : 196.9. Step 2: 5-bromo-4-chloro-1-methyl-imidazole-2-carboxylic acid methyl ester 5-bromo-4-chloro-1-methyl-imidazole (284 mg, 1.45 mmol)was dissolved in tetrahydrofuran (5 mL), 2 M lithium diisopropylamide (871.88 uL, 1.74 mmol) was added at -78 ºC, The reaction was stirred at -78 ºC for 30 mins, methyl chloroformate (164.79 mg, 1.74 mmol)was added at - 78ºC. The mixture was warmed to room temperature with stirring for 1 h. The reaction mixture was diluted with water (20 mL) and extracted two times with EtOAc (20 mL). The organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The crude product was directly used to the next step, to afford 5-bromo-4-chloro-1- methyl-imidazole-2-carboxylic acid methyl ester (360 mg) as light brown oil. MS [M+H] ⁺ : 254.9. Step 3: 5-bromo-4-chloro-1-methyl-imidazole-2-carboxylic acid 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), NaOH (284.05 mg, 7.1 mmol)was added at rt. The mixture was stirred at room temperature for 1 h. The PH of the reaction mixture was adjusted to 6. The reaction was concentrated to dryness. The crude product was directly used to the next step, to afford 5-bromo-4-chloro-1-methyl-imidazole-2-carboxylic acid (340 mg) as light yellow solid. MS [M+H] ⁺ : 240.9. Step 4: 4-(1-tert-butoxycarbonylisonipecotoyl)piperazine-1-carboxyli c acid benzyl ester 1-tert-butoxycarbonylisonipecotic acid (2.5 g, 10.9 mmol)was dissolved in N,N- dimethylformamide (31.25 mL), 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 rt. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (30 mL) and extracted two times with EtOAc (30 mL). The organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (5 % MeOH in DCM ). to afford 4-(1-tert-butoxycarbonylisonipecotoyl)piperazine- 1-carboxylic acid benzyl ester (3 g, 63.76%) as colorless oil. MS [M+H] ⁺ : 454.2. Step 5: 4-(piperazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester 4-(1-tert-butoxycarbonylisonipecotoyl)piperazine-1-carboxyli c acid benzyl ester (3 g, 6.95 mmol)was dissolved in methanol (50 mL), palladium hydroxide on carbon (97.63 mg, 0.695 mmol) was added at rt. The mixture was purge from the H ₂ ballon three times, and stirred at room temperature for 15 h. The reaction mixture was filtered, the filtrate was concentrated to dryness. The crude product was directly used to the next step to afford 4-(piperazine-1- carbonyl)piperidine-1-carboxylic acid tert-butyl ester (2.07 g) as colorless oil. MS [M+H] ⁺ : 298.2. Step 6: 4-[4-(4-amino-2-chloro-benzoyl)piperazine-1-carbonyl]piperid ine-1-carboxylic acid tert-butyl ester 4-(piperazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (1 g, 3.36 mmol) was dissolved in N,N-dimethylformamide (7 mL), 4-amino-2-chloro-benzoic 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 rt. The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (40 mL) and extracted two times with EtOAc (30 mL). The organic layers were washed with brine (30mL), dried over Na ₂ SO ₄ and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (10 % MeOH in DCM ). to afford 4-[4-(4- amino-2-chloro-benzoyl)piperazine-1-carbonyl]piperidine-1-ca rboxylic acid tert-butyl ester (1.09 g) as white solid. MS [M+H] ⁺ : 351.2. Step 7: 4-[4-[4-[(5-bromo-4-chloro-1-methyl-imidazole-2-carbonyl)ami no]-2-chloro- benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester 4-[4-(4-amino-2-chloro-benzoyl)piperazine-1-carbonyl]piperid ine-1-carboxylic acid tert-butyl ester (400 mg, 0.887 mmol) was dissolved in N,N-dimethylformamide (5 mL), 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 rt. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (30 mL) and extracted two times with EtOAc (30 mL). The organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (10 % MeOH in DCM ). to afford 4-[4-[4-[(5-bromo-4-chloro-1-methyl-imidazole- 2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carbonyl]pip eridine-1-carboxylic acid tert- butyl ester (277 mg) as light brown solid. MS [M+H] ⁺ : 573.1. Intermediate D11 tert-butyl (3R,4R)-3-[[(1S,5R)-6-[[4-[(5-bromo-1-methyl-imidazole-2-car bonyl)amino]-2- chloro-benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]a mino]-4-hydroxy- pyrrolidine-1-carboxylate In a 25 mL round bottomed-flask equiped with a magnetic stirrer-bar, a N2-balloon and a spetum-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 RT. After 15 min, N-(4-(((1R,5S,6s)-3- azabicyclo[3.1.0]hexan-6-yl)carbamoyl)-3-chlorophenyl)-5-bro mo-1-methyl-1H-imidazole-2- carboxamide hydrochloride (197.8 mg, 416 µmol) was added and the resulting light brownish reaction solution was stirred for 1.5 h.Water (7 mL) was added to the reaction mixture, but the product did not precipitate out. The aqueous layer was extracted with EA (2 x 10 mL). The organic layers were washed with LiCl-solution (5% in water) (10 mL each organic layer) and with sat.-NaCl solution (1 x 10 mL), dried over Na ₂ SO ₄ , filtered off and concentrated in vacuum at 40 °C. Crude product purified by silica gel chromatography, to yield 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. The following intermediates were prepared in analogy to Intermediate D11 Intermediate E1 and Intermediate E2 1-(2-methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2- yl)pyrazole(Intermediate E1) 1-(2-methoxyethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2-yl)pyrazole (Intermediate E2) Intermediate E1 Intermediate E2 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), K2CO ₃ (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 the microwave at 100 ºC for 15 h. The reaction mixture was filtered through glass fiber paper. The filtrate was concentrated in vacuum. The crude material was purified by flash chromatography to afford 2 g of crude product, The crude product was purified by preparative HPLC to afford 1-(2-methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-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. The following intermediates were prepared in analogy to Intermediate E1

Intermediate E18 5-ethyl-1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-diox aborolan-2-yl)pyrazole 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) were dissolved in THF (8.0 ml). The solution was cooled to -78 °C under argon atmosphere. N-butyllithium (2.0 mL, 3.0 mol) was then added dropwise to the solution. The resulting solution was stirred for 60 min at this temperature, and then the temperature was raise to room temperature gradually. The reaction mixture was quenched by methanol at 0 °C and evaporation of the solvent gave a 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. Intermediate E19 tert-butyl-dimethyl-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-2-yl)-2-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]butoxy]silane

^{Step 1} _{Step 2} Step 3 Intermediate E19 Step 1: 2-[(4-bromopyrazol-1-yl)methoxy]ethyl-trimethyl-silane 4-bromo-1H-pyrazole (7.35 g, 50 mmol) and DIPEA (13.0 g, 100 mmol) were dissolved in anhydrous CH ₂ Cl ₂ (50 ml). The solution was cooled to 0 °C and (2- (chloromethoxy)ethyl)trimethylsilane (10g, 60 mmol) was then added dropwise. The mixture was warmed to room tmperature and then stirred for 12.0 h. The mixture was poured into water and the aqueous solution was extracted with EtOAc (2 x 150 ml). The organic layers were combined and 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 afford 2-[(4-bromopyrazol-1-yl)methoxy]ethyl-trimethyl-silane (8.6 g). MS [M+H] ⁺ : 277.1. Step 2: 2-[[4-bromo-5-[4-[tert-butyl(dimethyl)silyl]oxybutyl]pyrazol -1-yl]methoxy]ethyl- trimethyl-silane 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 dropwise LDA (2.0 M in THF) (5.0 mmol) at -78 °C under argon. The resulting mixture was stirred for 1.0 h at -78 °C, 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 warmed to room temperature with stirring. The reaction was quenched by saturated aqueous solution of ammonium chloride and followed by extracted with EtOAc (2 x 50 mL). The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuum. 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. Step 3: tert-butyl-dimethyl-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-2-yl)-2-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]butoxy]silane 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 dropwise n-BuLi (1.6 M in THF) (1.3 mL, 2.0 mmol) at -78 °C under argon. The resulting mixture was stirred for 1.0 h at -78° C and then the reaction was warmed to room temperature, stirred overnight. The reaction was quenched by saturated aqueous solution of ammonium chloride and followed by extracted by EtOAc (2 x 50 mL). The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The crude material was purified by flash chromatography on silica gel to give tert-butyl-dimethyl-[4-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-trimethylsilyletho xymethyl)pyrazol-3- yl]butoxy]silane the title compound. (400.0 mg). MS [M+H] ⁺ : 511.0. Intermediate E20 1-(2-methoxyethyl)-5-(methoxymethyl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyrazole Intermediate E20 Step 1: 4-bromo-1-(2-methoxyethyl)pyrazole 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 then the mixture stirred at 0 ºC for 1 h.1-bromo-2-methoxyethane (8.34 g, 60 mmol) was added in batches to the mixture and then stirred for extra 2.0 h at room temperature. The reaction mixture was quenched by water at 0 ºC and then acidified with 1N HCl to PH =7-8, the aqueous solution was extracted with EtOAc, the combined extracts were concentrated in vacuum. The crude material was purified by flash chromatography on silica gel to afford 4-bromo-1-(2-methoxyethyl)pyrazole (7.2 g). Step 2: 4-bromo-2-(2-methoxyethyl)pyrazole-3-carbaldehyde To a solution of 4-bromo-1-(2-methoxyethyl)pyrazole (3.1 g, 15 mmol) in anhydrous THF (20 mL) was added dropwise LDA (22.5 mmol) at -78 °C under argon. The resulting mixture was stirred for 1.0 h at -78 °C and then DMF (1.65 g, 22.5 mmol) was added dropwise into the mixture and stirred for extra 8.0 h at room temperature. The reaction mixture was quenched by water at 0 ºC and then acidified with 1N HCl to PH =7-8. The aqueous solution was extracted with EtOAc, the combined extracts were concentrated in vacuum. The crude material was purified by flash chromatography on silica gel to afford afford 4-bromo-2-(2- methoxyethyl)pyrazole-3-carbaldehyde (3.0 g). MS [M+H] ⁺ : 232.9. Step 3: [4-bromo-2-(2-methoxyethyl)pyrazol-3-yl]methanol To a solution of 4-bromo-2-(2-methoxyethyl)pyrazole-3-carbaldehyde (3.5 g, 15 mmol) in anhydrous THF (65 mL) was added dropwise borane(1.0 M in THF) (22.5 mmol ) at -78 °C under argon. The resulting mixture was stirred for 2.0 h at -78 °C and then stirred for extra 5.0 h at room temperature. The reaction mixture was quenched by water at 0ºC and then extracted with EtOAc (75 mL×3), the combined extracts were concentrated in vacuum. The crude material was purified by flash chromatography on silica gel to afford [4-bromo-2-(2-methoxyethyl)pyrazol-3- yl]methanol (2.8 g). MS [M+H] ⁺ : 235.0. Step 4: 4-bromo-1-(2-methoxyethyl)-5-(methoxymethyl)pyrazole 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 then the suspension was stirred for 1 h. Iodomethane (1.1 g, 7.5 mmol) was added into the mixture, stirred for extra 2.0 h at room temperature. The mixture was quenched by water and then poured into water (50 mL) and the aqueous solution was extracted with EtOAC (100 mL × 2). The organic layers were combined and 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 afford 4-bromo-1-(2-methoxyethyl)-5-(methoxymethyl)pyrazole (0.86 g). MS [M+H] ⁺ : 249.0. Step 5: 1-(2-methoxyethyl)-5-(methoxymethyl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyrazole 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) were dissolved in THF (20 mL). The solution was cooled to -78 °C under argon atmosphere, n-butyllithium (7.5 mL, 12 mmol) was then added dropwise to the solution. The resulting solution was stirred for 1.0 h at this temperature, and then the temperature was raised to room temperature. The reaction mixture was quenched by methanol at 0 °C. Evaporation of the solvent gave a 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. Intermediate F1 and Intermediate F2 4-(4-bromo-2,3-difluoro-phenyl)-1-(2,2-difluoroethyl)-3-meth yl-pyrazole(Intermediate F1) 4-(4-bromo-2,3-difluoro-phenyl)-1-(2,2-difluoroethyl)-3-meth yl-pyrazole(Intermediate F2) I _{ntermediate F1} ^{Intermediate F2} Step 1: 4-(4-bromo-2,3-difluoro-phenyl)-3-methyl-1H-pyrazole To a 25 mL microwave vial was added 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole (1.7 g, 8.15 mmol), 1-bromo-2,3-difluoro-4-iodobenzene (2 g, 6.27 mmol), Na ₂ CO ₃ (1.99 g, 18.8 mmol) and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (459 mg, 627 µmol) in Dioxane (50 mL)/Water (5 mL). The vial was capped and heated in the microwave at 100 ºC for 15 h under N ₂ . The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography to afford 4-(4-bromo-2,3-difluorophenyl)-3-methyl-1H- pyrazole (1.7g). MS [M+H] ⁺ : 275.0. Step 2: 4-(4-bromo-2,3-difluoro-phenyl)-1-(2,2-difluoroethyl)-3-meth yl-pyrazole and 4-(4- bromo-2,3-difluoro-phenyl)-1-(2,2-difluoroethyl)-3-methyl-py razole In a 50 mL round-bottomed flask, 4-(4-bromo-2,3-difluorophenyl)-3-methyl-1H-pyrazole (1 g, 3.66 mmol), K ₂ CO ₃ (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 light 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 vacuum. The crude material was purified by flash chromatography to afford 400 mg the mixture product. The mixture was purified by preparative chiral-HPLC to obtain 4-(4-bromo-2,3-difluoro-phenyl)-1-(2,2-difluoroethyl)-3-meth yl-pyrazole (96.7 mg) and 4-(4-bromo-2,3-difluoro-phenyl)-1-(2,2-difluoroethyl)-5-meth yl-pyrazole (60 mg). MS [M+H] ⁺ : 337.1. Intermediate F3 4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)-1H-pyraz ole Intermediate F3 To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoro methyl)-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 ₂ (dppf)-CH ₂ Cl ₂ adduct (1.56 g, 1.91 mmol) in dioxane (90 mL) and water (9. mL). The resultant mixture was heated at 100 ºC for 10 h under N ₂ . The crude reaction mixture was concentrated in vacuum. The residue was purified by flash chromatography to afford 4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)-1H-pyraz ole (3.9 g). MS [M+H] ⁺ : 327.0. The following example was prepared in analogy to Intermediate F3 Intermediate G1 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)phenyl]-3-methyl- pyrazol-1-yl]methoxy]ethyl-trimethyl-silane Step 1: 2-[[4-(4-bromo-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]me thoxy]ethyl- trimethyl-silane In a 100 mL round-bottomed 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 h. The reaction mixture was poured into 50 mL H ₂ O and extracted with EtOAc ( 3 x 30 ml ). The organic layers were combined, washed with sat NaCl (1 x 25 mL), The organic layers were dried over Na ₂ SO ₄ and concentrated in vacuum to afford 2-[[4-(4-bromo-2,3- difluoro-phenyl)-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimeth yl-silane(1.51 g ). MS [M+H]+: 405.1. Step 2: 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)phenyl]-3-methyl- pyrazol-1-yl]methoxy]ethyl-trimethyl-silane In a 250 mL round-bottomed flask, bis(pinacolato)diboron (1.44 g, 5.65 mmol), 2-[4-(4-bromo- 2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]ethoxymethyl-trim ethyl-silane(1.52 g, 3.77 mmol), PdCl ₂ (dppf)-CH ₂ Cl ₂ 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 for 15 h under N ₂ . The crude reaction mixture was concentrated in vacuum. The reaction mixture was poured into 50 mL H ₂ O and extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with sat NaCl (1 x 50 mL), The organic layers were dried over Na ₂ SO ₄ and concentrated in vacuum. The crude material was purified by flash chromatography to afford 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2- yl)phenyl]-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-sil ane (1 g). 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 IntermediateE1 Intermediate G2 Step 1: 4-(4-bromo-2,3-difluoro-phenyl)-1-(2-methoxyethyl)-3-methyl- pyrazole In a 50 mL round-bottomed 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 ₂ (dppf)-CH ₂ Cl ₂ adduct (115 mg, 157 µmol) and Na ₂ CO ₃ (499 mg, 4.7 mmol) were combined with Dioxane (10 mL) / Water (1 mL) to give a dark red solution. The reaction mixture was heated to 100 °C and stirred for 15 h under N2. The reaction mixture was filtered through glass fiber paper. The filtrate was concentrated in vacuum. The crude material was purified by flash chromatography to afford 4-(4-bromo-2,3-difluoro-phenyl)-1-(2- methoxyethyl)-3-methyl-pyrazole (310 mg). MS [M+H] ⁺ : 333.1. 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 In a 50 mL round-bottomed flask, 4-(4-bromo-2,3-difluoro-phenyl)-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 ₂ (dppf)-CH ₂ Cl ₂ 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 for 15 h under N2. The reaction mixture was filtered through glass fiber paper. The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography to afford 4-[2,3-difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2-methoxyethy l)-3-methyl-pyrazole (350 mg). MS [M+H] ⁺ : 379.1. The following intermediates were prepared in analogy to Intermediate G2

Intermediate G33 1-[2-(difluoromethoxy)ethyl]-4-[2,3-difluoro-4-(4,4,5,5-tetr amethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-methyl-pyrazoleIntermediate

^{Step 1} _{Step 2} S ^{tep 3} _{Step 4} Intermediate G33 Step 1: 2-[4-(4-bromo-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]eth oxy-tert-butyl- dimethyl-silane To a solution of 1-bromo-2,3-difluoro-4-iodobenzene (1000 mg, 3.14 mmol) in the mixture 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 ₂ (dppf)-CH ₂ Cl ₂ adduct (256 mg, 314 µmol). The reaction was stirred for 3 h at 130 ^o C under microwave irritation and atmosphere of argon. The mixture was filtered and the filtrate was concentrated in vacuum. 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 (1 g). MS [M+H] ⁺ : 431.1. Step 2: 2-[4-(4-bromo-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]eth anol To a solution of 4-(4-bromo-2,3-difluorophenyl)-1-(2-((tert-butyldimethylsily l)oxy)ethyl)-3- methyl-1H-pyrazole (1 g, 2.32 mmol) in THF ( 10 mL) was added TBAF (6.95 mL, 6.95 mmol), the reaction was stirred for 1 h at room temperature. The reaction mixture was washed with brine (20 mL) and extracted in DCM (30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography to give2-[4- (4-bromo-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]ethanol (500 mg). MS [M+H] ⁺ : 317.0. Step 3: 4-(4-bromo-2,3-difluoro-phenyl)-1-[2-(difluoromethoxy)ethyl] -3-methyl-pyrazole To a solution of 2-(4-(4-bromo-2,3-difluorophenyl)-3-methyl-1H-pyrazol-1-yl)e than-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 ^o C, then the soution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (505 mg, 2.84 mmol) in Acetonitrile (5 mL) was addded dropwise over 5 min. The reaction was stirred for another 30 min. The reaction was cooled to room temperature and the mixture was concentrated in vacuum. The residue was purified by column chromatography to give 4-(4- bromo-2,3-difluoro-phenyl)-1-[2-(difluoromethoxy)ethyl]-3-me thyl-pyrazole (200 mg). MS [M+H] ⁺ : 367.0. Step 4: 1-[2-(difluoromethoxy)ethyl]-4-[2,3-difluoro-4-(4,4,5,5-tetr amethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-methyl-pyrazole 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 ₂ (dppf)-CH ₂ Cl ₂ adduct (44.5 mg, 54.5 µmol) and bis(pinacolato)diboron (138 mg, 545 µmol), the reaction was stirred for 15 h at 80 ^o C under atmosphere of argon. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuum 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. The following intermediates were prepared in analogy to Intermediate G33 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 Intermediate G35 Step 1: 4-bromo-3-isopropyl-1-(2-methoxyethyl)pyrazole To a solution of 4-bromo-3-isopropyl-1H-pyrazole (1000 mg, 5.29 mmol) in acetonitrile (10 mL) was added 1-bromo-2-methoxy-ethane (735.2 mg, 5.29 mmol) and cesium carbonate (3.45 g, 10.58 mmol), the reaction was stirred for 8 h at 100 ^o C. The reaction was mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuum 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. Step 2: 2,3-difluoro-4-[3-isopropyl-1-(2-methoxyethyl)pyrazol-4-yl]p henol To a solution of 4-bromo-3-isopropyl-1-(2-methoxyethyl)pyrazole (900 mg, 3.64 mmol) in the mixture solvent of 1,4-dioxane (12 mL) and water (2.4 mL) was added (2,3-difluoro-4-hydroxy- phenyl)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), the reaction was stirred for 3 h at 100 ^o C under atmosphere of nitrogen. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuum. The residue was purified by column chromatography to give 2,3-difluoro-4-[3-isopropyl-1-(2-methoxyethyl)pyrazol-4-yl]p henol (210 mg). MS [M+H] ⁺ : 297.1. Step 3: [2,3-difluoro-4-[3-isopropyl-1-(2-methoxyethyl)pyrazol-4-yl] phenyl] trifluoromethanesulfonate To a solution of 2,3-difluoro-4-[3-isopropyl-1-(2-methoxyethyl)pyrazol-4-yl]p henol (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), the reaction was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuum. 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. 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 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), the reaction was stirred for 5 h at 100 ^o C under atmosphere of nitrogen. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuum. 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. The following intermediates were prepared in analogy to Intermediate G35 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 Step 1: 3-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazo l-1-yl]propanamide 4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazo le (500 mg, 1.53 mmol), 3- bromopropanamide (279 mg, 1.83 mmol) and potassium carbonate (634 mg, 4.59 mmol) were heated in anhydrous acetonitrile (7.64 mL) 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 afford the final compound as yellow oil (550 mg). MS [M+H] ⁺ : 398.0. 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 To a solution of 3-(4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyr azol-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 ₂ (dppf)-CH ₂ Cl ₂ (122 mg, 148 µmol), the reaction was stirred for 18 hours at 100 ^o C under atmosphere of argon. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuum and the residue was purified by column chromatography to afford the product as yellow solid (390 mg). MS [M+H] ⁺ : 446.2. The following examples were prepared in analogy to Intermediate G38

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 Intermediate G47 Step 1: 1-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazo l-1-yl]propan-2-one 4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazo le (110 mg, 336 µmol), 1- bromopropan-2-one (55.3 mg, 404 µmol) and potassium carbonate (139 mg, 1.01 mmol) were stirred in anhydrous acetonitrile (3.36 mL) at room temperature for 30 min.100-200 mesh silica gel was added to absorb the material. The loaded sample was purified by flash chromatography to afford the final compound as light yellow oil (120 mg). MS [M+H] ⁺ : 383.0. Step 2: 1-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazo l-1-yl]propan-2-ol 1-(4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyr azol-1-yl)propan-2-one (120 mg, 313 µmol) was dissolved in MeOH. The solution was cooled to 0 °C. To this solution was added sodium tetrahydroborate (11.8 mg, 313 µmol), and the resulting mixture was stirred for 1 h at the same temperature.100-200 mesh silica gel was added to absorb the material; the loaded sample was then purified by flash chromatography to afford the final compound as light yellow oil (110 mg). MS [M+H] ⁺ : 385.0. 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 To a solution of 1-(4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyr azol-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 ₂ (dppf)-CH ₂ Cl ₂ (25.5 mg, 31.2 µmol), the reaction was stirred for 18 hours at 100 ^o C under atmosphere of argon. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuum and the residue was purified by column chromatography to afford the final compound as light brown oil (90 mg). MS [M+H] ⁺ : 433.2. 1-[2-(difluoromethoxy)ethyl]-4-[2,3-difluoro-4-(4,4,5,5-tetr amethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-(trifluoromethyl)pyrazole

_{Step 1} ^{Step 2} Intermediate F3 Step 3 Intermediate G48 Step 1: 2-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazo l-1-yl]ethanol To a solution of 4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazo le (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), the reaction was stirred for 3 hours at 90 ^o C. The reaction mixture was cooled to room temperature and washed with brine, extracted in DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by column chromatography to give 2-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazo l- 1-yl]ethanol (640 mg). MS [M+H] ⁺ : 371.1. Step 2: 4-(4-bromo-2,3-difluoro-phenyl)-1-[2-(difluoromethoxy)ethyl] -3- (trifluoromethyl)pyrazole To a solution of 2-(4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyr azol-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 ^o C, then the solution of 2,2-difluoro-2- (fluorosulfonyl)acetic acid (480 mg, 2.69 mmol) in Acetonitrile (5 mL) was addded dropwise over 5 min. The reaction was stirred for another 30 min. The reaction was cooled to room temperature and the mixture was concentrated in vacuum. The residue was purified by f column chromatgraphy to give 4-(4-bromo-2,3-difluoro-phenyl)-1-[2-(difluoromethoxy)ethyl] -3- (trifluoromethyl)pyrazole (260 mg). MS [M+H] ⁺ : 421.1. Step 3: 1-[2-(difluoromethoxy)ethyl]-4-[2,3-difluoro-4-(4,4,5,5-tetr amethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrazole 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 ₂ (dppf)-CH ₂ Cl ₂ (50.4 mg, 61.7 µmol) and bis(pinacolato)diboron (157 mg, 617 µmol), the reaction was stirred for 15 h at 80 ^o C under atmosphere of argon. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuum and the residue was purified by column chromatography to give1-[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. 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 Step 1: 4-(4-bromo-2,3-difluoro-phenyl)-1-(2-methylallyl)-3-(trifluo romethyl)pyrazole To a solution of 4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazo le (600 mg, 1.83 mmol) in DMF (5 mL) was added 3-iodo-2-methylprop-1-ene (334 mg, 1.83mmol) and potassium carbonate (761 mg, 5.5 mmol), the reaction was stirred for 3 h at 90 ^o C. The reaction mixture was cooled to room temperature and washed with brine, extracted in DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum. 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. Step 2: 3-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazo l-1-yl]-2-methyl- propan-1-ol To a solution of 4-(4-bromo-2,3-difluorophenyl)-1-(2-methylallyl)-3-(trifluor omethyl)-1H- pyrazole (400 mg, 1.05 mmol) in THF (5 mL) was added Borane tetrahydrofuran complex solution (2.1 mL, 2.1 mmol) drop wise at room temperature under atmosphere of nitrogen. The reaction was stirred for 4 h, 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 another 4 h. The reaction mixture was concentrated in vacuum and the residue was purified by column chromatography to give 3-[4-(4-bromo-2,3-difluoro-phenyl)-3-(trifluoromethyl)pyrazo l- 1-yl]-2-methyl-propan-1-ol (320 mg). MS [M+H] ⁺ : 399.1. 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 To a solution of 3-(4-(4-bromo-2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyr azol-1-yl)-2- methylpropan-1-ol (400 mg, 1 mmol) in dioxane (5 mL) was added potassium acetate (197 mg, 2 mmol), PdCl ₂ (dppf)-CH ₂ Cl ₂ (81.8 mg, 100 µmol) and bis(pinacolato)diboron (254 mg, 1 mmol), the reaction was stirred for 15 h at 80 ^o C under atmosphere of argon. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuum 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. Intermediate G50 [4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phe nyl]boronic acid

_{Step 1} ^{Step 2} S _{tep 3} ^{Step 4 Step 5} Intermediate G50 Step 1: 1-(4-benzyloxy-2,3-difluoro-phenyl)butan-2-one To a solution of 2-(4-benzyloxy-2,3-difluoro-phenyl)-N-methoxy-N-methyl-aceta mide (6.7 g, 20.85 mmol) in THF (50.0 mL) was added ethylmagnesium bromide in Et2O (3M) (10.43 mL, 31.28 mmol) slowly at -40 °C under N ₂ . This reaction mixture was stirred at -10 °C for 2 h. This reaction was quenched by NH4Cl (50.0 mL) and was extracted by EtOAc (50.0 mL x 2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get the crude product. This crude product was purified by silica gel chromatography (PE: EtOAc=8:1) to get 1-(4- benzyloxy-2,3-difluoro-phenyl)butan-2-one (1.4 g) as yellow solid. Step 2: 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-ethyl-1-(2-methoxyethy l)pyrazole To a mixture of 1-(4-benzyloxy-2,3-difluoro-phenyl)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 3h. The mixture was filtered and concentrated under reduced pressure affording the residue. The mixture of residue and N,N-dimethylformamide dimethyl acetal (7.07 mL, 86.81 mmol) was stirred at 100 °C for 16 h. This reaction was quenched by H ₂ O (10.0 mL) and was extracted by EtOAc (10.0 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get the crude product. The crude product was purified by silica gel chromatography (PE:EtOAc=5:1) to get 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-ethyl-1-(2-methoxyethy l)pyrazole (630.0 mg) as yellow oil. MS [M+H] ⁺ : 373.2. Step 3 : 4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phen ol To a solution of 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-ethyl-1-(2-methoxyethy l)pyrazole (630.0 mg, 1.69 mmol) in methanol (6 mL) was added palladium on carbon (180.03 mg) in one portion under N ₂ . This mixture was degassed and purged with N ₂ for 3 times. Then H ₂ (15 psi) was introduced into this system. The reaction mixture was stirred at 20 °C for 16 h under H ₂ atmosphere. The mixture was filtered and concentrated under reduced pressure affording the crude product 4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phen ol (470.0 mg) as a black oil.MS [M+H] ⁺ : 283.2. Step 4: [4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phe nyl] trifluoromethanesulfonate A mixture of 4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phen ol (220.0 mg, 0.78 mmol) and pyridine (0.09 mL, 1.17 mmol) in DCM (5 mL) was degassed and purged with N2 for 3 times. Then trifluoromethanesulfonic anhydride (0.15 mL, 0.94 mmol) was added dropwise into the mixture at 0 °C. The reaction mixture was stirred at 20 °C for 2 h under N2 atmosphere. This reaction was quenched by NaHCO ₃ (10 mL) and was extracted by DCM (10 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get the crude product [4- [3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl ] trifluoromethanesulfonate (390.0 mg) as red oil. MS [M+H] ⁺ : 415.1. Step 5 : [4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phe nyl]boronic acid A mixture of bis(pinacolato)diboron (478.03 mg, 1.88 mmol), [4-[3-ethyl-1-(2- methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl] 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 ₂ for 3 times. Then tris(dibenzylideneacetone)dipalladium (0) (43.1 mg, 0.05 mmol) was added into the mixture. The reaction mixture was stirred at 100 °C for 2 h under N2 atmosphere. This reaction was extracted by EtOAc (10 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get the crude product. The crude product was purified by preparative HPLC (TFA) to get [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 brown oil. MS [M+H] ⁺ : 311.2. Intermediate G51 [4-[3-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phe nyl]boronic acid _{Step1 Step 2} ^{Step 3} Step 4 S ^{tep 5} _{Step 6 Step 7} Intermediate G51 Step 1: methyl 4-bromo-1-(2-methoxyethyl)pyrazole-3-carboxylate 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 for 3 times. Then 1-bromo-2-methoxy-ethane(3.44 mL, 36.58 mmol) was added into the mixture. The reaction mixture was stirred at 80 °C for 2 h under N2 atmosphere. The mixture was filtered and concentrated under reduced pressure affording the crude product. The crude product (5 batches) was purified by Prep-HPLC to get methyl 4-bromo-1-(2-methoxyethyl)pyrazole-3-carboxylate (8.0 g). MS [M+H] ⁺ : 263.0. Step 2: [4-bromo-1-(2-methoxyethyl)pyrazol-3-yl]methanol 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 N2. This reaction mixture was stirred at 20 °C for 16 h. This reaction was quenched by HCl (1 M, 20 mL) and was extracted by EtOAc (20 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get the crude product [4-bromo-1-(2-methoxyethyl)pyrazol-3- yl]methanol (1.6 g). MS [M+H] ⁺ : 235.0. Step 3: [4-bromo-1-(2-methoxyethyl)pyrazol-3-yl]methoxy-tert-butyl-d imethyl-silane 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. This reaction mixture was stirred at 20 °C for 16 h. This reaction was quenched by brine (10 mL) and was extracted by EtOAc (20 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc=5:1) to get [4-bromo-1-(2- methoxyethyl)pyrazol-3-yl]methoxy-tert-butyl-dimethyl-silane (1.36 g). MS [M+H] ⁺ : 349.1. Step 4: [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyraz ol-3-yl]methoxy-tert- butyl-dimethyl-silane 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-d imethyl- 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 N2 for 3 times. Then [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (276.36 mg, 0.38 mmol) was added into the mixture. The reaction mixture was stirred at 100 °C for 16 h under N2 atmosphere. The mixture was filtered and concentrated under reduced pressure affording the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 5:1) to get [4-(4- benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyrazol-3-y l]methoxy-tert-butyl-dimethyl- silane (1.17 g). MS [M+H] ⁺ : 489.2. Step 5: 4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyethy l)pyrazol-4-yl]-2,3- difluoro-phenol To a solution of [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyraz ol-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 N ₂ . This mixture was degassed and purged with N ₂ for 3 times. Then H ₂ (15 psi) was introduced into this system. The reaction mixture was stirred at 20 °C for 2 h under H ₂ atmosphere. The mixture was filtered and concentrated under reduced pressure affording the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 2:1) to get 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. Step 6: [4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyeth yl)pyrazol-4-yl]-2,3- difluoro-phenyl] trifluoromethanesulfonate A mixture of 4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyethy l)pyrazol-4-yl]-2,3- difluoro-phenol (250.0 mg, 0.63 mmol) and pyridine (0.08 mL, 0.94 mmol) in DCM (5 mL) was degassed and purged with N ₂ for 3 times. Then trifluoromethanesulfonic anhydride (0.12 mL, 0.75 mmol) was added dropwise into the mixture at 0 °C. The reaction mixture was stirred at 20 °C for 2 h under N2 atmosphere. This reaction was quenched by NaHCO ₃ (10 mL) and was extracted by DCM (10 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get 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. Step 7 : [4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyeth yl)pyrazol-4-yl]-2,3- difluoro-phenyl]boronic acid A mixture of [4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyeth yl)pyrazol-4-yl]-2,3- difluoro-phenyl] 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 N2 for 3 times. Then tris(dibenzylideneacetone)dipalladium (0) (28.48 mg, 0.03 mmol) was added into the mixture. The reaction mixture was stirred at 100 °C for 3 h under N2 atmosphere. This reaction was extracted by EtOAc (10 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get the crude product. The crude product was purified by preparative HPLC (TFA) to get [4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyeth yl)pyrazol-4-yl]-2,3- difluoro-phenyl]boronic acid (210.0 mg).MS [M+H] ⁺ : 427.3. Intermediate G52 [2,3-difluoro-4-[1-(2-methoxyethyl)-3-(methylamino)pyrazol-4 -yl]phenyl]boronic acid Step 1: 4-bromo-1-(2-methoxyethyl)pyrazole-3-carboxylic acid 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. This reaction mixture was stirred at 25 °C for 4 h. HCl (1 M) was added into this mixture to make pH < 3. This mixture was extracted by EtOAc (30 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get 4-bromo-1-(2-methoxyethyl)pyrazole-3-carboxylic acid (900.0 mg), The crude product would be used in the next step directly without further purification. MS [M+H] ⁺ : 249.0. Step 2: tert-butyl N-[4-bromo-1-(2-methoxyethyl)pyrazol-3-yl]carbamate 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 azide (1.56 mL, 7.23 mmol) in one portion. This reaction mixture was stirred at 80 °C for 4 h. This reaction mixture was concentrated to get the residue. The residue was diluted with EtOAc (30 mL) and washed by saturated aqueous Na ₂ CO ₃ (5 mL x 2). The organic layer was dried over Na ₂ SO ₄ and concentrated to get the crude product. This crude product was purified by silica gel chromatography (PE: EtOA c= 1:1~1:2) to get tert-butyl N-[4-bromo-1-(2- methoxyethyl)pyrazol-3-yl]carbamate (1.0 g). MS [M+H] ⁺ : 320.0. Step 3: tert-butyl N-[4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyr azol-3- yl]carbamate 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) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (228.53 mg, 0.31 mmol) in one portion under N ₂ . This reaction mixture was stirred at 100 °C for 16 h. This reaction mixture was filtered, and the filtrate was concentrated to get the residue. This residue was diluted with EtOAc (50 mL) and was washed by brine (10 mL x 2). The organic layer was dried over Na ₂ SO ₄ and concentrated to get the crude product. This crude product was purified by silica gel chromatography (PE: EtOAc = 5:1~1:1) to get 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. Step 4: tert-butyl N-[4-(2,3-difluoro-4-hydroxy-phenyl)-1-(2-methoxyethyl)pyraz ol-3- yl]carbamate To a solution of tert-butyl N-[4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyr azol- 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. Then H ₂ (15 psi) was introduced into this system. The reaction mixture was stirred at 25 °C for 16 h. This reaction mixture was filtered, and the filtrate was concentrated to get tert-butyl N-[4-(2,3-difluoro-4-hydroxy-phenyl)-1-(2- methoxyethyl)pyrazol-3-yl]carbamate (600.0 mg), the crude product would be used in the next step directly without further purificaiton. MS [M+H] ⁺ : 370.0. Step5: [4-[3-(tert-butoxycarbonylamino)-1-(2-methoxyethyl)pyrazol-4 -yl]-2,3-difluoro- phenyl] trifluoromethanesulfonate To a solution of tert-butyl N-[4-(2,3-difluoro-4-hydroxy-phenyl)-1-(2-methoxyethyl)pyraz ol-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. Then this reaction mixture was warmed to 25 °C and stirred for 1 h. This reaction was quenched by saturated aqueous NaHCO ₃ (10 mL) and extracted by DCM (10 mL x 2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get [4-[3-(tert-butoxycarbonylamino)-1-(2- methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenyl] trifluoromethanesulfonate (800.0 mg), MS [M+H] ⁺ : 502.0. Step 6: [4-[3-(tert-butoxycarbonylamino)-1-(2-methoxyethyl)pyrazol-4 -yl]-2,3-difluoro- phenyl]boronic acid 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-dif luoro-phenyl] trifluoromethanesulfonate (800.0 mg, 1.6 mmol) and potassium acetate (313.17 mg, 3.19 mmol) in 1,4-dioxane (10.0 mL) was added tris(dibenzylideneacetone)dipalladium (0) (146.1 mg, 0.16 mmol) and X-PHOS (76.06 mg, 0.16 mmol) in one portion under N2. This reaction mixture was stirred at 100 °C for 2 h. This reaction mixture was filtered, and the filtrate was concentrated to get the crude product. This crude product was purified by Prep-HPLC (TFA) to get [4-[3-(tert- butoxycarbonylamino)-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-dif luoro-phenyl]boronic acid (190.0 mg). MS [M+H] ⁺ : 342.1. Intermediate G53 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)phenyl]-3-phenyl- pyrazol-1-yl]methoxy]ethyl-trimethyl-silane ^{Step 1} _{Step 2} Step 3 S ^{tep 4 Step 5} _{Step 6} Intermediate G53 Step 1: 3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole 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. Then 2- (trimethylsilyl)ethoxymethyl chloride (1.6 mL, 9.02 mmol) was added and the mixture was stirred at 0 °C for 12 h. The reaction mixutre waspoured into water (100 mL) and extracted with EtOAc (100 mL x 3), and the organics washed with water (50 mL x 2) then saturated brine solution (50 mL x 1). The organics were then separated and dried (MgSO ₄ ) before concentration to dryness. The crude was then purified by flash column and dried by lyophilization to give trimethyl-[2-[(3-phenylpyrazol-1-yl)methoxy]ethyl]silane (1.85 g). MS [M+H] ⁺ : 275.4. Step 2: 4-bromo-3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyr azole 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 taken up in EtOAc (50 mL) and the organics washed with water (50 mL x 2) then saturated brine solution (50 mL x 1). The organics were then separated and dried (MgSO ₄ ) before concentration to dryness to give 2-[(4-bromo-3- phenyl-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane (300 mg). MS [M+H] ⁺ : 353.1. Step 3: 4-(4-(benzyloxy)-2,3-difluorophenyl)-3-phenyl-1-((2-(trimeth ylsilyl)ethoxy)methyl)- 1H-pyrazole To a solution of 2-[(4-bromo-3-phenyl-pyrazol-1-yl)methoxy]ethyl-trimethyl-si lane (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 ₂ (206.9 mg, 0.28 mmol) under argon in glove box. The mixture was stirred at 90 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum 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-y l]methoxy]ethyl-trimethyl-silane (1 g). MS [M+H] ⁺ : 493.2. Step 4: 4-(4-(benzyloxy)-2,3-difluorophenyl)-3-phenyl-1-((2-(trimeth ylsilyl)ethoxy)methyl)- 1H-pyrazole To a solution of 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-3-phenyl-pyrazol-1-y l]methoxy]ethyl- trimethyl-silane (1.0 g, 2.03 mmol) in methanol (20.0 mL) was added Pd/C (1.0 g) under nitrogen. Then the mixture was stirred under hydrogen at 20 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give 2,3-difluoro-4-[3-phenyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]phenol (800.0 mg).MS [M+H] ⁺ : 403.1. Step 5: 2,3-difluoro-4-(3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-pyrazol-4- yl)phenyl trifluoromethanesulfonate To a solution of 2,3-difluoro-4-[3-phenyl-1-(2-trimethylsilylethoxymethyl)pyr azol-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 taken up in EtOAc (50 mL) and the organics washed with water (50 mL x 2) then saturated brine solution (50 mL x 1). The organics were then separated and dried (MgSO ₄ ) before concentration to dryness to give [2,3-difluoro-4-[3-phenyl-1-(2-trimethylsilylethoxymethyl)py razol-4- yl]phenyl] trifluoromethanesulfonate (400 mg). MS [M+H] ⁺ : 535.1. 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 To a solution of [2,3-difluoro-4-[3-phenyl-1-(2-trimethylsilylethoxymethyl)py razol-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) was added Pd(dppf)Cl ₂ (54.7 mg, 0.07 mmol) and potassium acetate (110.1 mg, 1.12 mmol) under argon in glove box. The mixture was stirred at 100 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue, which was purified by flash column and dried by lyophilization to give 2-[[4-[2,3- difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen yl]-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. 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 Intermediate G54 Step 1: 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 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 at 20 °C for 12 h under N ₂ . The reaction mixture was quenched by water (10 mL), extracted with DCM (20 mL x 3). The combined organic layers were washed brine (20 mL), dried (Na ₂ SO ₄ ) 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. Step 2: 3-(4-benzyloxy-2,3-difluoro-phenyl)-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole A mixture of cpd 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (0.8 g, 4.28 mmol ), 2-(4- benzyloxy-2,3-difluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dio xaborolane(1.6 g, 4.70 mmol), K2CO ₃ (1.2 g, 8.55 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (349.0 mg, 0.43 mmol) in a flask. The flask was degassed and purged with N2 gas for four times.1,4-dioxane (5 mL) and water (1 mL) was added by injector to the mixture. The mixture was stirred at 90 °C for 2 h under N ₂ . The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove the solvent, and the crude was purified by chromatography column flash 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. Step 3: 4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluoro-p henol To a solution of 3-(4-benzyloxy-2,3-difluoro-phenyl)-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 ₂ . The suspension was degassed under vacuum and purged with H ₂ several times 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-difluoro-phe nol (600.0 mg) as orange oil. MS [M+H] ⁺ : 237.0. Step 4: [4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluoro- phenyl] trifluoromethanesulfonate A solution of 4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluoro-p henol (600.0 mg, 2.54 mmol) in Pyridine (6.0 mL) was added trifluoromethanesulfonic anhydride (1.3 mL, 5.08 mmol) under 0 ºC, The reaction was stirred at 20 °C for 1 h. The reaction was added water (20 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed by brine (30 mL x 2), dried (Na ₂ SO ₄ ) and concentrated to give 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. Step 5: [4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2,3-difluoro- phenyl]boronic acid 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-difluoro- phenyl] trifluoromethanesulfonate (850.0 mg, 2.31 mmol) and potassium acetate (453.0 mg, 4.62 mmol) in a flask.1,4-dioxane (8 mL) was added by injector to the mixture. The flask was degassed and purged with N ₂ gas for four times. The mixture was stirred at 100 °C for 2 h under N ₂ atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove the solvent, then the product was purified by reversed-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. Intermediate G55 [2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol- 4-yl]phenyl]boronic acid Intermediate 55 Step 1: [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyraz ol-3-yl]methoxy-tert- butyl-dimethyl-silane To a solution of 4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(2-methoxyethy l)pyrazol-4-yl]- 2,3-difluoro-phenol (200.0 mg, 0.5 mmol) in DMF (5mL) 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 x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure to afford the crude product. The crude product was purified by TLC (PE: EtOAc = 3:1) to get [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyraz ol-3- yl]methoxy-tert-butyl-dimethyl-silane (220.0 mg). MS [M+H] ⁺ : 489.2. Step 2: [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyraz ol-3-yl]methanol To a solution of compound [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyraz ol-3- yl]methoxy-tert-butyl-dimethyl-silane (220.0 mg, 0.45 mmol) in DCM (5 mL) was added hydrochloric acid in MeOH (4M) (1.8 mL, 7.2 mmol). The reaction mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to afford the crude product [4-(4- benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyrazol-3-y l]methanol (170.0 mg). MS [M+H] ⁺ : 375.2. Step 3: 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-(fluoromethyl)-1-(2-me thoxyethyl)pyrazole To a solution of [4-(4-benzyloxy-2,3-difluoro-phenyl)-1-(2-methoxyethyl)pyraz ol-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 N2. This reaction mixture was stirred at -60 °C for 1 h. This reaction was quenched by NaHCO ₃ (20 mL) and was extracted by EtOAc (10 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get the crude product. The crude product was purified by TLC (PE: EtOAc = 1:1) to get 4-(4-benzyloxy-2,3-difluoro- phenyl)-3-(fluoromethyl)-1-(2-methoxyethyl)pyrazole (130.0 mg). MS [M+H] ⁺ : 377.1. Step 4: 2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol-4 -yl]phenol 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 N ₂ . This mixture was degassed and purged with N2 for three times. Then H ₂ (15 psi) was introduced into this system. The reaction mixture was stirred at 20 °C for 2 h under H ₂ atmosphere. The mixture was filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by TLC (PE: EtOAc = 1:1) to get 2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol-4 -yl]phenol (90.0 mg). MS [M+H] ⁺ : 287.1. Step 5: [2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol- 4-yl]phenyl] trifluoromethanesulfonate 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 N ₂ for three times. Then trifluoromethanesulfonic anhydride (0.07 mL, 0.44 mmol) was added into the mixture at 0 °C. The reaction mixture was stirred at 20 °C for 2 h under N ₂ atmosphere. This reaction was quenched by NaHCO ₃ (10 mL) and was extracted by DCM (10 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get 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. Step 6: [2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol- 4-yl]phenyl]boronic acid 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 N2 for three times. Then tris(dibenzylideneacetone)dipalladium (28.46 mg, 0.03 mmol) was added into the mixture. The reaction mixture was stirred at 100 °C for 2 h under N2 atmosphere. This reaction was filtered and concentrated to get the crude product. The crude product was purified by TLC (PE: EtOAc = 3:1) to get [2,3-difluoro-4-[3-(fluoromethyl)-1-(2-methoxyethyl)pyrazol- 4-yl]phenyl]boronic acid (70.0 mg). MS [M+H] ⁺ : 315.1. Intermediate G56 [4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-ph enyl]boronic acid Intermediate G56 Step 1: 3-chloro-1-(2-methoxyethyl)pyrazole 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 for three times. Then 1-bromo-2- methoxy-ethane (12.37 mL, 131.68 mmol) was added into the mixture. The reaction mixture was stirred at 80 °C for 16 h under N ₂ atmosphere. The mixture was filtered and concentrated under reduced pressure to afford the crude product. The crude product was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel chromatography, to get 3-chloro-1-(2-methoxyethyl)pyrazole (6.5 g) as yellow oil. MS [M+H] ⁺ : 161.1. Step 2: 4-bromo-3-chloro-1-(2-methoxyethyl)pyrazole 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. This reaction was quenched by Na ₂ SO3 (40 mL) and was extracted by EtOAc (40 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get the crude product 4-bromo-3-chloro-1-(2-methoxyethyl)pyrazole (1.8 g). MS ([M+H] ⁺ /[M+2+H] ⁺ ): 239.0/241.0. Step 3: 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-chloro-1-(2-methoxyeth yl)pyrazole A mixture of 4-bromo-3-chloro-1-(2-methoxyethyl)pyrazole (1.8 g, 7.52 mmol), 2-(4-benzyloxy- 2,3-difluoro-phenyl)-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 N2 for three times. Then [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (274.97 mg, 0.38 mmol) was added dropwise into the mixture. The reaction mixture was stirred at 80 °C for 9 h under N2 atmosphere. The mixture was filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 10:1~2:1) to get 4-(4-benzyloxy-2,3- difluoro-phenyl)-3-chloro-1-(2-methoxyethyl)pyrazole (1.7 g). MS [M+H] ⁺ : 379.1. Step 4: 4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phe nol To a solution of 4-(4-benzyloxy-2,3-difluoro-phenyl)-3-chloro-1-(2-methoxyeth yl)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 Ar2. This mixture was degassed and purged with Ar2 for 3 times. Then H ₂ (15 psi) was introduced into this system. The reaction mixture was stirred at 20 °C for 6 h under H ₂ atmosphere. This reaction was filtered carefully and concentrated to get the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 4:1~1:1) to get 4-[3- chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phenol (2.4 g). MS [M+H] ⁺ : 289.1. Step 5: [4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-ph enyl] trifluoromethanesulfonate A mixture of 4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-phe nol (500.0 mg, 1.73 mmol) and pyridine (0.28 mL, 3.46 mmol) in DCM (5 mL) was degassed and purged with N ₂ for 3 times. Then trifluoromethanesulfonic anhydride (0.4 mL, 2.42 mmol) was added into the mixture at 0 °C. The reaction mixture was stirred at 20 °C for 2 h under N2 atmosphere. This reaction was quenched by NaHCO ₃ (10 mL) and was extracted by DCM (10 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get the crude product [4- [3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-pheny l] trifluoromethanesulfonate (750.0 mg). MS [M+H] ⁺ : 421.0. Step 6: [4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-ph enyl]boronic acid A mixture of [4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-ph enyl] 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 ₂ for 3 times. Then tris(dibenzylideneacetone)dipalladium (0) (97.94 mg, 0.11 mmol) was added into the mixture. The reaction mixture was stirred at 90 °C for 2 h under N2 atmosphere. This reaction was filtered and concentrated to get the crude product. The crude product was purified by TLC (PE: EA= 3:1) to get [4-[3-chloro-1-(2-methoxyethyl)pyrazol-4-yl]-2,3-difluoro-ph enyl]boronic acid (450.0 mg). MS [M+H] ⁺ : 317.0. The following examples were prepared in analogy to Intermediate G54 Intermediate G58 [2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trimethylsilylethoxymeth yl)pyrazol-4-yl]phenyl]boronic acid ^{Step 1 Step 2} _{Step 3} S ^{tep 4} Step 5 _{Step 6} Intermediate G58 Step 1: 2-(4-bromo-1H-pyrazol-5-yl)pyridine To a solution of 2-(1H-pyrazol-5-yl)pyridine (3.0 g, 20.7 mmol) in acetic acid (20 mL) was added and bromine (3.6 g, 22.7 mmol), the mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated, the residue was diluted with 20 mL of water, the solution was added to the solution of NaOH in water (30 mL, 1 M), the precipitate was filtered off and dried in vacuum to give 2-(4-bromo-1H-pyrazol-5-yl)pyridine (4.6 g). MS [M+H] ⁺ : 223.9. Step2: 2-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5 -yl)pyridine 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), the mixture was stirred at 70 °C for 1 h. The mixture was filtered off, the filtrate was concentrated, the residue was purified by prep-HPLC to give 2-[[4-bromo-5-(2- pyridyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (3.82 g). MS [M+H] ⁺ : 354.0. Step 3: 2-(4-(4-(benzyloxy)-2,3-difluorophenyl)-1-((2-(trimethylsily l)ethoxy)methyl)-1H- pyrazol-5-yl)pyridine To a solution of 2-[[4-bromo-5-(2-pyridyl)pyrazol-1-yl]methoxy]ethyl-trimethy l-silane (1.0 g, 2.82 mmol) in 1,4-dioxane (10 mL) was added 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) in glove box, the mixture was stirred at 100 °C for 16 h under Ar ₂ . The mixture was diluted with 10 mL of ethyl acetate and filtered off, the filtrated was concentrated, 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. Step 4: 2,3-difluoro-4-(5-(pyridin-2-yl)-1-((2-(trimethylsilyl)ethox y)methyl)-1H-pyrazol-4- yl)phenol 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, then the mixture was flashed with H ₂ and stirred with a H ₂ balloon at 20 °C for 2 h. The mixture was filtered off, 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. Step 5: 2,3-difluoro-4-(5-(pyridin-2-yl)-1-((2-(trimethylsilyl)ethox y)methyl)-1H-pyrazol-4- yl)phenyl trifluoromethanesulfonate To solution of 2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trimethylsilylethoxymethy l)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) at 0 °C under N ₂ . The mixture was stirred at 20 °C for 0.5 h. the mixture was diluted with 50 mL of ethyl acetate, washed with 20 mL of water and 20 mL of brine, the organic layer was dried over Na ₂ SO ₄ 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. Step 6 : (2,3-difluoro-4-(5-(pyridin-2-yl)-1-((2-(trimethylsilyl)etho xy)methyl)-1H-pyrazol-4- yl)phenyl)boronic acid To a solution of [2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trimethylsilylethoxymeth yl)pyrazol-4- yl]phenyl] trifluoromethanesulfonate (350.0 mg, 0.65 mmol) in 1,4-dioxane (2.0 mL) was added 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) in glove box. The mixture was stirred at 100 °C for 8 h. The mixture was filtered off, the filtrate was concentrated, the residue was purified by Prep-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. Intermediate G59 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)phenyl]-5-(4- methoxyphenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane Intermediate G59 Step 1: 2-[(4-bromopyrazol-1-yl)methoxy]ethyl-trimethyl-silane To a solution of 4-bromo-1H-pyrazole (20.0 g, 136.08 mmol) in THF (500 mL) was added sodium hydride, 60% in oil (6.5 g, 163.3 mmol) slowly at 0 ºC. After addition, this reaction mixture was stirred at 0 ºC for 1 h. Then 2-(trimethylsilyl)ethoxymethyl chloride (36.1 mL, 204.12 mmol) was added into this mixture slowly at 0 ºC. This reaction mixture was warmed to 20 °C and stirred for 15 h. This reaction was quenched by saturated aqueous NH4Cl (50 mL) and extracted by EtOAc (50 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get 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 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) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.3 g, 1.8 mmol) in one portion under N ₂ . This reaction mixture was stirred at 100 °C for 4 h. and the filtrate was concentrated to get the residue. This residue was diluted with EtOAc (200 mL) and was washed by brine (50 mL x 2). The organic layer was dried over Na ₂ SO ₄ and concentrated to get the crude product. This crude product was purified by silica gel chromatography (PE: EtOAc = 5:1~1;1) to get 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)pyrazol-1-yl]methoxy] ethyl-trimethyl-silane (10.0 g). MS [M+H] ⁺ : 417.2. Step 3: 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-5-bromo-pyrazol-1-yl ]methoxy]ethyl- trimethyl-silane 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. This reaction mixture was stirred at 80 °C for 16 h. This reaction was quenched by saturated aqueous Na ₂ SO ₃ (100 mL) and extracted by EtOAc (50 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get the crude product. This crude product was purified by Prep-HPLC to get 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. Step 4: 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-5-(4-methoxyphenyl)p yrazol-1- yl]methoxy]ethyl-trimethyl-silane 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) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (59.1 mg, 0.08 mmol) in one portion under N ₂ . This reaction mixture was stirred at 100 °C for 4 h. This reaction mixture was filtered, and the filtrate was concentrated to get the residue. This residue was diluted with EtOAc (50 mL) and was washed by brine (10 mL x 2). The organic phase was dried over Na ₂ SO ₄ and concentrated to get the crude product. This crude product was purified by silica gel chromatography to get 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-5-(4-methoxyphenyl)p yrazol-1- yl]methoxy]ethyl-trimethyl-silane (330.0 mg). MS [M+H] ⁺ : 523.2. Step 5: 2,3-difluoro-4-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethox ymethyl)pyrazol-4- yl]phenol To a solution of 2-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-5-(4-methoxyphenyl)p yrazol-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. Then H ₂ (15 psi) was introduced into this system. This reaction mixture was stirred at 20 °C for 16 h. This reaction mixture was filtered, and the filtrate was concentrated to get 2,3-difluoro-4-[5-(4-methoxyphenyl)-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]phenol (230.0 mg, 0.53 mmol), which would be used in the next step directly without further purification. MS [M+H] ⁺ : 433.2. Step 6: [2,3-difluoro-4-[5-(4-methoxyphenyl)-1-(2-trimethylsilyletho xymethyl)pyrazol-4- yl]phenyl] trifluoromethanesulfonate To a solution of 2,3-difluoro-4-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethox ymethyl) 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 ºC. Then reaction mixture was warmed to 20 °C and stirred for 2 h. This reaction was quenched by saturated aqueous Na ₂ CO ₃ (10 mL) and extracted by DCM (10 mL x 2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get [2,3-difluoro-4-[5-(4-methoxyphenyl)-1- (2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl] trifluoromethanesulfonate (320.0 mg). MS [M+H] ⁺ : 565.0. Step 7: 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)phenyl]-5-(4- methoxyphenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane To a solution of [2,3-difluoro-4-[5-(4-methoxyphenyl)-1-(2-trimethylsilyletho xymethyl) 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) was added X-PHOS (27.0 mg, 0.06 mmol) and tris(dibenzylideneacetone)dipalladium (0) (51.9 mg, 0.06 mmol) in one portion under N2. This reaction mixture was stirred at 100 °C for 2 h. This reaction mixture was filtered, and the filtrate was concentrated to get the crude product. This crude product was purified by silica gel chromatography to get 2-[[4-[2,3-difluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(4-me thoxyphenyl)pyrazol-1- yl]methoxy]ethyl-trimethyl-silane (250.0 mg, 0.46 mmol). MS [M+H] ⁺ : 543.3. The following examples were prepared in analogy to Intermediate G59

Intermediate G70 tert-butyl N-[6-[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)phenyl]-3- methyl-pyrazol-1-yl]-3-pyridyl]carbamate Intermediate G70 Step 1: 2-(4-bromo-3-methyl-1H-pyrazol-1-yl)-5-nitropyridine To a solution of 4-bromo-3-methyl-1H-pyrazole (2.5g, 15.53 mmol) in DMF (100 mL) was added sodium hydride (750.0 mg, 18.75 mmol) at 0 °C portionwise under N ₂ , after the addition was complete, the mixture was stirred at 0 °C for 0.5 h. Then 2-chloro-5-nitropyridine (2.5 g, 15.77 mmol) was added to the above mixture at 0 °C and the resultant mixture was warmed to 20 °C gradually and stirred for 11.5 h. Then the mixture was quenched with saturated NH ₄ Cl (800 mL), filtered, the filter cake was washed with ACN (50 mL), dried under vacuum to afford 2-(4- bromo-3-methyl-pyrazol-1-yl)-5-nitro-pyridine (3.8 g). MS [M+H] ⁺ : 283.0. Step 2: 6-(4-bromo-3-methyl-1H-pyrazol-1-yl)pyridin-3-amine 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) was added Fe powder (2.5 g, 44.29 mmol) at 20 °C under N2, the resultant mixture was stirred at 80 °C for 3 h under N ₂ . TLC (PE: EA =1: 1) indicated the desired product was formed. After the reaction mixture was cooled down to 20 °C, the mixture was added saturated NaHCO ₃ (60 mL), extracted with brine (150 mL) and EtOAc (120 mL x 3). The combined organics were dried over Na ₂ SO ₄ , filtered, concentrated in vacuo to afford 6-(4-bromo-3-methyl-pyrazol-1-yl)pyridin-3-amine (3.2 g). Step 3: tert-butyl (6-(4-bromo-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)carbamate( 4) To a solution of afford 6-(4-bromo-3-methyl-pyrazol-1-yl)pyridin-3-amine (3.2 g, 12.64 mmol) and Boc ₂ O (5.5 g, 25.30 mmol) in methanol (50 mL) was added triethylamine (3.5 mL, 25.29 mmol), the resultant mixture was stirred at 20 °C for 14 h. Then the mixture was concentrated in vacuum to give a residue, which was purified by HPLC and evaporated under vacuum to afford tert-butyl N-[6-(4-bromo-3-methyl-pyrazol-1-yl)-3-pyridyl]carbamate (2.8 g). MS [M+H] ⁺ : 353.0. Step 4: tert-butyl (6-(4-(4-(benzyloxy)-2,3-difluorophenyl)-3-methyl-1H-pyrazol -1- yl)pyridin-3-yl)carbamate 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 (1.5g, 4.33 mmol) and potassium carbonate (800.0 mg, 5.79 mmol) in 1,4-dioxane (25 mL) and water (5.0 mL) was added Pd(dppf)Cl ₂ (207.0 mg, 0.28 mmol) under N ₂ at 20 °C, then the mixture was stirred at 85 °C for 15 h under N ₂ . After the mixture was cooled down to 20 °C, the mixture was filtered through celite, the filtrate was extracted with brine (200 mL) and EtOAc (100 mL x 3). The combined organics were dried over Na ₂ SO ₄ , filtered, concentrated in vacuum to give a residue, which was purified by HPLC and evaporated under vacuum to afford tert-butyl N-[6-[4- (4-benzyloxy-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]-3-p yridyl]carbamate (1.1 g) as yellow solid. MS [M+H] ⁺ : 493.1. Step 5: tert-butyl (6-(4-(2,3-difluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazol-1-y l)pyridin-3- yl)carbamate 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) at 20 °C under H ₂ , the resultant mixture was stirred at 20 °C for 12 h under a balloon of H ₂ . Then the mixture was filtered through celite, the filtrate was concentrated in vacuum to afford tert-butyl N-[6-[4-(2,3-difluoro-4-hydroxy-phenyl)-3-methyl-pyrazol-1-y l]- 3-pyridyl]carbamate (325.0 mg). MS [M+H] ⁺ : 403.1. Step 6: 4-(1-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-3-methyl-1 H-pyrazol-4-yl)-2,3- difluorophenyl trifluoromethanesulfonate To a solution of tert-butyl N-[6-[4-(2,3-difluoro-4-hydroxy-phenyl)-3-methyl-pyrazol-1-y l]-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, the resultant mixture was stirred at 20 °C for 2 h. Then the mixture was extracted with saturated NH4Cl (70.0 mL) and EtOAc (60 mL x 3). The combined organics were dried over Na ₂ SO ₄ , filtered, concentrated in vacuo to afford [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. Step 7: tert-butyl (6-(4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)phenyl)- 3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)carbamate To a solution of [4-[1-[5-(tert-butoxycarbonylamino)-2-pyridyl]-3-methyl-pyra zol-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 ₂ (42.0 mg, 0.06 mmol) at 20 °C under N2, the resultant mixture was stirred at 100 °C for 14 h under N2. After the mixture was cooled down, filtered through celite, the filtrate was concentrated in vacuum to give a residue, which was purified by prep-HPLC (FA) and concentrated under vacuum to afford 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. The following examples were prepared in analogy to Intermediate G70

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 Intermediate G75 Step 1: 6-bromo-2-fluoropyridin-3-ol To a solution of 2-fluoropyridin-3-ol (2.0 g, 17.69 mmol) in acetic acid (20.0 mL) was added sodium acetate (1.3 mL, 17.69 mmol), after the solid was dissolved, bromine (2.8 g, 17.69 mmol) was added by drops at 0 °C. The mixture was stirred at 20 °C for 3 h.1 g of sodium sulfite was added to the reaction mixture, then the mixture was concentrated. The residue was diluted with 20 mL of water and neutralized with 2 M NaOH solution, the solid was filtered off and dried in vacuum to give 6-bromo-2-fluoro-pyridin-3-ol (1.8 g). MS [M+H] ⁺ : 191.9. Step 2: 3-(benzyloxy)-6-bromo-2-fluoropyridine 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, the mixture was stirred at 20 °C for 16 h. The mixture was quenched with 30 mL of NH ₄ Cl water solution at 0 °C, then the mixture was extracted with ethyl acetate (30 mL x 3), the organic layer was concentrated, the residue was purified by Prep- HPLC to give 3-benzyloxy-6-bromo-2-fluoro-pyridine (1.7 g). MS [M+H] ⁺ : 281.9. Step 3: 3-(benzyloxy)-2-fluoro-6-(1-((2-(trimethylsilyl)ethoxy)methy l)-1H-pyrazol-4- yl)pyridine 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), K ₂ CO ₃ (1.1 g, 10.63 mmol) in glovebox, the mixture was stirred at 60 °C for 16 h under Ar2. The mixture was filtered off, the filtrate was concentrated, the residue was purified by silica gel column to give 2-[[4-(5- benzyloxy-6-fluoro-2-pyridyl)pyrazol-1-yl]methoxy]ethyl-trim ethyl-silane (1.55 g) as a yellow solid. MS [M+H] ⁺ : 400.1. Step 4: 3-(benzyloxy)-6-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-pyrazol-4-yl)-2- fluoropyridine To a solution of 2-[[4-(5-benzyloxy-6-fluoro-2-pyridyl)pyrazol-1-yl]methoxy]e thyl-trimethyl- silane (1.5 g, 3.75 mmol) in DMF (15 mL) was added NBS (1.34 g, 7.51 mmol), the mixture was stirred at 60 °C for 16 h. The mixture was purified by Prep-HPLC to give 2-[[4-(5-benzyloxy-6- fluoro-2-pyridyl)-5-bromo-pyrazol-1-yl]methoxy]ethyl-trimeth yl-silane (800.0 mg). MS [M+H] ⁺ : 478.1. Step 5: 3-(benzyloxy)-2-fluoro-6-(5-(4-methoxyphenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridine 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) was 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), K2CO ₃ (518.4 mg, 4.89 mmol) in glovebox, the mixture was stirred at 60 °C for 4 h under Ar2. The mixture was filtered off, the filtrate was concentrated, the residue was purified by silica gel column to give 2-[[4-(5- benzyloxy-6-fluoro-2-pyridyl)-5-(4-methoxyphenyl)pyrazol-1-y l]methoxy]ethyl-trimethyl-silane (550.0 mg). MS [M+H] ⁺ : 506.2. Step 6: 2-fluoro-6-(5-(4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1H-pyrazol-4- yl)pyridin-3-ol A mixture of 2-[[4-(5-benzyloxy-6-fluoro-2-pyridyl)-5-(4-methoxyphenyl)py razol-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, then the miture flushed with H ₂ and stirred with a H ₂ balloon for 6 h at 15 °C. The mixture was filtered off, 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. Step 7: tert-butyl 2-fluoro-6-(5-(4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1H- pyrazol-4-yl)pyridin-3-yl trifluoromethanesulfonate A mixture of 2-fluoro-6-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethoxymet hyl)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, then the mixture was stirred at 15 °C for 1 h. The mixture was diluted with 50 mL of ethyl acetate, washed with 30 mL of water and 30 mL of brine. The organic layer was dried over Na ₂ SO ₄ 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. 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 To a solution of [2-fluoro-6-[5-(4-methoxyphenyl)-1-(2-trimethylsilylethoxyme thyl)pyrazol-4- yl]-3-pyridyl] trifluoromethanesulfonate (560.0 mg, 1.02 mmol) in 1,4-dioxane (1.0 mL) was added 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) in glovebox, the mixture was stirred at 90 °C for 16 h. The mixture was filtered off, the filtrate was concentrated, the residue was purified by Prep-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. Intermediate G76 2-[2-[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)phenyl]-3-methyl- pyrazol-1-yl]ethyl]-6-methoxy-pyridine

_{Step 1} ^{Step 2} _{Step 3} ^{Step 4 Step 5} _{Step 6} intermediate G76 Step 1 : 2-methoxy-6-vinylpyridine A mixture of 2-bromo-6-methoxy-pyridine (6.5 mL, 53.19 mmol) and potassium;trifluoro(vinyl)boranuide (8.6 g, 63.82 mmol) in 1,4-dioxane (120 mL) was added [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 glove box. The mixture was stirred at 100 °C for 16 h under Ar. The mixture was distilled in vacuum, the collector was cooled with dry ice, the distillment was added 20 mL of HCl /1,4-dioxane (4 M), stirred at 60 °C for 2 h, then the mixture was concentrated to give 2-methoxy-6-vinyl-pyridine;hydrochloride (2.6 g) as a yellow gum. MS [M+H] ⁺ : 136.1. Step 2: 2-(2-(4-bromo-3-methyl-1H-pyrazol-1-yl)ethyl)-6-methoxypyrid ine 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) the mixture was stirred at 80 °C for 12 h. The mixture was filtered off, the filtrate was purified by Prep-HPLC (TFA as 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. Step 3: 2-(2-(4-(4-(benzyloxy)-2,3-difluorophenyl)-3-methyl-1H-pyraz ol-1-yl)ethyl)-6- methoxypyridine To a solution of 2-[2-(4-bromo-3-methyl-pyrazol-1-yl) ethyl]-6-methoxy-pyridine (2.2 g, 6.36 mmol), Pd(dppf)2Cl ₂ (0.9 g, 0.70 mmol), 2-(4-benzyloxy-2,3-difluoro-phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane(1.8 g, 6.08 mmol) and K ₂ CO ₃ (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 by vacuum, the residue was purified by column and dried by vacuum to obtain 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 off-white solid. MS [M+H] ⁺ : 435.9. Step 4: 2,3-difluoro-4-(1-(2-(6-methoxypyridin-2-yl)ethyl)-3-methyl- 1H-pyrazol-4-yl)phenol 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 h. It was filtered and dried by vacuum to get 2,3-difluoro-4-[1-[2-(6-methoxy-2- pyridyl)ethyl]-3-methyl-pyrazol-4-yl]phenol (560.0 mg) as off-white solid. MS [M+H] ⁺ : 345.8. Step 5: 2,3-difluoro-4-(1-(2-(6-methoxypyridin-2-yl)ethyl)-3-methyl- 1H-pyrazol-4-yl)phenyl trifluoromethanesulfonate A mixture of 2,3-difluoro-4-[1-[2-(6-methoxy-2-pyridyl)ethyl]-3-methyl-py razol-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, it was stirred at 0 °C for 2 h. The reaction mixture was poured into ice-water (50 mL), extracted by EA (50 mL), and dried by Na ₂ SO ₄ , the organic phase was concentrated under reduced pressure to obtian [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 light yellow gum. MS [M+H] ⁺ : 478.1. Step 6: 2-(2-(4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)phenyl)-3- methyl-1H-pyrazol-1-yl)ethyl)-6-methoxypyridine A mixture of [2,3-difluoro-4-[1-[2-(6-methoxy-2-pyridyl)ethyl]-3-methyl-p yrazol-4-yl]phenyl] trifluoromethanesulfonate (600.0 mg, 2.36 mmol), bis(pinacolato)diboron (800.0 mg, 1.68 mmol), Pd(dppf)Cl ₂ (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 Prep-HPLC (FA) to obtain 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. Intermediate G78 2-[[4-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-2-yl)phenyl]-3-methyl- pyrazol-1-yl]methyl]triazol-1-yl]methoxy]ethyl-trimethyl-sil ane Intermediate G78 Step 1 : 4-bromo-3-methyl-1-prop-2-ynyl-pyrazole A mixture of propargyl bromide (11.1 g, 93.17 mmol) in NMP (100.0 mL) was addded 4-bromo- 3-methyl-1H-pyrazole(10.0 g, 62.11 mmol) and potassium carbonate (17.2 g, 124.22 mmol), The mixture was stirred at 100 °C for 16 h. This reaction mixture was poured into water(300 mL) and EtOAc (200 mL) and was washed by brine (200 mL x 2). The organic layer was dried over Na ₂ SO ₄ and concentrated to give crude product which was further purified by prep-HPLC(FA) to get the mixture of 4-bromo-3-methyl-1-prop-2-ynyl-pyrazole (2) (8.0 g). MS [M+H] ⁺ : 198.7. Step 2 : 4-[(4-bromo-3-methyl-pyrazol-1-yl)methyl]-1H-triazole 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. This reaction mixture was diluted with EtOAc (100 mL) and was washed by saturated aqueous Na ₂ CO ₃ (200 mL x 2). The organic layer was dried over Na ₂ SO ₄ and concentrated to give crude product which was further purified by prep-HPLC (FA) to give a mixture of isomers which was further purified by chiral separation to get 4-[(4-bromo-3-methyl-pyrazol-1-yl)methyl]-1H-triazole (1.7 g). MS [M+H] ⁺ : 242.0. Step 3 : 2-[[4-[(4-bromo-3-methyl-pyrazol-1-yl)methyl]triazol-1-yl]me thoxy]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 (20mL) was added NaH (396.6 mg, 9.91 mmol) and 2-(trimethylsilyl) ethoxymethyl chloride (1.2 mL, 6.94 mmol) at 0 °C, The mixture was stirred at 25 °C for 12 h under N2. The reaction mixture was quenched by (30 mL) NH4Cl (aq), extracted with EtOAc (80 mL x 3), the organic phase was washed with brine (50 mL x 2), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum 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. Step 4 : 2-[[4-[[4-(4-benzyloxy-2,3-difluoro-phenyl)-3-methyl-pyrazol -1-yl]methyl]triazol-1- yl]methoxy]ethyl-trimethyl-silane A mixture of 2-[[4-[(4-bromo-3-methyl-pyrazol-1-yl)methyl]triazol-1-yl]me thoxy]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), Na ₂ CO ₃ (740.1 mg, 6.98 mmol) and Pd(dppf)Cl ₂ (307.6 mg, 0.35 mmol) in a flask. The flask was degassed and purged with N ₂ gas for four times.1,4-dioxane (15.0 mL) and water (2.0 mL) was added by injector to the mixture. The mixture was stirred at 80 °C for 2 h under N2. The reaction mixture was filterrd and the filtrate was concentrated under reduced pressure to remove the solvent, then the product was purified by chromatography column flash (petroleum/EtOAc=20/1~1/1) 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. Step 5 : 2,3-difluoro-4-[3-methyl-1-[[1-(2-trimethylsilylethoxymethyl )triazol-4- yl]methyl]pyrazol-4-yl]phenol 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 with H ₂ several times at 20 °C for 2 h. The reaction mixture was filterrd 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. Step 6 : [2,3-difluoro-4-[3-methyl-1-[[1-(2-trimethylsilylethoxymethy l)triazol-4- yl]methyl]pyrazol-4-yl]phenyl] trifluoromethanesulfonate 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) under 0 ºC, The reaction was stirred at 20 °C for 2 h. The mixture was poured into ice water (20 mL) and extracted with EtOAc (50 mL x 2). The mixture was combined and washed with brine (20 mL). The organic layer was dried and concentrated under vacuum 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. Step 7 : 2-[[4-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-2-yl)phenyl]-3- methyl-pyrazol-1-yl]methyl]triazol-1-yl]methoxy]ethyl-trimet hyl-silane A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2- dioxaborolane(908.3 mg, 3.58 mmol), Pd(dppf)Cl ₂ (243.2 mg, 0.30 mmol), [2,3-difluoro-4-[3- methyl-1-[[1-(2-trimethylsilylethoxymethyl)triazol-4-yl]meth yl]pyrazol-4-yl]phenyl] trifluoromethanesulfonate (1650.0 mg, 2.98 mmol) and potassium acetate (585.1 mg, 5.96 mmol) in a flask.1,4-dioxane (20 mL) was added by injector to the mixture. The flask was degassed and purged with N2 gas for four times. The mixture was stirred at 80 °C for 2 h under N2 atmosphere. The reaction mixture was filterrd and the filtrate was concentrated under reduced pressure to remove the solvent, then the product was purified by reversed-phase chromatography (FA as additive) to give 2-[[4-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-2-yl)phenyl]- 3-methyl-pyrazol-1-yl]methyl]triazol-1-yl]methoxy]ethyl-trim ethyl-silane (800.0 mg). MS [M+H] ⁺ : 532.3. Intermediate G79 [2-fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-3-pyr idyl]boronic acid _{Step 1 Step 2} ^{Step 3 Step 4} S _{tep 5} ^{Step 6} Intermediate G79 Step 1 : 6-bromo-2-fluoropyridin-3-ol 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 the solid was dissolved, bromine (3.5 g, 22.11 mmol) was added by drops at 0 °C, then the mixture was stirred at 20 °C for 3 h. The reaction mixture was poured into ice-water, it was extracted by EtOAc (2 x 200 mL). The reaction mixture was washed by 100 mL solution of sodium sulfite in water, and then organid layer was dried in vacuum to give 6-bromo-2-fluoro-pyridin-3-ol (3.15 g). MS [M+H] ⁺ : 191.6. Step 2 : 3-(benzyloxy)-6-bromo-2-fluoropyridine A solution of 6-bromo-2-fluoro-pyridin-3-ol (3.1 g, 16.15 mmol, 1.0 eq), benzyl bromide (1.95 mL, 16.37 mmol, 1.0 eq) and K ₂ CO ₃ (3.1 g, 22.43 mmol, 1.39 eq) in ACN (30 mL) was stirred at 25 °C for 12 h. The reation mixture was filtred and washed by EtOAc (100 mL), then the filter was washed by brine (2 x 200 mL), it was dried by vacuum to obtain 3-benzyloxy-6-bromo-2- fluoro-pyridine (4.1 g). MS [M+H] ⁺ : 281.6. Step 3 : 3-(benzyloxy)-2-fluoro-6-(1-(2-methoxyethyl)-5-methyl-1H-pyr azol-4-yl)pyridine To a solution of 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-dioxabor olan-2-yl)pyrazole (1.0 g, 3.76 mmol) in 1,4-dioxane (10 mL) and water (3 mL) was added Pd(dppf)Cl ₂ (300.0 mg, 0.37 mmol) and Na ₂ CO ₃ (0.8 g, 7.55 mmol). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was purified by Pre-HPLC (FA as additive) and dried by vacuum to obtain 3-benzyloxy-2-fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol- 4-yl]pyridine (340 mg). MS [M+H] ⁺ : 342.1. Step 4 : 2-fluoro-6-(1-(2-methoxyethyl)-5-methyl-1H-pyrazol-4-yl)pyri din-3-ol 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 at 25 °C for 12 h under H ₂ balloon. The reaction mixture was filtered and it was dried by vacuum to obtain 2- fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]pyridin-3 -ol (236.0 mg). MS [M+H] ⁺ : 251.8. Step 5 : 2-fluoro-6-(1-(2-methoxyethyl)-5-methyl-1H-pyrazol-4-yl)pyri din-3-yl trifluoromethanesulfonate 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, The reaction mixture was stirred at 0 °C for 2 h. This reaction mixture was poured into ice-water (50 mL), it was extracted by EA (50 mL), organic layer was dried over Na ₂ SO ₄ , filtered and then 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. Step 6 : [2-fluoro-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-3-pyr idyl]boronic acid A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-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 ₂ (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 mxiture was purified by Pre-HPLC (FA) and dried by vacuum to obtain [2-fluoro-6-[1- (2-methoxyethyl)-5-methyl-pyrazol-4-yl]-3-pyridyl]boronic acid (126.0 mg). MS [M+H] ⁺ : 279.8. The following examples were prepared in analogy to Intermediate G79

Intermediate G86 ^{Step 1} _{Step 2 Step 3 Step 4} S ^{tep 5 Step 6} _{Step 7} Intermediate G86 Step 1: (6-bromo-3-pyridyl)-[3-[tert-butyl(dimethyl)silyl]oxypropyl] amine (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). To this solution was added sodium triacetoxyborohydride (3.6 g, 16.99 mmol) portionwise. The mixture was stirred at rt for 1 h after addition. The mixture was poured into 100 mL water and extracted with DCM (50 mL x 2). The extracts were combined, washed with brine and dried over sodium sulfate. The solvent was removed in vacuum and the residue was purified by flash chromatography (silica gel; EtOAc:PE = 0:1 to 1:1). To afford (6-bromo-3-pyridyl)-[3-[tert-butyl(dimethyl)silyl]oxypropyl] amine (3 g). MS [M+H] ⁺ : 345.6. Step 2: N-(6-bromo-3-pyridyl)-N-(3-hydroxypropyl)carbamic acid 9H-fluoren-9-ylmethyl ester (6-bromo-3-pyridyl)-[3-[tert-butyl(dimethyl)silyl]oxypropyl] amine (3.00 g, 8.69 mmol) was dissolved in 5 mL toluene and this solution was added dropwise to a solution of chlorocarbonic acid 9H-fluoren-9-ylmethyl ester (2.25 g, 8.69 mmol) in anhydrous toluene, extra dry (20 mL) at 0 °C. After addition, the mixture was stirred at 0 °C for 1 h and then at rt for another 1 h. yellow precipitate formed. The mixture was left overnight. The solvent was removed in vacuum, and the residue was purified by flash chromatography (silica gel; EtOAc:PE = 0:1 to 1:0). To afford N- (6-bromo-3-pyridyl)-N-(3-hydroxypropyl)carbamic acid 9H-fluoren-9-ylmethyl ester (2 g). MS [M+H] ⁺ : 453.1. Step 3: 3-[(6-bromo-3-pyridyl)-(9H-fluoren-9-ylmethoxycarbonyl)amino ]propionic acid 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 to this mixture was added acetonitrile (10.99 mL) and water (5.99 mL). The reaction mixtures were stirred for 3 h before another batch of iodobenzene diacetate (703.41 mg, 2.18 mmol) was added. The stirring was continued 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 afford 3-[(6-bromo-3-pyridyl)-(9H-fluoren-9- ylmethoxycarbonyl)amino]propionic acid (778 mg). MS [M+H] ⁺ : 467.1. Step 4: N-(3-amino-3-keto-propyl)-N-(6-bromo-3-pyridyl)carbamic acid 9H-fluoren-9- ylmethyl ester 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 min. HATU (751.82 mg, 1.98 mmol) was added to the mixture, and the resulting solution was stirred at 25 °C for 1 h. The mixture was poured into 100 mL water and extracted with EtOAc (50 mL x 3). The extracts were combined, washed with 50 mL brine, dried over sodium sulfate and concentrated in vacuum. The residue was purified by flash chromatography (silica gel; EtOAc:PE = 0:1 to 1:0), to afford N-(3-amino-3-keto-propyl)- N-(6-bromo-3-pyridyl)carbamic acid 9H-fluoren-9-ylmethyl ester (725mg). MS [M+H] ⁺ : 466.2. Step 5: N-(3-amino-3-keto-propyl)-N-[6-(2,3-difluoro-4-hydroxy-pheny l)-3- pyridyl]carbamic acid 9H-fluoren-9-ylmethyl ester In a microwave tube were placed N-(3-amino-3-keto-propyl)-N-(6-bromo-3-pyridyl)carbamic acid 9H-fluoren-9-ylmethyl ester (400 mg, 0.858 mmol), palladiumtetrakis (99.12 mg, 0.086 mmol), Na ₂ CO ₃ (272.74 mg, 2.57 mmol) and (2,3-difluoro-4-hydroxy-phenyl)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, evacuated and backfilled with nitrogen for 5 times. The mixture was then heated at 100 °C for 0.5 h. The mixture was cooled to rt, 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 afford N-(3-amino-3-keto-propyl)-N-[6-(2,3-difluoro-4-hydroxy-pheny l)-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 N-(3-amino-3-keto-propyl)-N-[6-(2,3-difluoro-4-hydroxy-pheny l)-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 dichloromethane, extra dry (3.3 mL). Tf ₂ O (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 afford 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. Step 7: N-(3-amino-3-keto-propyl)-N-[6-[2,3-difluoro-4-(4,4,5,5-tetr amethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-pyridyl]carbamic acid 9H-fluoren-9-ylmethyl ester trifluoromethanesulfonic acid [4-[5-[(3-amino-3-keto-propyl)-(9H-fluoren-9- ylmethoxycarbonyl)amino]-2-pyridyl]-2,3-difluoro-phenyl] 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 1,4-dioxane, extra dry (3.61 mL) in a microwave tube. The tube was sealed with a rubber septum, evacuated and backfilled with nitrogen for 5 times. The mixture was heated at 100°C for 1 h. The mixture was cooled to rt and absorbed to 100-200 mesh silica gel. The loaded sample was purified by flash chromatography (silica gel; MeOH:DCM = 0:1 to 1:10), to afford N-(3-amino-3-keto-propyl)-N-[6-[2,3-difluoro-4-(4,4,5,5-tetr amethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-pyridyl]carbamic acid 9H-fluoren-9-ylmethyl ester (90 mg). MS [M+H] ⁺ : 648.3. The following examples were prepared in analogy to Intermediate G86

Intermediate H1 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[2,3-difluoro-4- [1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-i midazole-2-carboxamide Intermediate G2 step 1 Intermediate D1 step 2 Intermediate H1 Step 1: tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-m ethyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azine-1- carbonyl]piperidine-1-carboxylate 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]piper idine-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 Na ₂ CO ₃ (89.7 mg, 846 µmol) in 1,4-Dioxane (15 mL) / Water (1.5 mL). The vial was capped and heated in the microwave at 100 ºC for 3 h under N ₂ . The reaction mixture was filtered through glass fiber paper. The filtrate was concentrated in vacuum. The crude material was purified by flash chromatography to afford tert-butyl 4-[4-[2- chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-py razol-4-yl]phenyl]-1-methyl- imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]pip eridine-1-carboxylate (150 mg). MS [M+H] ⁺ : 809.5. Step 2: N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[2,3- difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl] -1-methyl-imidazole-2- carboxamide In a 50 mL round-bottomed flask, tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2- methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-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. HCl water solution (1.24 mL, 14.8 mmol) was added. The reaction was stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum. The crude product was directly used to the next step to afford N-[3- chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phe nyl]-5-[2,3-difluoro-4-[1-(2- methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide (131 mg). MS [M+H] ⁺ : 709.3. The following intermediates were prepared in analogy to Intermediate H1

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 Intermediate G3 Step 1 Intermediate B1 Step 2 Intermediate I1 Step 1: tert-butyl 4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-meth yl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azine-1-carboxylate In a 100 mL round-bottomed 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)phen yl)-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 Na ₂ CO ₃ (90.5 mg, 854 µmol) were combined with dioxane (10 mL) /Water (1 mL) to give a dark red solution. The reaction mixture was heated to 100 °C and stirred for 15 h under N2. The crude reaction mixture was concentrated in vacuum. The crude product was directly used to the next step to afford tert-butyl 4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazine-1-carboxylate (160 mg). MS [M+H] ⁺ : 698.2. 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-imidazo le-2-carboxamide In a 50 mL round-bottomed flask, tert-butyl 4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazine-1-carboxylate (160 mg, 229 µmol) was combined with THF (2 mL) to give a light brown solution. HCl water solution (1.15 ml, 13.8 mmol) was added. The reaction was stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum. The crude product was directly used to the next step, To afford N-[3-chloro-4- (piperazine-1-carbonyl)phenyl]-5-[2,3-difluoro-4-[1-(2-metho xyethyl)-5-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide (137 mg). MS [M+H] ⁺ : 598.1. The following intermediates were prepared in analogy to Intermediate I1

Intermediate J1 N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbo nyl]phenyl]-1-methyl-5-[4- [3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]pheny l]imidazole-2-carboxamide Intermediate G8 I ^{ntermediate D3} _{Intermediate J1} Under N2 protection,a mixture 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 (400mg, 782 µmol), Na ₂ CO ₃ (249 mg, 2.34 mmol) and 1,1-bis(di-tert- butylphosphino)ferrocene palladium 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. Then the mixture was filtered and concentrated in vacuum. The crude product was purified by flash column to afford 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-c arboxamide (50 mg) as a yellow solid. MS [M+H] ⁺ : 719.2. The following examples were prepared in analogy to Intermediate J1

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

Step 1 Intermediate I2 DCM, TFA Step 2 Intermediate K1 Step 1: tert-butyl (2S,4R)-2-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyet hyl)-3-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]piperazine-1- carbonyl]-4-hydroxy-pyrrolidine-1-carboxylate At room temperature, 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 for 16 h. Then the mixture was poured into water. The water layer was extracted with DCM. The combined organic layers were washed with water and concentrated in vacuum. The residue was purified by flash column to afford tert-butyl (2S,4R)-2- [4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-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. Step 2: N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]pi perazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide At room temperature, 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-imidazo le-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-hydroxy-pyrr olidine-1-carboxylate (310 mg, 382 µmol) in DCM (10 mL) and TFA (5 mL) was stirred for 1 h. Then the mixture was concentrated in vacuum. The residue was basified by NH ₃ .H ₂ O to PH 8-9. The water layer was extracted with DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum to afford the 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. The following examples were prepared in analogy to Intermediate K1

Intermediate L1 2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phe nyl]-1-methyl-imidazole-2- carbonyl]amino]benzoic acid Step 2 Intermediate G1 Step 1 Intermediate A1 Intermediate L1 Step 1: tert-butyl 2-chloro-4-[[5-[2,3-difluoro-4-[3-methyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]-1-methyl-imi dazole-2- carbonyl]amino]benzoate In a round bottomed flask were placed 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)eth oxy)methyl)-1H-pyrazole (4.29 g, 9.52 mmol), PdCl ₂ (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 backfilled with argon for 5 times. The mixture was heated at 100 °C for 18h. The reaction was cooled to room temperature and poured into 100 mL 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 afford the product (2.46 g). MS [M+H] ⁺ : 658.2. Step 2: 2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phe nyl]-1-methyl- imidazole-2-carbonyl]amino]benzoic acid tert-butyl 2-chloro-4-(5-(2,3-difluoro-4-(3-methyl-1-((2-(trimethylsily l)ethoxy)methyl)-1H- pyrazol-4-yl)phenyl)-1-methyl-1H-imidazole-2-carboxamido)ben zoate (2.45 g, 3.72 mmol) was stirred in TFA (3.72 mL) and CH ₂ Cl ₂ (14.9 mL) for 5h. The solvent was removed in vacuum and the residue was azeotroped with toluene (50 mL x 3) to give the product which was used next without further purification (1.74 g). MS [M+H] ⁺ : 472.2. The following examples were prepared in analogy to Intermediate L1

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 Intermediate L1 Intermediate M1 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-carbo xylate 1-((dimethylamino)(dimethyliminio)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)ben zoic acid (100 mg, 212 µmol) and tert-butyl piperazine-1-carboxylate (47.4 mg, 254 µmol) in DMA (4.24 mL) and stirred for 2h at room temperature. The mixture was poured into 100 mL water and extracted with EtOAc (50 mL x 4). The organic layer was washed with 50 mL brine, dried over sodium sulfate, and concentrated in vacuum. The residue was purified by flash chromatography to afford the product (105 mg). MS [M+H] ⁺ : 640.2. 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;hydroc hloride tert-butyl 4-(2-chloro-4-(5-(2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)p henyl)-1-methyl-1H- imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (1.38 g, 2.16 mmol) was dissolved in 4M HCl / MeOH (10.8 mL) solution. The solution was stirred at room temperature for 1h. The solvent was removed in vacuum 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. The following examples were prepared in analogy to Intermediate M1

Intermediate N1 and Intermediate N2 tert-butyl (1R,5S)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyet hyl)-3-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]piperazine-1- carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(Intermedia te N1) and tert-butyl (1R,5S)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyet hyl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]piperazine-1- carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(Intermedia te N2)

Step 1: tert-butyl (1S,5R)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-py razol-4- yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azine-1-carbonyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate In a 100 mL round-bottomed 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 H ₂ O and extracted with EtOAc (3 x 25 mL). The organic layers were combined, washed with sat NaCl (1 x 25 mL), The organic layers were dried over Na ₂ SO ₄ and concentrated in vacuum. The crude material was purified by flash chromatography to afford 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. Step 2: tert-butyl (1R,5S)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyet hyl)-3-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]piperazine-1- carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(Intermedia te N1) and tert-butyl (1R,5S)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyet hyl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]piperazine-1- carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(Intermedia te N2) 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-carboxyla te (330 mg, 440 µmol), 1-bromo- 2-methoxyethane (91.8 mg, 661 µmol ) and K2CO ₃ (122 mg, 881 µmol) in DMF (3 mL). The vial was capped and heated in the microwave at 70 ºC for 1 h. The reaction mixture was poured into 50 mL H ₂ O and extracted with EtOAc (3 x 25 mL). The organic layers were combined, washed with sat NaCl (1 x 25 mL), The organic layers were dried over Na ₂ SO ₄ and concentrated in vacuum. The crude material was purified by flash chromatography to afford 220mg crude product, The crude product was purified by preparative chiral-HPLC to afford tert-butyl (1R,5S)-6-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyet hyl)-3-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azine-1-carbonyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (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. Intermediate O1 2-[4-[4-[2-[[4-[4-(1-tert-butoxycarbonylpiperidine-4-carbony l)piperazine-1-carbonyl]-3- chloro-phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluor o-phenyl]-3-methyl-pyrazol- 1-yl]acetic acid Intermediate G16 step 1 Intermediate D1 step 2 Intermediate O1 Step 1: tert-butyl 4-[4-[2-chloro-4-[[5-[4-[1-(2-ethoxy-2-oxo-ethyl)-3-methyl-p yrazol-4-yl]- 2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]piperazine-1- carbonyl]piperidine-1-carboxylate A mixture of tert-butyl 4-[4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chl oro- 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), Na ₂ CO ₃ (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 N2 gas for four times.1,4-dioxane (30 mL) and water (6 mL) was added by injector to the mixture. The mixture was stirred at 90 °C for 2 h under N ₂ . The reaction mixture was filterrd and the filtrate was concentrated under reduced pressure to remove the solvent, then the product was purified by reversed-phase chromatography and dried by lyophilization 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-carb onyl]amino]benzoyl]piperazine-1- carbonyl]piperidine-1-carboxylate (2750.0 mg). MS [M+H] ⁺ : 837.3. 2-[4-[4-[2-[[4-[4-(1-tert-butoxycarbonylpiperidine-4-carbony l)piperazine-1-carbonyl]-3- chloro-phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluor o-phenyl]-3-methyl-pyrazol- 1-yl]acetic acid To a solution of tert-butyl 4-[4-[2-chloro-4-[[5-[4-[1-(2-ethoxy-2-oxo-ethyl)-3-methyl-p yrazol- 4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]ami no]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 at 20 °C for 12 h under N2. The reaction mixture was quenched by water (50 mL), extracted with EtOAc (100 x 3 mL). The combined organic layers were washed brine (50 mL), dried (Na ₂ SO ₄ ) and concentrated to give 2-[4-[4-[2-[[4-[4-(1-tert-butoxycarbonylpiperidine-4-carbony l)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. The following examples were prepared in analogy to Intermediate O1 Intermediate P1 N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]pipera zine-1-carbonyl]-3-chloro- phenyl]-5-bromo-1-methyl-imidazole-2-carboxamide intermediate D1 Intermediate P1 Step 1: 5-bromo-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1 -carbonyl]phenyl]-1- methyl-imidazole-2-carboxamide To a solution of tert-butyl 4-(4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2- chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (1.9 g, 3.0 mmol) in DCM (25 mL) and was TFA (5 mL) then the resultant mixture was stirred for 1.0 h at room temperature. The mixture was basified with aqueous ammonia to pH=9-10 and then the mixture was poured into water (50 mL) and then extracted with dichloromethane / isopropanol (100 / 10 mL), the organic layer was concentrated in vacuum 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 next step without purification. MS [M+H] ⁺ : 537.3 Step 2: N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]pipera zine-1-carbonyl]-3- chloro-phenyl]-5-bromo-1-methyl-imidazole-2-carboxamide 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) and DIPEA (1.55 g, 12 mmol) in acetonitrile (25 ml) was added 2-iodoacetamide (888 mg, 4.8 mmol) at room temperature, and then the resultant mixture was stirred overnight The mixture was poured into water (50 mL) and then extracted with dichloromethane / isopropanol (100 /10 mL), the organic layer was concentrated to give a red oil, which was purified by flash chromatography on silica gel to afford 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]piperazi ne-1-carbonyl]piperidine-1- carboxylate intermediate Q1 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]ami no]-2-chloro- benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate 4-[4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chl oro-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]-dime thyl-silane (1.46 g, 3.06 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (153.24 mg, 0.235 mmol) and Na ₂ CO ₃ (747.64 mg, 7.05 mmol) were added at rt. The mixture was stirred at 100 °C for 15 h under N2. The reaction was filtered, the filtrate was concentrated under vacuum, The crude compound was purified by flash chromatography on silica gel, to afford 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-ca rbonyl]piperidine-1-carboxylic acid tert-butyl ester (1.2 g). MS [M+H] ⁺ : 910.1. Step 2: tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-hydroxyethyl)-5-m ethyl-pyrazol- 4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]pip erazine-1- carbonyl]piperidine-1-carboxylate 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-chlo ro-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), ammonium fluoride ((NH4)F) (977.37 mg, 26.39 mmol) was added at rt. The reaction was stirred at 60 °C for 1 h. The reaction mixture was diluted with water( 80 mL) and extracted two times with EtOAc (40 mL). The organic layers were washed with brine (30mL), dried over Na ₂ SO ₄ and concentrated to dryness. The crude product was directly used to the next step, to afford 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]am ino]benzoyl]piperazine-1- carbonyl]piperidine-1-carboxylate (1.04 g). MS [M+H] ⁺ : 795.9. 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-imidazo le-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-ca rboxylate tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-hydroxyethyl)-5-m ethyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azine-1-carbonyl]piperidine-1- carboxylate (1 g, 1.26 mmol) was dissolved in dichloromethane (30 mL), Methanesulfonic anhydride (328.57 mg, 1.89 mmol) and DIEA (325.02 mg, 2.51 mmol )were added at rt. The mixture was stirred at room temperature for 3 h. The reaction was concentrated under vacuum, The crude material was purified by flash chromatography on silica gel to afford tert- butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[5-methyl-1-(2-methylsu lfonyloxyethyl) pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]piperazine-1- carbonyl]piperidine-1-carboxylate (580 mg). MS [M+H] ⁺ : 873.8. 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-benzoy l]piperazine-1- carbonyl]piperidine-1-carboxylate tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[5-methyl-1-(2-methylsu lfonyloxyethyl) pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]piperazine-1- carbonyl]piperidine-1-carboxylate (580 mg, 0.664 mmol) was dissolved in methanol (10 mL), 7 M ammonia (3.73 g, 33.21 mmol) was added at rt. The mixture was stirred at 80 °C for 15 h. The reaction was concentrated under vacuum, the crude product was directly used to the next step, to afford 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]piperazi ne-1-carbonyl]piperidine-1- carboxylate (527 mg). MS [M+H] ⁺ : 794.8. The following examples were prepared in analogy to Intermediate Q1 Intermediate R1 O1-tert-butyl O2-methyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxypyrrolidine-1,2- dicarboxylate Step 1 Intermediate R1 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 CH ₂ Cl ₂ (10.2 mL) for 18 h. The reaction mixture was quenched with a saturated aqueous Na ₂ CO ₃ solution until pH = 10. The aqueous layer was extracted with CH ₂ Cl ₂ and the combined organic phases were dried over Na ₂ SO ₄ and filtered. The solvent was removed in vacuum to afford an oil, which was purified by flash column chromatography on silica gel to afford the product (902 mg). MS [M+H] ⁺ : 484.2. Intermediate R2 (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin e-2-carboxylic acid Intermediate R2 Step 1: methyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxypyrrolidine-2-carbox ylate O1-tert-butyl O2-methyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxypyrrolidine-1,2-dica rboxylate (700 mg, 1.45 mmol) was dissolved in 5 mL 20% TFA/DCM solution and stirred at room temperature for 1 h. The solvent was removed in vacuum. The residue was neutralized with 100 mL sat. K2CO ₃ , extracted with MeOH/DCM (50 mL x 4, v/v = 1:10), dried over sodium sulfate and concentrated in vacuo to afford the product (545 mg). MS [M+H] ⁺ : 384.2. Step 2: methyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin e-2-carboxylate methyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-2-carbox ylate (270 mg, 704 µmol) and formaldehyde (85.7 mg, 1.06 mmol) (37% aqueous solution) was dissolved in 1,2- dichloroethane (3.52 mL) and stirred at room temperature for 30 min before adding of NaBH ₃ CN (66.4 mg, 1.06 mmol). The mixture was then continued for 3 h. The mixture was poured into 100 mL water and extracted with DCM (50 mL x 3). The organic layers were combined, washed with 50 mL brine, dried over sodium sulfate and concentrated in vacuum. The residue was purified by flash chromatography to afford the product (230 mg) as colorless oil. MS [M+H] ⁺ : 398.2. Step 3: (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin e-2-carboxylic acid methyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-methyl-pyrrolidin e-2-carboxylate (230 mg) was dissolved in 5 mL MeOH and 1 mL water. To this solution was added 100 mg LiOH. The resulting mixture was stirred at room temperature for 48 h. The solution was poured into 100 mL 1N HCl and extracted with DCM (50 mL x 4). The organic layers were combined, washed with 50 mL brine, dried over sodium sulfate and concentrated in vacuum. The crude product (200 mg) was used in the next step without purification. MS [M+H] ⁺ : 384.2. Intermediate R3 (2S,4R)-1-tert-butoxycarbonyl-4-[tert-butyl(diphenyl)silyl]o xy-pyrrolidine-2-carboxylic acid Intermediate R1 Intermediate R3 1-(tert-butyl) 2-methyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dica rboxylate (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 h. After completion, the mixture was poured into 100 mL 1M HCl. The aqueous phase was extracted with DCM (50 mL x 3). The organic layers were combined, washed with 50 mL brine, dried over sodium sulfate and concentrated in vacuum. The crude product was used in the coming step without purification. MS [M+H] ⁺ : 470.3. Intermediate R4 5-(difluoromethyl)-4-iodo-1-(2-methoxyethyl)pyrazole Intermediate R4 To a solution of 4-iodo-2-(2-methoxyethyl)pyrazole-3-carbaldehyde (1000 mg, 3.57 mmol) in dichloromethane (10 mL) was added dast (748.22 mg, 613.3 uL, 4.64 mmol) slowly at 0 ^o C, the reaction was gradually warmed to room tremperature and stirred for 18 h. The reaction was quenched with water. The reaction mixture was washed with brine and extracted in DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum The residue was purified by column chromatography to give 5-(difluoromethyl)-4-iodo-1-(2- methoxyethyl)pyrazole (800 mg). MS [M+H]+: 303.0. Intermediate R5 4-methyl-1-(4-piperidylmethyl)piperazin-2-one Intermediate R5 Step 1: tert-butyl 4-[(4-methyl-2-oxo-piperazin-1-yl)methyl]piperidine-1-carbox ylate sodium hydride (275 mg, 6.84 mmol) was added to a solution of 4-methylpiperazin-2-one (650 mg, 5.7 mmol) in anhydrous DMF (15 ml). After 30 min, tert-butyl 4-(bromomethyl)piperidine- 1-carboxylate (1.60 g, 5.7 mmol) was added and the mixture was stirred for 12 h at room temperature.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 vacuum to give tert-butyl 4-[(4-methyl-2-oxo-piperazin-1-yl)methyl]piperidine- 1-carboxylate (1.2 g), which was directly used in the next step without further purification. MS [M+H] ⁺ : 312.2. Step 2: 4-methyl-1-(4-piperidylmethyl)piperazin-2-one To a solution of tert-butyl 4-((4-methyl-2-oxopiperazin-1-yl)methyl)piperidine-1-carboxy late (1.2 g, 3.8 mmol) in DCM (10 mL) and was added TFA (3 mL) then the resultant mixture was stirred for 1.0 h at room temperature. The solvent was concentrated under reduced pressure to give 4-methyl-1-(4-piperidylmethyl)piperazin-2-one (600 mg). MS [M+H] ⁺ : 212.2. Intermediate R6 rac-(2S)-1-tert-butoxycarbonyl-4-(hydroxymethyl)pyrrolidine- 2-carboxylic acid Intermediate R6 Step 1: O1-tert-butyl O2-methyl rac-(2S)-4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate 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 added 9-borabicyclo[3.3.1]nonane (0.5 M in THF) (9.95 mL, 4.97 mmol) slowly under N2 at 0ºC. After addition, this reaction mixture was warmed to 20 °C and stirred for 4 h. Then sodium hydroxide(2 M) (5.18 mL, 10.36 mmol) and hydrogen peroxide(1.46 g, 12.85 mmol) were added into this mixture slowly at 0 °C. This reaction mixture was stirred at 0 °C for 1 h. Then the reaction mixture was warmed to 20 °C and stirred for further 2 h. This reaction was quenched by saturated aqueous Na ₂ SO3 (50 mL) and extracted by EtOAc(20 mL x 2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get the crude product. This crude product was purified by silica gel chromatography(PE: EtOAc= 1:1) to get O1-tert-butyl O2-methyl rac-(2S)-4-(hydroxymethyl)pyrrolidine-1,2- dicarboxylate (500.0 mg) as colorless oil. MS [M+H] ⁺ : 260.2. Step2: rac-(2S)-1-tert-butoxycarbonyl-4-(hydroxymethyl)pyrrolidine- 2-carboxylic acid 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. This reaction mixture was stirred at 25 °C for 1 h. This reaction mixture was concentrated to get the crude product. This crude product was purified by Prep-HPLC (FA) to get rac-(2S)-1-tert-butoxycarbonyl-4- (hydroxymethyl)pyrrolidine-2-carboxylic acid (160.0 mg, 0.65 mmol, 34.34% yield) as yellow oil. MS [M+H] ⁺ : 146.0. Intermediate R7 2-[4-hydroxy-4-(hydroxymethyl)-1-piperidyl]-1-piperazin-1-yl -ethanone;2,2,2- trifluoroacetic acid Intermediate R7 Step 1: tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate To a solution of tert-butyl piperazine-1-carboxylate (500.0 mg, 2.68 mmol) and in DCM (10.0 mL) was added 2-bromoacetyl chloride (464.78 mg, 2.95 mmol) slowly at 0 °C. After addition, the reaction mixture was stirred at 0 °C for 2 h. This reaction was quenched by saturated aqueous NaHCO ₃ (20 mL) and extracted by DCM (10 mL x 2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to get tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (800.0 mg), the crude product would be used in the next step directly without further purification. MS [M+H-C ₄ H ₈ ] ⁺ :251.0. Step 2: tert-butyl 4-[2-[4-hydroxy-4-(hydroxymethyl)-1-piperidyl]acetyl]piperaz ine-1- carboxylate 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 h. This reaction mixture was filtered, and the filtrate was concentrated to get the crude product. This crude product was purified by Prep-HPLC (FA). The solution of desired product in ACN/H ₂ O was lyophilized to get tert-butyl 4-[2-[4-hydroxy-4-(hydroxymethyl)-1- piperidyl]acetyl]piperazine-1-carboxylate (180.0 mg). MS [M+H] ⁺ : 358.1. Step 3: 2-[4-hydroxy-4-(hydroxymethyl)-1-piperidyl]-1-piperazin-1-yl -ethanone;2,2,2- trifluoroacetic acid To a solution of tert-butyl 4-[2-[4-hydroxy-4-(hydroxymethyl)-1-piperidyl]acetyl]piperaz ine-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. This reaction mixture was stirred at 25 °C for 1 h. This reaction mixture was concentrated to get 2-[4-hydroxy-4-(hydroxymethyl)-1-piperidyl]-1-piperazin-1-yl - ethanone;2,2,2-trifluoroacetic acid (190.0 mg), The crude product would be used in the next step directly without further purification. MS [M+H] ⁺ : 258.1. Intermediate R8 tetrahydropyran-3-amine Intermediate R8 Step 1: tetrahydropyran-3-one oxime 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 h. This reaction mixture was filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel chromatography to get tetrahydropyran-3-one oxime (400.0 mg). Step 2: tetrahydropyran-3-amine 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 N2. This mixture was degassed and purged with N ₂ for 3 times. Then H ₂ (15 psi) was introduced into this system. The reaction mixture was stirred at 30 °C for 6 h under H ₂ atmosphere. This reaction was filtered carefully and concentrated to get the crude product tetrahydropyran-3-amine (150.0 mg). Intermediate R9 4-methyl-N-(tetrahydropyran-4-ylideneamino)benzenesulfonamid e Intermediate R9 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) the mixture was stirred at 20 °C for 3 h. 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. Intermediate R10 4-(tert-butoxycarbonylamino)-1,1-dimethyl-piperidin-1-ium-4- carboxylic acid;chloride Intermediate R10 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), the reaction was stirred for two hours at room temperature. The reaction mixture was acidified with 3N HCl and concentrated in vacuum to give 4-(tert- butoxycarbonylamino)-1,1-dimethyl-piperidin-1-ium-4-carboxyl ic acid;chloride, the crude product was directly used for the next step without further purification. MS [M] ⁺ : 273.2 Intermediate R11 (2-tert-butoxy-2-oxo-ethyl)-(3-carboxypropyl)-bis[3- (methylamino)propyl]ammonium;bromide ^{Step 1} _{Step 2} Step 3 Intermediate R11 Step 1: benzyl 4-[bis[3-(tert-butoxycarbonylamino)propyl]amino]butanoate 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, then the mixture was stirred at 70 °C for 16 h.The solution was concentrated, the residue was purified by reversed phase-HPLC (FA) to afford benzyl 4-[bis[3-(tert-butoxycarbonylamino) propyl]amino]butanoate (2.2 g). MS [M+H] ⁺ : 508.4. Step 2: (4-benzyloxy-4-oxo-butyl)-bis[3-(tert-butoxycarbonylamino)pr opyl]-(2-tert-butoxy- 2-oxo-ethyl)ammonium;bromide 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, then the mixture was stirred at 80 °C for 16 h. The solution was concentrated, the residue was purified by reversed phase-HPLC (TFA) to afford (4-benzyloxy-4-oxo-butyl)-bis[3-(tert- butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)ammon ium;bromide (1 g) as colorless oil. MS [M] ⁺ : 622.5. Step 3: bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo -ethyl)-(3- carboxypropyl)ammonium;bromide A solution of palladium on actived caobon (151.44 mg, 0.140 mmol) in Methanol (10 mL) was added (4-benzyloxy-4-oxo-butyl)-bis[3-(tert-butoxycarbonylamino)pr opyl]-(2-tert-butoxy-2- oxo-ethyl)ammonium;bromide (1.0 g, 1.42 mmol) under N ₂ , then the mixture was stirred under H ₂ at 10 °C for 16 h. The strating materials were consumed completed. The mixture was filtered and concentrated to afford bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2- oxo-ethyl)-(3-carboxypropyl)ammonium;bromide (700 mg). MS [M] ⁺ : 532.4. The following examples were prepared in analogy to Intermediate R11 Intermediate R13 [(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-yl]-piper azin-1-yl-methanone Intermediate R13 Step 1: benzyl 4-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2- carbonyl]piperazine-1-carboxylate To a mixture of 1-CBZ-piperazine (5.0 g, 22.7 mmol) in THF (25 mL) and DMF (25 mL) was added N,N-diisopropylethylamine (17.57 g, 136.2 mmol) and BOC-HYP-OH (5.25 g, 22.7 mmol). Then the mixture was added propylphosphonic anhydride (18.78 g, 29.51 mmol) after 10min. The reaction mixture was stirred at 25 °C for 16 h. The solution was extracted with water (50mL) and EA (100mL) and washed with sat.aq NaCl (50 mL), dried by anhydrous Na ₂ SO ₄ . The crude was purified by prep-HPLC(FA) to obtain the title compound (9.8 g). MS [M+H] ⁺ : 434.5. Step 2: benzyl 4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carb oxylate 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 h. The solution was not purified and used next step directly to obtain the title compound (7.56 g). MS [M+H] ⁺ : 334.5. Step 3: benzyl 4-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carbony l]piperazine- 1-carboxylate To a mixture of benzyl 4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carb oxylate (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 h. The mixture was concentrated to remove solvent, purified by prep-HPLC (0.1%FA) to afford the title compound (4 g). MS [M] ⁺ : 362.4. Step 4: piperazin-1-yl-[(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1- ium-2-yl]methanone 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) and were added ammonium hydroxide (2.0 mL, 4.41 mmol) and wet palladium 10% on actived carbon (0.140 mmol, 0.030 eq). The reaction mixture was stirred at 25 °C for 16 h under hydrogen at 15 psi. The mixture was filtered and filtrate was concentrated to remove solvent, to afford the title compound (1 g). MS [M] ⁺ : 228.2. Intermediate R14 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-but oxy-2-oxo-ethyl)piperidin-1- ium-4-carboxylate Step 1: benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]piperidine-4-c arboxylate To a solution of benzyl piperidine-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 h. Then the mixture was stirred at 50°C for another 16 h. The mixture was diluted with EtOAc (100 mL) and then washed with brine (30 mL x 3). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (PE:EA=2:1~0:1) to give the title compound (710 mg, 1.83 mmol, 74.17% yield) as light yellow gum. MS [M+H] ⁺ : 389.1. Step 2: benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-but oxy-2-oxo- ethyl)piperidin-1-ium-4-carboxylate formate To a solution of benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]piperidine-4-c arboxylate (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 under vacuum. The residue was purified twice by prep-HPLC (FA condition) to give the title compound (5 g, 9.93 mmol, 82.06% yield) as a yellow solid. MS [M] ⁺ : 503.2. Step 3: 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-but oxy-2-oxo- ethyl)piperidin-1-ium-4-carboxylate To a solution of benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-but oxy-2-oxo- ethyl)piperidin-1-ium-4-carboxylate formate (4.7 g, 8.57 mmol) in methanol (150 mL) was added palladium on charcoal (400 mg, 10% purity) and palladium hydroxide on charcoal (400.0 mg, 10% wt) under nitrogen atmosphere. The mixture was degassed and then stirred at 15°C for 4 h under hydrogen (760 mmHg). The mixture was filtered through celit pad, the solid was washed with MeOH (20 mL x 4). The combined filtrate was concentrated under vacuum. 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-e thyl)piperidin-1-ium-4- carboxylate (3.5 g, 8.48 mmol, 93.86% yield) as a white solid. MS [M] ⁺ : 413.2. Intermediate R15 Tert-butyl 2-[1-[3-(tert-butoxycarbonylamino)propyl]piperazin-1-ium-1-y l]acetate formate Step 1: benzyl 4-[3-(tert-butoxycarbonylamino)propyl]piperazine-1-carboxyla te 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) ,then the mixture was stirred at 25 °C for 16 h. The mixture was concentrated in vacuum and purified by silica gel column (PE/EA=100:1~1:2) to obtain the title compound (5.2 g, 13.78 mmol, 60.69% yield) as light brown solid. MS [M+H] ⁺ : 378.3. Step 2: benzyl 4-[3-(tert-butoxycarbonylamino)propyl]-4-(2-tert-butoxy-2-ox o- ethyl)piperazin-4-ium-1-carboxylate formate To a solution of benzyl 4-[3-(tert-butoxycarbonylamino)propyl]piperazine-1-carboxyla te (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), then the mixture was stirred at 50 °C for 16 h. The mixture was concentrated in vacuum and purified by prep-HPLC (0.1%FA)-MeOH to obtain the title compound (4 g, 59% yield) as light yellow solid. MS [M+H] ⁺ : 492.4. Step 3: tert-butyl 2-[1-[3-(tert-butoxycarbonylamino)propyl]piperazin-1-ium-1-y l]acetate formate To a solution of benzyl 4-[3-(tert-butoxycarbonylamino)propyl]-4-(2-tert-butoxy-2-ox o- 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 stirred under hydrogen atmosphere at 25 °C for 16 h. The mixture was concentrated in vacuum and purified by prep-HPLC (0.1%FA)-ACN to obtain tert-butyl 2-[1-[3-(tert-butoxycarbonylamino)propyl]piperazin-1-ium-1-y l]acetate formate (1.5 g, 4.18 mmol, 51.53% yield) as white solid. MS [M] ⁺ : 358.3. Example A1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]- 5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl] phenyl]-1-methyl-imidazole-2- carboxamide;formate In a 50 mL round-bottomed flask, afford N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-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 h. The crude reaction mixture was concentrated in vacuum. The crude material was purified by preparative HPLC to afford N-[3-chloro-4-[4- (1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[2,3-difluoro-4-[1-(2- methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide;formate (80 mg). MS [M] ⁺ : 737.3. The following examples were prepared in analogy to Examples A1

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-methoxyet hyl)-3-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide;formate 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]ph enyl]-1-methyl-imidazole-2- carboxamide In a 100 mL round-bottomed flask, afford N-[3-chloro-4-[4-(piperidine-4-carbonyl) piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methox yethyl)-3-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide (350 mg, 494 µmol), formaldehyde (74.1 mg, 2.47 mmol) and NaBH3CN (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 vacuum. The reaction mixture was poured into 25 mL sat NaHCO ₃ and extracted with EtOAc (3 x 25 mL). The organic layers were combined, washed with sat NaCl (1 x 25 mL), The organic layers were dried over Na ₂ SO ₄ and concentrated in vacuum to afford N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1 - carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide (357 mg). MS [M+H] ⁺ : 723.4. 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-methoxy ethyl)-3-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide;formate In a 50 mL round-bottomed flask, N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine- 1-carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-m ethyl-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 h. The crude reaction mixture was concentrated in vacuum. The crude material was purified by preparative HPLC to afford N-[4- [4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-carbo nyl]piperazine-1-carbonyl]-3- chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methy l-pyrazol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide;formate (22.6 mg). MS [M] ⁺ : 780.3. Example B2 & 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-methoxyet hyl)-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-methoxyet hyl)-3-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide;formate(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-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide;formate was purified by preparative chial-HPLC. To afford N- [4-[4-[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-ca rbonyl]piperazine-1-carbonyl]-3- chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methy l-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-p henyl]-5-[2,3-difluoro-4-[1-(2- methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide;formate(38 mg). MS [M] ⁺ : 780.2. The following examples were prepared in analogy to Examples B1

Example B17 N-[3-chloro-4-[4-[1-(2-hydrazino-2-oxo-ethyl)-1-methyl-piper idin-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 Step 3 Step 1 Step 2 Intermediate H2 S ^{tep 4} _{Step 5} Example B17 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-4-yl]ph enyl]-1-methyl-imidazole-2- carboxamide N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide (420 mg, 0.592 mmol) was dissolved in methanol (10 mL), formaldehyde (88.92 mg, 2.96 mmol) and sodium cyanoborohydride (186.08 mg, 2.96 mmol) were added at rt. The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated and diluted with water (20mL) and extracted two times with EtOAc (20 mL). The organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The crude product was directly used to the next step to afford N-[3-chloro-4-[4-(1-methylisonipecotoyl)piperazine-1-carbony l]phenyl]-5-[2,3- difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl] -1-methyl-imidazole-2- carboxamide (400 mg). MS [M+H] ⁺ : 723.6. Step 2: tert-butyl 2-[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]ben zoyl]piperazine-1- carbonyl]-1-methyl-piperidin-1-ium-1-yl]acetate N-[3-chloro-4-[4-(1-methylisonipecotoyl)piperazine-1-carbony l]phenyl]-5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide (100 mg, 0.138 mmol) was dissolved in acetonitrile (10 mL), and tert-butyl bromoacetate (107.88 mg, 0.553 mmol) and DIEA(71.48 mg, 0.553 mmol) were added at rt. The mixture was stirred at room temperature for 1 h. The reaction was concentrated under vacuum, the crude product was directly used to the next step to afford tert-butyl 2-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-methyl-piper idin-1-ium-1-yl]acetate(115 mg). MS [M] ⁺ : 837.7. Step 3: 2-[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]piper azine-1-carbonyl]-1- methyl-piperidin-1-ium-1-yl]acetic acid tert-butyl 2-[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]piper azine-1-carbonyl]-1-methyl- piperidin-1-ium-1-yl]acetate (115 mg, 0.137 mmol) was dissolved in tetrahydrofuran (2 mL) and 4 M HCl (in dioxane) (2.06 g, 6.86 mmol) was added at rt. The mixture was stirred at room temperature for 2 h. The reaction was concentrated under vacuum, the crude product was directly used to the next step to afford 2-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)- 5- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]am ino]benzoyl]piperazine-1- carbonyl]-1-methyl-piperidin-1-ium-1-yl]acetic acid (107 mg). MS [M] ⁺ : 781.7. Step 4: tert-butyl N-[[2-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyeth yl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]piperazine-1- carbonyl]-1-methyl-piperidin-1-ium-1-yl]acetyl]amino]carbama te 2-[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-carbo nyl]-1-methyl-piperidin-1-ium- 1-yl]acetic acid (107 mg, 0.137 mmol) was dissolved in N,N-dimethylformamide (3 mL), N- aminocarbamic acid tert-butyl ester(126.54 mg, 0.957 mmol), DIEA (35.36 mg, 0.274 mmol) and HATU (364.06 mg, 0.957 mmol) were added at rt. The mixture was stirred at room temperature for 1h. The reaction was directly used to the next step to afford tert-butyl N-[[2-[4- [4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1-methyl- imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1- methyl-piperidin-1-ium-1- yl]acetyl]amino]carbamate(122.61 mg) as light brown solid. MS [M] ⁺ : 895.8. Step 5: N-[3-chloro-4-[4-[1-(2-hydrazino-2-oxo-ethyl)-1-methyl-piper idin-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 N-[[2-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyeth yl)-5-methyl-pyrazol-4-yl]phenyl]- 1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-car bonyl]-1-methyl-piperidin-1- ium-1-yl]acetyl]amino]carbamate (122.61 mg, 0.137 mmol) was dissolved in N,N- dimethylformamide (2 mL), and TFA (779.79 mg, 6.84 mmol ) was added at rt. The mixture was stirred at room temperature for 1h. The reaction was concentrated under vacuum, the crude product was purified by HPLC to afford N-[3-chloro-4-[4-[1-(2-hydrazino-2-oxo-ethyl)-1- methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]phen yl]-5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide;formic acid;formate(12.7 mg, 10.25%) as white powder. MS [M] ⁺ : 795.7. Example B18 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2-methoxyethyl)-3- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]am ino]benzoyl]piperazine-1- carbonyl]piperidin-1-ium-1-yl]acetic acid;formic acid;formate Step 1: tert-butyl 3-[[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]ben zoyl]piperazine-1- carbonyl]-1-piperidyl]methyl]azetidine-1-carboxylate In a 100 mL round-bottomed flask, N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide (175 mg, 247 µmol), tert-butyl 3-formylazetidine-1- carboxylate (91.4 mg, 494 µmol) and NaBH3CN (77.5 mg, 1.23 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 vacuum. The reaction mixture was poured into 25 mL sat NaHCO ₃ and extracted with EtOAc (3 x 25 mL). The organic layers were combined, washed with sat NaCl (1 x 25 mL), The organic layers were dried over Na ₂ SO ₄ and concentrated in vacuum to afford tert-butyl 3-[[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2- methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidyl]me thyl]azetidine-1-carboxylate (217 mg). MS [M] ⁺ : 879.0. Step 2: tert-butyl 3-[[1-(2-tert-butoxy-2-oxo-ethyl)-4-[4-[2-chloro-4-[[5-[2,3- difluoro-4-[1-(2- methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium -1-yl]methyl]azetidine-1- carboxylate;bromide In a 50 mL round-bottomed flask, tert-butyl 3-[[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2- methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidyl]me thyl]azetidine-1-carboxylate (108 mg, 123 µmol), tert-butyl 2-bromoacetate (36 mg, 184 µmol) and DIPEA (31.8 mg, 42.9 µl, 246 µmol) were combined with MeCN (3 mL) to give a light brown solution. The reaction mixture was heated to 40 °C and stirred for 15 h. The crude reaction mixture was concentrated in vacuum. The crude product was directly used to the next step to afford tert-butyl 3-[[1-(2-tert- butoxy-2-oxo-ethyl)-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]methyl]az etidine-1-carboxylate;bromide (122 mg). MS [M] ⁺ : 993.1. Step 3: 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-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;formic acid;formate In a 50 mL round-bottomed flask, tert-butyl 3-[[1-(2-tert-butoxy-2-oxo-ethyl)-4-[4-[2-chloro-4- [[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-y l]phenyl]-1-methyl-imidazole-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium -1-yl]methyl]azetidine-1- carboxylate;bromide (122 mg, 123 µmol) was combined with THF (2 mL) to give a light brown solution. HCl water solution (1.53 ml, 18.4 mmol) was added. The reaction was stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum. The crude material was purified by preparative HPLC to afford 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;formic acid;formate (23.7 mg). MS [M] ⁺ : 836.7. The following examples were prepared in analogy to Examples B18

Example B28 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]am ino]benzoyl]piperazine-1- carbonyl]piperidin-1-ium-1-yl]acetic acid;formate 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-but oxy-2-keto-ethyl)piperidin-1-ium-4- carboxylate (28 mg, 0.068 mmol, Intermediate R14) was dissolved in dichloromethane, extra dry (1 mL) (purged with Ar) and 5-[3-chloro-2-fluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol- 4- yl]phenyl]-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-me thyl-imidazole-2-carboxamide .1:1 hydrogen chloride (30 mg, 0.045 mmol), Intemediate H11 was added. DIEA (34.78 mg, 47 uL, 0.269 mmol) and (7-azabenzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (33 mg, 0.063 mmol ) were added to the reaction mixture which was then stirred at rt for 1.5 h under Ar.4 M HCl (1.2 g, 1 mL, 4 mmol) in dioxane was added (slowly, reaction is slightly exothermic) and the mixture was stirred at rt for 30 min. The volatiles were removed under reduced pressure to give a colourless solid (in some brownish oil). The crude reaction mixture was purified by prepHPLC and lyophilized to get 10 mg of a colourless foam, purity (LC/MS, UV) 96%, yield 24%. MS: [M] ⁺ : 852.3. The following examples were prepared in analogy to Examples B28 Example B29 & Example B30 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2-methoxyethyl)-5- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]am ino]benzoyl]piperazine-1- carbonyl]piperidin-1-ium-1-yl]acetic acid;formic acid;formate (Example B29) 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2-methoxyethyl)-5- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]am ino]benzoyl]piperazine-1- carbonyl]piperidin-1-ium-1-yl]acetic acid;formic acid;formate (Example B30) E ^{xample B29} _{Example B30} 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2-methoxyethyl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]piperazine-1- carbonyl]piperidin-1-ium-1-yl]acetic acid;formic acid;formate (80 mg) was purified by preparative chial-HPLC to afford 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o- 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;formic acid;formate (19.4 mg) and 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1- (2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imid azole-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium -1-yl]acetic acid;formic acid;formate (28.3 mg). MS [M] ⁺ : 836.0. Example B31 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 Step 1: 3-(iodomethyl)-1,1-dimethyl-azetidin-1-ium In a 50 mL round-bottomed flask, 3-(iodomethyl)azetidine (126 mg, 640 µmol), MeI (454 mg, 3.2 mmol) and DIPEA (413 mg, 3.2 mmol) were combined with MeCN (6 mL) to give a light brown solution. The reaction was stirred at room temperature for 2 h. The crude reaction mixture was concentrated in vacuum. The crude product was directly used to the next step to afford 3- (iodomethyl)-1,1-dimethylazetidin-1-ium (145 mg). MS [M] ⁺ : 225.9. Step 2: 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 In a 50 mL round-bottomed flask, N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide (70 mg, 98.7 µmol), 3-(iodomethyl)-1,1-dimethyl-1l4- azetidine (22.3 mg, 98.7 µmol) and DIPEA (63.8 mg, 494 µmol) were combined with MeCN (6 mL) to give a light brown solution. The reaction mixture was heated to 50 °C and stirred for 15 h. The crude reaction mixture was concentrated in vacuum. The crude material was purified by preparative HPLC to afford Product 1 (17.8 mg). MS [M] ⁺ : 806.7. Example B32 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-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetate Example B32 Step 1: N-[3-chloro-4-[4-[1-(2,2-difluoroethyl)piperidine-4-carbonyl ]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide To a solution of N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[2,3- difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl] -1-methyl-imidazole-2- carboxamide (300 mg, 423 µmol) and DIPEA (164 mg, 1.27 mmol) in DCM (2 mL) was added slowly a solution of 2,2-difluoroethyl trifluoromethanesulfonate (272 mg, 1.27 mmol) in DCM (1 mL) at 0 °C. The ice bath was removed after 1 h and the mixture was stirred for another 16 h. Then the solution was concentrated in vacuum to afford the crude product N-[3-chloro-4-[4-[1- (2,2-difluoroethyl)piperidine-4-carbonyl]piperazine-1-carbon yl]phenyl]-5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide. MS [M+H] ⁺ : 773.0. Step 2: 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;2,2,2- trifluoroacetate A mixture of N-[3-chloro-4-[4-[1-(2,2-difluoroethyl)piperidine-4-carbonyl ]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide (150 mg, 194 µmol), iodomethane (551 mg, 3.88 mmol) and DIPEA (501 mg, 3.88 mmol) in acetonitrile (5 mL) was stirred at room temperature for 48 h. Then the mixture was concentrated in vacuum and the residue was purified by Prep-HPLC to afford 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-m ethyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetate (46 mg). MS [M] ⁺ : 787.2. Example B33 N-[3-chloro-4-[4-[1-(2-sulfamoylethyl)piperidine-4-carbonyl] piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide

Step 1 Intermediate H ₂ Step 2 Example B33 Step 1: 2-[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]piper azine-1-carbonyl]-1- piperidyl]ethanesulfonyl fluoride A mixture of N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[2,3- difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl] -1-methyl-imidazole-2- carboxamide (150 mg, 212 µmol) and ethenesulfonyl fluoride (27.9 mg, 254 µmol) in DMF (2 mL) was stirred at room temperature for 3 h. Then the mixture was heated at 50 °C for 1 h. The mixture was concentrated in vacuum to afford the crude material 2-[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]-1-piperidyl]et hanesulfonyl fluoride. The crude material was used into next step reaction without further purification. MS [M+H] ⁺ : 819.4. Step 2: N-[3-chloro-4-[4-[1-(2-sulfamoylethyl)piperidine-4-carbonyl] piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide At room temperature, 2-[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]ben zoyl]piperazine-1-carbonyl]-1- piperidyl]ethanesulfonyl fluoride was dissolved in DMF (2 mL). Then 7 M NH3 (3 mL) in methanol solution was added. The mixture was stirred for 16 h. Then the mixture was concentrated in vacuum. The crude material was purified by Prep-HPLC to afford N-[3-chloro-4- [4-[1-(2-sulfamoylethyl)piperidine-4-carbonyl]piperazine-1-c arbonyl]phenyl]-5-[2,3-difluoro-4- [1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-i midazole-2-carboxamide (10 mg). MS [M+H] ⁺ : 816.1. Example B34 N-[3-chloro-4-[4-[1-methyl-1-(2-sulfamoylethyl)piperidin-1-i um-4-carbonyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide;formate E ^{xample B33} _{Example B34} At room temperature, iodomethane (2 mL) was added into a solution of N-[3-chloro-4-[4-[1-(2- sulfamoylethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]p henyl]-5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide (150 mg, 184 µmol) in DMF (2 mL). The mixture was stirred for 16 h. Then the mixture was purified by Prep- HPLC to afford N-[3-chloro-4-[4-[1-methyl-1-(2-sulfamoylethyl)piperidin-1-i um-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;format e (6 mg). MS [M] ⁺ : 830.4. Example B35 N-[3-chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-pyrrolidin-1-i um-2-carbonyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl )phenyl]-1-methyl-imidazole- 2-carboxamide;2,2,2-trifluoroacetate

Step 1 Intermediate K11 Step 2 Example B35 Step 1: N-[4-[4-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrrolidin e-2-carbonyl]piperazine- 1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-(3-methyl-1H- pyrazol-4-yl)phenyl]-1- methyl-imidazole-2-carboxamide N-(3-chloro-4-(4-prolylpiperazine-1-carbonyl)phenyl)-5-(2,3- difluoro-4-(3-methyl-1H-pyrazol- 4-yl)phenyl)-1-methyl-1H-imidazole-2-carboxamide (83 mg, 130 µmol) and 2-((tert- butyldimethylsilyl)oxy)acetaldehyde (34.1 mg, 195 µmol) were stirred in dry THF (2.61 mL) before adding of NaBH(OAc)3 (41.4 mg, 195 µmol). The resulting mixture was stirred at room temperature for 1 h. Silica gel was was added to absorb the material. The solid sample was purifed by flash chromatography to afford the product (59 mg). MS [M] ⁺ : 795.4. Step 2: N-[3-chloro-4-[4-[1-(2-hydroxyethyl)-1-methyl-pyrrolidin-1-i um-2- carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(3- methyl-1H-pyrazol-4- yl)phenyl]-1-methyl-imidazole-2-carboxamide;2,2,2-trifluoroa cetate N-(4-(4-((2-((tert-butyldimethylsilyl)oxy)ethyl)prolyl)piper azine-1-carbonyl)-3-chlorophenyl)-5- (2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1 H-imidazole-2-carboxamide (59 mg, 74.2 µmol) and iodomethane (52.6 mg, 23.1 µL, 371 µmol) were stirred in MeCN (1.48 mL) for 5h. The solvent was removed in vacuum and the residue was treated with tetrabutylammonium fluoride (223 µL, 223 µmol, 1M in THF) at room temperature. After completion, the product was purified directly by prep. HPLC to afford the product (59 mg) as white powder. MS [M] ⁺ : 695.2. The following examples were prepared in analogy to Example B35 Example B38 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-(2-methoxyethyl)-5- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]am ino]benzoyl]piperazine-1- carbonyl]piperazin-1-ium-1-yl]acetic acid;formate Step 1: tert-butyl 3-[[1-(2-tert-butoxy-2-oxo-ethyl)-4-[4-[2-chloro-4-[[5-[2,3- difluoro-4-[1- (2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imid azole-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperazin-1-ium -1-yl]methyl]azetidine-1- carboxylate;formate To a mixture of tert-butyl 3-[[1-(2-tert-butoxy-2-oxo-ethyl)piperazin-1-ium-1- yl]methyl]azetidine-1-carboxylate (100.0 mg, 0.270 mmol) Intermediate R15 and bis(trichloromethyl)carbonate (27.23 mg, 0.090 mmol) in DCM (2 mL) was stirred at 20 °C for 1 h. Then, N,N-diisopropylethylamine (0.1 mL, 0.590 mmol) and N-[3-chloro-4-(piperazine- 1-carbonyl)phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-m ethyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide (161.41 mg, 0.270 mmol) in DCM (1 mL) was added to the above solution. The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated in vacuum to give the residue, which was purified by prep-HPLC (FA) to afford the title compound (100 mg, 0.100 mmol, 37.25% yield) as yellow solid. MS [M-56] ⁺ : 937.6. Step 2: 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-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;formate To a solution of tert-butyl 3-[[1-(2-tert-butoxy-2-oxo-ethyl)-4-[4-[2-chloro-4-[[5-[2,3- difluoro-4- [1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-i midazole-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperazin-1-ium -1-yl]methyl]azetidine-1- carboxylate;formate (49.33 mg, 0.050 mmol, 1 eq) in DCM (1 mL) was added trifluoroacetic acid (1.0 mL, 12.98 mmol, 273.51 eq). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was then purified by prep-HPLC (FA) to afford the title compound (19.3 mg, 0.020 mmol, 45.03% yield) as yellow solid. MS 837.2, [M]+, ESI+ Example C1 N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-y l)acetyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide;formate _{Step 1} ^{Step 2} Intermediate I1 Step 3 Example C1 Step 1: N-[3-chloro-4-[4-(2-chloroacetyl)piperazine-1-carbonyl]pheny l]-5-[2,3-difluoro-4- [1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-i midazole-2-carboxamide In a 50 mL round-bottomed flask, 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, 229 µmol) and DIPEA (88.8 mg, 687 µmol) were combined with MeCN (5 mL) to give a light yellow solution.2-chloroacetyl chloride (51.7 mg, 458 µmol) was added. The reaction was stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography to afford N-[3-chloro-4-[4-(2- chloroacetyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4 -[1-(2-methoxyethyl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide (150 mg). MS [M+H] ⁺ : 674.2. Step 2: N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidin-1-yl)acetyl]piperaz ine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide To a 5 mL microwave vial was added N-[3-chloro-4-[4-(2-chloroacetyl)piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide (70 mg, 104 µmol), pyrrolidin-3-ol (18.1 mg, 208 µmol) and DIPEA (40.2 mg, 311 µmol) in MeCN (3 mL). The vial was capped and heated in the microwave at 70 ºC for 30 min. The reaction was directly used the next step to afford N-[3- chloro-4-[4-[2-(3-hydroxypyrrolidin-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 (75.3 mg). MS [M+H] ⁺ : 725.2. Step 3: N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-y l)acetyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide;formate In a 50 mL round-bottomed flask, N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidin-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 (75.3 mg, 104 µmol), MeI (73.7 mg, 519 µmol) and DIPEA (67.1 mg, 519 µmol) were combined with MeCN (3 mL) to give a light yellow solution. The reaction mixture was heated to 40 °C and stirred for 2 h. The crude reaction mixture was concentrated in vacuum. The crude material was purified by preparative HPLC to afford N-[3-chloro-4-[4-[2-(3-hydroxy-1-methyl-pyrrolidin-1-ium-1-y l)acetyl]piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide;formate (16.6 mg). MS [M] ⁺ : 739.3. The following examples were prepared in analogy to Examples C1

Example D1 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-m ethyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide;formate

Step 1: tert-butyl (2S,3S)-2-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyet hyl)-3-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]piperazine-1- carbonyl]-3-hydroxy-pyrrolidine-1-carboxylate In a 50 mL round-bottomed flask, (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-pyrrolidine-2- carboxylic acid(40.2 mg, 174 µmol), 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 (80 mg, 134 µmol), HATU (66.1 mg, 174 µmol) and DIPEA (17.3 mg, 134 µmol) were combined with DMF (3 mL) to give a light brown solution. The reaction was stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum. The crude product was directly used to the next step to afford tert-butyl (2S,3S)-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]-3-hydroxy-pyrr olidine-1-carboxylate (100 mg). MS [M+H] ⁺ : 811.3. Step 2: N-[3-chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]pi perazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide In a 50 mL round-bottomed flask, tert-butyl (2S,3S)-2-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2- methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carbonyl]amino] benzoyl]piperazine-1-carbonyl]-3-hydroxy-pyrrolidine-1-carbo xylate (100 mg, 123 µmol) was combined with THF (2 mL) to give a light brown solution. HCl (1.03 ml, 12.3 mmol) was added. The reaction was stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum. The crude product was directly used to the next step to afford N-[3- chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperaz ine-1-carbonyl]phenyl]-5-[2,3- difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl] -1-methyl-imidazole-2- carboxamide (87.7 mg). MS [M+H] ⁺ : 711.2. Step 3: 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;format e In a 50 mL round-bottomed flask, tert-butyl (2S,3S)-2-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2- methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]-3-hydroxy-pyrr olidine-1-carboxylate (87 mg, 122 µmol), MeI (86.8 mg, 612 µmol) and DIPEA (79.1 mg, 612 µmol) were combined with MeCN (5 mL) to give a light red solution. The reaction mixture was heated to 40 °C and stirred for 15 h. The crude reaction mixture was concentrated in vacuum. The crude material was purified by preparative HPLC to afford 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-imidazo le-2-carboxamide;formate (16.1 mg). MS [M] ⁺ : 739.1. The following examples were prepared in analogy to Examples D1

Example D22 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;formic acid Step 1 Intermediate I4 Step 2 Example D22 Step 1: tert-butyl 4-[4-[4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyr azol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-ben zoyl]piperazine-1- carbonyl]-3-hydroxy-piperidine-1-carboxylate At room temperature, a mixture of 5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4- yl]phenyl]-1-methyl-N-[3-methyl-4-(piperazine-1-carbonyl)phe nyl]imidazole-2-carboxamide (300 mg, 519 µmol), 1-tert-butoxycarbonyl-3-hydroxy-piperidine-4-carboxylic acid (191 mg, 779 µmol), HATU (296 mg, 779 µmol) and DIPEA (201 mg, 1.56 mmol) in DMF (2 mL) was stirred for 16 h. Then the mixture was poured into water. The water layer was extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum. The crude product tert-butyl 4-[4-[4-[[5-[2,3-difluoro-4-[1-(2- methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carbonyl]amino]-2-methyl- benzoyl]piperazine-1-carbonyl]-3-hydroxy-piperidine-1-carbox ylate was used into next step reaction directly. MS [M+H] ⁺ : 805.5. Step 2: 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;formic acid At room temperature, a solution of tert-butyl 4-[4-[4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]am ino]-2-methyl- benzoyl]piperazine-1-carbonyl]-3-hydroxy-piperidine-1-carbox ylate (400 mg, 497 µmol) in DCM (10 mL) and TFA (5 mL) was stirred for 1 h. Then the mixture was concentrated in vacuum. The residue was basified by NH ₃ .H ₂ O to PH 8-9. The water layer was extracted with DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by Prep-HPLC to afford 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;formic acid. MS [M+H] ⁺ : 705.4. The following examples were prepared in analogy to Example D22

Example D43 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-d ifluoro-phenyl]-1-methyl- imidazole-2-carboxamide;formate

intermediate R13 T ₃ P intermediate L4 To a mixture of 2-chloro-4-[[5-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,3-difluor o-phenyl]-1- methyl-imidazole-2-carbonyl]amino]benzoic acid (105.0 mg, 0.220 mmol) in THF (5 mL) and DMF (5 mL) was added [(2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-yl]-piper azin-1- yl-methanone (49.34 mg, 0.220 mmol), N,N-diisopropylethylamine (0.4 mL, 2.3 mmol) and propylphosphonic anhydride (438.99 mg, 1.38 mmol). The reaction mixture was stirred at 25 °C for 16 h.The mixture was concentrated to remove solvent, purified by prep-HPLC (0.1%FA)- ACN to afford 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;formate (2.5 mg). MS [M] ⁺ : 695.3. Example E1 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[4-[1-(2,2- difluoroethyl)-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1 -methyl-imidazole-2- carboxamide

Intermediate G4 step 1 Intermediate D1 step 2 Example E1 Step 1: tert-butyl 4-[4-[2-chloro-4-[[5-[4-[1-(2,2-difluoroethyl)-5-methyl-pyra zol-4-yl]-2,3- difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl ]piperazine-1- carbonyl]piperidine-1-carboxylate 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]piper idine-1-carboxylate (48 mg, 75.2 µmol), 4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-1- (2,2-difluoroethyl)-5-methyl-1H-pyrazole (31.8 mg, 82.8 µmol), 4-(2,3-difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(2,2-difluoroe thyl)-5-methyl-1H-pyrazole (31.8 mg, 82.8 µmol) and Na ₂ CO ₃ (23.9 mg, 226 µmol) in 1,4-Dioxane (10 mL) / Water (1 mL). The vial was capped and heated in the microwave at 100 ºC for 3 h under N2. The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography to afford tert-butyl 4-[4-[2-chloro-4-[[5-[4-[1-(2,2-difluoroethyl)-5-methyl-pyra zol-4-yl]-2,3- difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl ]piperazine-1- carbonyl]piperidine-1-carboxylate (26 mg). MS [M-100] ⁺ : 715.2. Step 2: N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[4-[1-(2,2- difluoroethyl)-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1 -methyl-imidazole-2- carboxamide In a 50 mL round-bottomed flask, tert-butyl 4-(4-(2-chloro-4-(5-(4-(1-(2,2-difluoroethyl)-5- methyl-1H-pyrazol-4-yl)-2,3-difluorophenyl)-1-methyl-1H-imid azole-2- carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carbo xylate (26 mg, 31.9 µmol) was combined with THF (2 mL) to give a light brown solution. HCl water solution (797 µL, 9.57 mmol) was added. The reaction was stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum. The crude material was purified by preparative HPLC to afford N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[4-[1-(2,2- difluoroethyl)-5-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1 -methyl-imidazole-2-carboxamide (1.4 mg). MS [M+H] ⁺ : 715.4. The following examples were prepared in analogy to Examples E1

Example F1 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)piperazi ne-1-carbonyl]phenyl]-1- methyl-imidazole-2-carboxamide;formate Step 1: tert-butyl 4-[4-[4-[[5-[4-[1-(3-amino-3-oxo-propyl)-3-(trifluoromethyl) pyrazol-4-yl]- 2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2- chloro-benzoyl]piperazine-1- carbonyl]piperidine-1-carboxylate 3-(4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phenyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)propanamide (100 mg, 225 µmol), tert-butyl 4-(4-(4-(5-bromo-1-methyl-1H- imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbon yl)piperidine-1-carboxylate (129 mg, 202 µmol), sodium carbonate (71.4 mg, 674 µmol) and Pd-118 (29.3 mg, 44.9 µmol) were placed in water (408 µL) and dioxane (4.08 ml) in microwave tube. The tube was evacuated and backfilled with argon for 5 times. The mixture was then heated at 100 °C for 1 h. The mixture was cooled to room temperature, 100-200 mesh silica gel was added to absorb the material. The loaded sample was purified by flash chromatography to afford the product (98 mg). MS [M+H] ⁺ : 876.3. Step 2: 5-[4-[1-(3-amino-3-oxo-propyl)-3-(trifluoromethyl)pyrazol-4- yl]-2,3-difluoro- phenyl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1 -carbonyl]phenyl]-1-methyl- imidazole-2-carboxamide tert-butyl 4-(4-(4-(5-(4-(1-(3-amino-3-oxopropyl)-3-(trifluoromethyl)-1 H-pyrazol-4-yl)-2,3- difluorophenyl)-1-methyl-1H-imidazole-2-carboxamido)-2-chlor obenzoyl)piperazine-1- carbonyl)piperidine-1-carboxylate (98 mg, 112 µmol) was dissolved in 2 mL 20% TFA/DCM solution and the resulting solution was stirred for 1 h at room temperature. After completion, the solvent was removed in vacuo to afford the product which was used without purification (70 mg). MS [M+H] ⁺ : 776.2. Step 3: 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-carb onyl)piperazine-1- carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide;formate 5-[4-[1-(3-amino-3-oxo-propyl)-3-(trifluoromethyl)pyrazol-4- yl]-2,3-difluoro-phenyl]-N-[3- chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phe nyl]-1-methyl-imidazole-2- carboxamide (70 mg) was dissolved in DMA (2.24 mL), to this solution was added N-ethyl-N- isopropylpropan-2-amine (72.3 mg, 559 µmol) and iodomethane (31.7 mg, 224 µmol). The solution was stirred at rt for 2 h. After completion, the product was purified by preparative HPLC directly to afford the product (28.9 mg). MS [M] ⁺ : 804.3. The following examples were prepared in analogy to Example F1

Example F58 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-pyra zol-4-yl]-2,3-difluoro- phenyl]-1-methyl-imidazole-2-carboxamide;formate

Step 1 Step 2 intermediate M2 Step 3 Step 4 Example F58 Step 1: tert-butyl (2S,4R)-2-[4-[2-chloro-4-[[5-[4-(3,5-dimethyl-1H-pyrazol-4-y l)-2,3- difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl ]piperazine-1-carbonyl]-4- hydroxy-pyrrolidine-1-carboxylate To a mixture of N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[4-(3,5-dimet hyl-1H-pyrazol-4- yl)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide (1.0 g, 1.44 mmol) and BOC-HYP- OH (400.73 mg, 1.73 mmol) in THF (10 mL) was added N,N-diisopropylethylamine (0.56 g, 4.33 mmol) and PROPYLPHOSPHONIC ANHYDRIDE (1.19 g, 1.88 mmol). The reaction mixture was stirred at 25 °C for 4 h. The solution was extracted with water (10 mL) and EA (20 mL) and washed with sat.aq NaCl (10 mL), dried by anhydrous Na ₂ SO ₄ .The crude was purified by prep-HPLC(FA) to obtain the title compound (600 mg). MS [M+H] ⁺ : 767.1. Step 2: tert-butyl (2S,4R)-2-[4-[2-chloro-4-[[5-[4-[1-(3-cyanopropyl)-3,5-dimet hyl-pyrazol- 4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]ami no]benzoyl]piperazine-1- carbonyl]-4-hydroxy-pyrrolidine-1-carboxylate To a mixture of tert-butyl (2S,4R)-2-[4-[2-chloro-4-[[5-[4-(3,5-dimethyl-1H-pyrazol-4-y l)-2,3- difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl ]piperazine-1-carbonyl]-4- hydroxy-pyrrolidine-1-carboxylate (100.0 mg, 0.130 mmol) in DMF (3 mL) was added 4-bromo butyronitrile (28.94 mg, 0.200 mmol) and cesium carbonate (127.4 mg, 0.390 mmol). The reaction mixture was stirred at 80 °C for 16 h.The solution was purified by prep-HPLC(FA) directly to obtain the title compound (50 mg). MS [M+H] ⁺ : 834.3. Step 3: N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]pi perazine-1- carbonyl]phenyl]-5-[4-[1-(3-cyanopropyl)-3,5-dimethyl-pyrazo l-4-yl]-2,3-difluoro-phenyl]- 1-methyl-imidazole-2-carboxamide To a mixture of tert-butyl (2S,4R)-2-[4-[2-chloro-4-[[5-[4-[1-(3-cyanopropyl)-3,5-dimet hyl- pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carb onyl]amino]benzoyl]piperazine-1- carbonyl]-4-hydroxy-pyrrolidine-1-carboxylate (30.0 mg, 0.040 mmol) in DCM (2 mL) was added TFA (2.0 mL, 0.110 mmol). The reaction mixture was stirred at 25 °C for 16 h. The solution was concentrated in vacuum directly to obtain the title compound (26.4 mg). MS [M+H] ⁺ : 734.1. Step 4: 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-cyanopropy l)-3,5-dimethyl-pyrazol-4- yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;fo rmate To a mixture of N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]pi perazine-1- carbonyl]phenyl]-5-[4-[1-(3-cyanopropyl)-3,5-dimethyl-pyrazo l-4-yl]-2,3-difluoro-phenyl]-1- methyl-imidazole-2-carboxamide (26.4 mg, 0.040 mmol) in MeCN (2 mL) and water (0.200 mL) was added TEA (0.1 mL, 0.110 mmol) and iodomethane (0.1 mL, 0.040 mmol). The reaction mixture was stirred at 25 °C for 16 h. The solution was concentrared in vacuum and the crude was purified by prep-HPLC(FA) to obtain the title compound (16.9 mg). MS [M] ⁺ : 762.2. Example F60 rac-(1S,5R)-6-[[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxy ethyl)-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]hexan e-3-carboxamide;formate

^{Step 1} _{Step 2} Step 3 Example F60 Step 1: rac-tert-butyl (3R,4R)-3-[[(1S,5R)-6-[[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2 - methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imi dazole-2- carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-ca rbonyl]amino]-4-hydroxy- pyrrolidine-1-carboxylate In a 5 mL sealed , tert-butyl (trans)-3-amino-4-hydroxypyrrolidine-1-carboxylate (45.9 mg, 227 µmol) was combined with DMF (0.5 ml), TEA (38.3 mg, 52.8 µl, 378 µmol) and CDI (30.7 mg, 189 µmol) were added and the reaction mixture was stirred at RT for 20 min. Then N-(4-(((exo)- 3-azabicyclo[3.1.0]hexan-6-yl)carbamoyl)-3-chlorophenyl)-5-( 2,3-difluoro-4-(1-(2- methoxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1-methyl- 1H-imidazole-2-carboxamide hydrochloride (50 mg, 75.7 µmol) was added and the reaction was stirred at RT. The product was submitted for purification by prep HPLC. To afford the title compound (15.5 mg). MS [M+H] ⁺ : 852.3. Step 2: rac-tert-butyl (3R,4R)-3-[[(1S,5R)-6-[[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2 - methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imi dazole-2- carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-ca rbonyl]amino]-4-hydroxy- pyrrolidine-1-carboxylate In a 5 mL round-bottomed flask , rac-tert-butyl (3R,4R)-3-[[(1S,5R)-6-[[2-chloro-4-[[5-[2,3- difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phe nyl]-1-methyl-imidazole-2- carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-ca rbonyl]amino]-4-hydroxy- pyrrolidine-1-carboxylate (15 mg, 17.6 µmol) was combined with DCM (150 µL) to give a light brown solution . HCl 4 M in dioxane (22 µL, 88 µmol) was added and the reaction mixture was stirred at RT. The reaction mixture was concentrated to dryness then lyophilized. To afford the title compound (14.1 mg). MS [M+H] ⁺ 752.3. Step 3: rac-(1S,5R)-6-[[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxy ethyl)-3,5-dimethyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]amino]-N-[(3R,4R)-4- hydroxy-1,1-dimethyl-pyrrolidin-1-ium-3-yl]-3-azabicyclo[3.1 .0]hexane-3- carboxamide;formate In a 5 mL round-bottomed flask , rac-tert-butyl (3R,4R)-3-[[(1S,5R)-6-[[2-chloro-4-[[5-[2,3- difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phe nyl]-1-methyl-imidazole-2- carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-ca rbonyl]amino]-4-hydroxy- pyrrolidine-1-carboxylate (14 mg, 17.8 µmol) was combined with acetonitrile (300µL) to give a light brown suspension. DIPEA (6.88 mg, 9.3 µl, 53.3 µmol) and MeI (6.05 mg, 42.6 µmol) were added and the reaction mixture was stirred overnight at RT. The reaction mixture was concentrated to dryness and submitted for purification to prep HPLC. Finally the product was lyophilized to afford the title compound (6.8 mg). MS [M] ⁺ : 780.3. Example G1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]- 5-[2,3-difluoro-4-[1-[2-(isopropylamino)-2-oxo-ethyl]-3-meth yl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide;formate

Step 1 Intermediate O1 step 2 step 3 Example G1 Step 1: tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-[2-(isopropylamino)- 2-oxo-ethyl]-3- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]am ino]benzoyl]piperazine-1- carbonyl]piperidine-1-carboxylate 2-[4-[4-[2-[[4-[4-(1-tert-butoxycarbonylisonipecotoyl)pipera zine-1-carbonyl]-3-chloro- phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluoro-pheny l]-3-methyl-pyrazol-1-yl]acetic acid (150 mg, 0.185 mmol), DIPEA (71.87 mg, 0.556 mmol) and isopropylamine (16.43 mg, 0.278 mmol) were dissolved in acetonitrile (1.85 mL). To this stirred solution was added HATU (84.57 mg, 0.222 mmol) in one portion. The resulting yellow solution was stirred at room temperature for 30 min. The solvent was removed in vacuo, and the residue was purified by flash chromatography to afford the product (141 mg). MS [M+H] ⁺ : 850.8. Step 2: N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[2,3- difluoro-4-[1-[2-(isopropylamino)-2-oxo-ethyl]-3-methyl-pyra zol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-[2-(isopropylamino)- 2-keto-ethyl]-3-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azine-1-carbonyl]piperidine-1- carboxylic acid tert-butyl ester (141 mg, 0.166 mmol) was stirred in 5 mL 1.5 N HCl /MeOH solution at room temperature for 5 h. The solvent was removed in vacuum, and the crude product (140 mg) was used without purification. MS [M+H] ⁺ : 750.6. Step 3: N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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;formate N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[2,3-difluoro-4-[1-[2- (isopropylamino)-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]- 1-methyl-imidazole-2- carboxamide (140 mg) was dissolved in N,N-dimethylacetamide (2 mL). To this solution was added DIPEA (214.3 mg, 1.66 mmol) and iodomethane (70.61 mg, 0.497 mmol). The solution was stirred at room temperature for 1 h. The product was purified by preparative HPLC directly to afford the product as amorphous powder (56 mg). MS [M] ⁺ : 778.5. The following examples were prepared in analogy to Example G1

Example H1 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-diflu oro-phenyl]-5-methyl- pyrazol-1-yl]ethyl]pyridine-2-carboxamide;formate

^Step1 _{Step 2} intermediate Q1 Step 3 Example H1 Step 1: tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[5-methyl-1-[2-(pyridin e-2- carbonylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole- 2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-ca rboxylate 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]piperazi ne-1-carbonyl]piperidine-1- carboxylate (100 mg, 0.126 mmol) was dissolved in dichloromethane (5 mL), 2-picolinic acid (18.6 mg, 0.151 mmol), HATU (57.44 mg, 0.151 mmol) and DIEA (32.54 mg, 0.252 mmol) were added at rt. The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (30 mL) and extracted two times with DCM (25 mL). The organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated to dryness. the crude product was directly used to the next step .to afford tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[5- methyl-1-[2-(pyridine-2-carbonylamino)ethyl]pyrazol-4-yl]phe nyl]-1-methyl-imidazole-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-ca rboxylate(113 mg). MS [M+H] ⁺ : 899.7. Step 2: N-[2-[4-[4-[2-[[3-chloro-4-[4-(piperidine-4-carbonyl)piperaz ine-1- carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-diflu oro-phenyl]-5-methyl- pyrazol-1-yl]ethyl]pyridine-2-carboxamide tert-butyl 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[5-methyl-1-[2-(pyridin e-2- carbonylamino)ethyl]pyrazol-4-yl]phenyl]-1-methyl-imidazole- 2-carbonyl]amino] benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (113 mg, 0.126 mmol) was dissolved in tetrahydrofuran (2 mL) and 12 M HCl (in water) (628.21 mg, 6.28 mmol) was added at rt. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum, the crude product was directly used to the next step, to afford N-[2-[4-[4-[2-[[3-chloro- 4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]car bamoyl]-3-methyl-imidazol-4-yl]- 2,3-difluoro-phenyl]-5-methyl-pyrazol-1-yl]ethyl]pyridine-2- carboxamide(100 mg) as light brown solid. MS [M+H] ⁺ : 799.9. Step 3: 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-diflu oro-phenyl]-5-methyl- pyrazol-1-yl]ethyl]pyridine-2-carboxamide;formate N-[2-[4-[4-[2-[[3-chloro-4-[4-(piperidine-4-carbonyl)piperaz ine-1-carbonyl]phenyl] carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluoro-phenyl]-5-me thyl-pyrazol-1-yl]ethyl]pyridine- 2-carboxamide (100 mg, 0.125 mmol) was dissolved in acetonitrile (6 mL), iodomethane(53.28 mg, 0.375 mmol) and DIEA(48.51 mg, 0.375 mmol) were added at rt. The mixture was stirred at room temperature for 1 h. The reaction was concentrated under vacuum, the crude product was purified by HPLC to afford N-[2-[4-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4 - carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-im idazol-4-yl]-2,3-difluoro- phenyl]-5-methyl-pyrazol-1-yl]ethyl]pyridine-2-carboxamide;f ormate(56.6 mg) as white powder. MS [M] ⁺ : 828.1. The following examples were prepared in analogy to Examples H1

Example I1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]- 5-[2,3-difluoro-4-[5-(2-pyridyl)-1H-pyrazol-4-yl]phenyl]-1-m ethyl-imidazole-2- carboxamide;formate Step 1: N-(3-chloro-4-(4-(1-methylpiperidine-4-carbonyl)piperazine-1 -carbonyl)phenyl)-5- (2,3-difluoro-4-(5-(pyridin-2-yl)-1-((2-(trimethylsilyl)etho xy)methyl)-1H-pyrazol-4- yl)phenyl)-1-methyl-1H-imidazole-2-carboxamide To a solution of 5-bromo-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)pipe razine-1- carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide (80.0 mg, 0.14 mmol) in 1,4-dioxane (1.0 mL) was added [2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trimethylsilylethoxymeth yl)pyrazol-4- yl]phenyl]boronic acid (75.0 mg, 0.17 mmol), sodium carbonate (46.1 mg, 0.43 mmol), [1,1- Bis(di-tert-butylphosphino)ferrocene]palladium(II) Dichloride (19.2 mg, 0.02 mmol) and water (0.1 mL) in glove box, the mixture was stirred at 100 °C for 2 h. The mixture was diluted with 10 mL of DCM and filtered off, the filtrate was concentrated, the residue was purified by Prep- HPLC (FA as additive) to give N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1 - carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trime thylsilylethoxymethyl)pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide (45 mg). MS [M+H] ⁺ : 858.4. Step 2: N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trime thylsilylethoxymethyl)pyrazol- 4-yl]phenyl]-1-methyl-imidazole-2-carboxamide;iodide To a solution of N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1 - carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trime thylsilylethoxymethyl)pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide(39.0 mg, 0.05 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.03 mL, 0.18 mmol) and iodomethane (25.8 mg, 0.18 mmol), the mixture was stirred at 25 °C for 0.5 h. The mixture was purified by Flash-HPLC and lyophilized to give N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trime thylsilylethoxymethyl) pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide;iodide (35.0 mg). MS[M] ⁺ : 872.5. Step 3 : N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(2-pyridyl)-1H-pyrazol -4-yl]phenyl]-1-methyl- imidazole-2-carboxamide;formate The mixture of N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[5-(2-pyridyl)-1-(2-trime thylsilylethoxymethyl)pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide;iodide (35.0 mg, 0.04 mmol) and HCl/MeOH (4.0 mL) was stirred at 25 °C for 16 h. The mixture was concentrated at 20 °C in vacuum, the residue was purified by Prep-HPLC (FA as additive) and lyophilized to give N-[3-chloro-4-[4- (1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[2,3-difluoro-4-[5-(2- pyridyl)-1H-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbox amide;formate (10.1 mg). MS [M] ⁺ : 742.4. The following examples were prepared in analogy to Examples I1 Example J1 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-py razol-4-yl)phenyl]-1-methyl- imidazole-2-carboxamide;formate Step 1: tert-butyl 3-[[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazo l-4- yl)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azine-1-carbonyl]-1- piperidyl]methyl]azetidine-1-carboxylate In a 50 mL round-bottomed flask, 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 (88 mg, 135 µmol), tert-butyl 3-formylazetidine-1-carboxylate (50.1 mg, 270 µmol) and NaBH3CN (25.5 mg, 405 µmol) were combined with MeOH (5 mL) to give a light brown solution. The reaction mixture was heated to 45 °C and stirred for 3 h. The crude reaction mixture was concentrated in vacuum. The reaction mixture was poured into 25 mL sat NaHCO ₃ and extracted with EtOAc (3 x 25 mL). The organic layers were combined, washed with sat NaCl (1 x 25 mL), The organic layers were dried over Na ₂ SO ₄ and concentrated in vacuum to afford tert-butyl 3-[[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-(3-methyl-1H-pyrazo l-4-yl)phenyl]-1- methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbo nyl]-1- piperidyl]methyl]azetidine-1-carboxylate(111 mg). MS [M+H] ⁺ : 821.1. Step 2: tert-butyl 4-[4-[2-[[4-[4-[1-[(1-tert-butoxycarbonylazetidin-3-yl)methy l]piperidine-4- carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]carbamoyl]-3 -methyl-imidazol-4-yl]-2,3- difluoro-phenyl]-3-methyl-pyrazole-1-carboxylate In a 100 mL round-bottomed flask, tert-butyl 3-[[4-[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]- 1-piperidyl]methyl]azetidine-1-carboxylate (110 mg, 134 µmol), Boc2O (43.9 mg, 201 µmol) and TEA (20.4 mg, 201 µmol) were combined with DCM (5 mL) to give a light brown solution. The reaction was stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum. The crude product was directly used to the next step to afford tert-butyl 4-[4-[2-[[4-[4-[1-[(1-tert-butoxycarbonylazetidin-3-yl)methy l]piperidine-4-carbonyl]piperazine- 1-carbonyl]-3-chloro-phenyl]carbamoyl]-3-methyl-imidazol-4-y l]-2,3-difluoro-phenyl]-3- methyl-pyrazole-1-carboxylate(123 mg, 134 µmol). MS [M+H] ⁺ : 920.8. Step 3: tert-butyl 4-[4-[2-[[4-[4-[1-[(1-tert-butoxycarbonylazetidin-3-yl)methy l]-1-methyl- piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-p henyl]carbamoyl]-3-methyl- imidazol-4-yl]-2,3-difluoro-phenyl]-3-methyl-pyrazole-1-carb oxylate;iodide In a 100 mL round-bottomed flask, tert-butyl 4-[4-[2-[[4-[4-[1-[(1-tert-butoxycarbonylazetidin- 3-yl)methyl]piperidine-4-carbonyl]piperazine-1-carbonyl]-3-c hloro-phenyl]carbamoyl]-3- methyl-imidazol-4-yl]-2,3-difluoro-phenyl]-3-methyl-pyrazole -1-carboxylate (123 mg,134 µmol), MeI (94.8 mg, 668 µmol) and DIPEA(86.4 mg, 668 µmol) were combined with MeCN (5 mL) to give a light brown solution. The reaction was stirred at room temperature for 15 h. The crude reaction mixture was concentrated in vacuum. The crude product was directly used to the next step to afford tert-butyl 4-[4-[2-[[4-[4-[1-[(1-tert-butoxycarbonylazetidin-3-yl)methy l]-1- methyl-piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-c hloro-phenyl]carbamoyl]-3- methyl-imidazol-4-yl]-2,3-difluoro-phenyl]-3-methyl-pyrazole -1-carboxylate;iodide(125 mg). MS [M] ⁺ : 935.1. Step 4: 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-py razol-4-yl)phenyl]-1-methyl- imidazole-2-carboxamide;2,2,2-trifluoroacetate In a 100 mL round-bottomed flask, tert-butyl 4-[4-[2-[[4-[4-[1-[(1-tert-butoxycarbonylazetidin- 3-yl)methyl]-1-methyl-piperidin-1-ium-4-carbonyl]piperazine- 1-carbonyl]-3-chloro- phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluoro-pheny l]-3-methyl-pyrazole-1- carboxylate;iodide (120 mg, 128 µmol) was combined with DCM (3 mL) to give a light brown solution.2,2,2-trifluoroacetic acid (1.46 g, 12.8 mmol) was added. The reaction was stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum. The crude material was purified by preparative HPLC to afford N-[4-[4-[1-(azetidin-3-ylmethyl)-1-methyl- piperidin-1-ium-4-carbonyl]piperazine-1-carbonyl]-3-chloro-p henyl]-5-[2,3-difluoro-4-(3- methyl-1H-pyrazol-4-yl)phenyl]-1-methyl-imidazole-2-carboxam ide;2,2,2-trifluoroacetate (17.4 mg). MS [M] ⁺ : 734.9. Example K1 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;2,2,2-trif luoroacetate Step 1: 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-(2-hydrazinoethoxy)ethyl]- 3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbo xamide;formate To a mixture of 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;formate(100.0 mg, 0.140 mmol) in DMF (10 mL) was added tert-butyl N-[2-(2-bromoethoxy)ethyl]carbamate (385.18 mg, 1.44 mmol), and sodium borohydride (108.69 mg, 2.87 mmol). The reaction mixture was stirred at 80 °C for 16 h. The mixture was concentrated to remove solvent and purified by prep-HPLC (0.1%FA)-ACN to afford 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-(2-hydrazinoethoxy)ethyl]- 3,5-dimethyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbo xamide;formate (60 mg). MS [M] ⁺ : 882.3. Step 2: 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;2,2,2-trif luoroacetate 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-(2-hydrazinoethoxy) ethyl]-3,5-dimethyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide;formate (60.0 mg, 0.070 mmol) was added into HCl/dioxane (5.0 mL, 0.070 mmol). The reaction mixture was stirred at 25 °C for 2 h. The mixture was concentrated to get crude product and purified by prep-HPLC (0.1%TFA)-ACN to obtain 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;2,2,2-trif luoroacetate (13.3 mg). MS [M] ⁺ : 782.5. The following examples were prepared in analogy to Examples K1

Intermediate G94 tert-butyl 2-[3-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)phenyl]pyrazol-1- yl]acetate Intermediate G94 Step 1: tert-butyl 2-[4-(4-bromophenyl)-3-methyl-pyrazol-1-yl]acetate A mixture of 4-bromophenylboronic acid (6.23 g, 31.04 mmol), tert-butyl 2-(4-iodo-3-methyl- pyrazol-1-yl)acetate (10.0 g, 31.04 mmol)(isomer mixture), sodium carbonate (6.58 g, 62.08 mmol) and Pd(dppf)Cl ₂ (2.27 g, 3.1 mmol) in 1,4-dioxane (200 mL)/Water (20 mL) was stirred under N2 at 85 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum, purified by silica column (PE: EA=5:1) to afford tert-butyl 2-[4-(4-bromophenyl)-3- methyl-pyrazol-1-yl] acetate (3.3 g, 9.4 mmol, 30.27% yield)(isomer mixture) as yellow oil. MS [(M+2+H)+]: 353.0. Step 2: tert-butyl 2-[3-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]pyrazol-1-yl]acetate A mixture of tert-butyl 2-[4-(4-bromophenyl)-3-methyl-pyrazol-1-yl]acetate (3.3 g, 9.4 mmol)(isomer mixture), potassium acetate (1.84 g, 18.79 mmol), bis(pinacolato)diboron (7157.49 mg, 28.19 mmol) and Pd(dppf)Cl ₂ (0.69 g, 0.94 mmol) in 1,4-dioxane (50 mL) was evacuated and backfilled with N2 (3 ×), then the mixture was stirred under N2 at 95 °C for 16 h. The mixture was cooled to room temperature, filtered and concentrated in vacuum to afford a residue. The residue was purified by silica column (PE:EA=10:1 to 1:1) to afford tert-butyl 2-[3- methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe nyl]pyrazol-1-yl]acetate (3.7 g, 9.29 mmol, 98.87% yield)(isomer mixture) as yellow solid. MS [(M+H)+]: 399.3. The following examples were prepared in analogy to Intermediate G94

Intermediate G97 Step 1: 1-[2-(difluoromethoxy)ethyl]-4-iodo-5-methyl-pyrazole To a mixture of 4-iodo-3-methyl-1H-pyrazole (13.0 g, 62.5 mmol) and 2-(difluoromethoxy)ethyl 4-methylbenzenesulfonate (14.98 g, 56.25 mmol) in DMF (150 mL) was added potassium carbonate (21.59 g, 156.25 mmol) at 25 °C. Then the mixture was stirred at 65 °C for 16 h. The reaction mixture was pour into water (150 mL), extracted with EA (150 mL × 2). The combined organic layer was washed with brine (200 mL), dry over sodium sulfate, concentrated in vacuum to give the residue, which was purified by column (PE:EA=10:1 to 3:1) to afford 1-[2- (difluoromethoxy)ethyl]-4-iodo-5-methyl-pyrazole (12.0 g, 39.72 mmol, 31.78% yield)(isomer mixture) as yellow oil. MS [(M+H)+]:303.0. Step 2: 4-(4-bromo-2-fluoro-3-methyl-phenyl)-1-[2-(difluoromethoxy)e thyl]-5-methyl- pyrazole To a mixture of 1-[2-(difluoromethoxy)ethyl]-4-iodo-5-methyl-pyrazole (12.98 g, 42.95 mmol)(isomer mixture), (4-bromo-2-fluoro-3-methyl-phenyl)boronic acid (10.0 g, 42.95 mmol) and sodium carbonate (11.38 g, 107.37 mmol) in 1,4-dioxane (200 mL)/ Water (20 mL) was added Pd(dppf)Cl ₂ (3.14 g, 4.30 mmol) at 25 °C, the mixture was evacuated, backfilled with N2 (3 ×) and stirred at 60 °C for 4 h under N2. The reaction mixture was filtered, the filtrate was concentrated in vacuum to give the residue, which was purified by column (PE: EA=10:1 to 2:1) to afford 4-(4-bromo-2-fluoro-3-methyl-phenyl)-1-[2-(difluoromethoxy)e thyl]-5-methyl- pyrazole (12.0 g, 33.04 mmol, 76.94% yield)(isomer mixture) as yellow oil. MS [(M+H)+]:364.9. Step 3: 1-[2-(difluoromethoxy)ethyl]-4-[2-fluoro-3-methyl-4-(4,4,5,5 -tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-5-methyl-pyrazole A stirred mixture of 4-(4-bromo-2-fluoro-3-methyl-phenyl)-1-[2-(difluoromethoxy)e thyl]-5- methyl-pyrazole (12.0 g, 33.04 mmol)(isomer mixture), Pd(dppf)Cl ₂ (2.42 g, 3.3 mmol), bis(pinacolato)diboron (12.59 g, 49.56 mmol) and potassium acetate (5.16 mL, 82.61 mmol) in 1,4-dioxane (200 mL) was evacuated and backfilled with N2 (3 ×) at 25 °C. Then the mixture was stirred at 95 °C for 16 h under N2. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated in vacuum to give the residue, which was purified by column (PE: EA=10:1 to 3:1) to afford 1-[2-(difluoromethoxy)ethyl]-4-[2-fluoro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methy l-pyrazole (10.0 g, 24.38 mmol, 73.77% yield)(isomer mixture) as yellow solid. MS [(M+H)+]:410.9. The following examples were prepared in analogy to Intermediate G2.

The following example were prepared in analogy to Intermediate H1.

Intermediate I13 N-[3-chloro-4-[4-(methylamino)piperidine-1-carbonyl]phenyl]- 5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide formic To 188 mg of 2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl- pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoic acid (23.5 mg, 0.0338 mmol) dissolved in 1 ml DMF was added HATU (15.4 mg, 0.041 mmol, 1.200 eq) and Et3N (24 uL, 0.169 mmol, 5.000 eq). The mixture was stirred at room temperature for 10 min and then N- methyl-N-(4-piperidyl)carbamic acid tert-butyl ester (9.4 mg, 0.0439 mmol, 1.300 eq) was added and the mixture was stirred at room temperature over night. The mixture was then evaporated to dryness, dissolved in 1 ml DCM and treated with an excess of 4N HCl in dioxan (250 uL, 1.01 mmol, 30.000 eq) over night at RT. The mixtures was then evaporated to dryness and directly purified by preparative HPLC to afford the title compound (2 mg.8.8% yield). MS [(M-H)-]: 624.3. The following example was prepared in analogy to Intermediate I13. Intermediate O4 Step 1: ethyl 5-[4-[1-(2-tert-butoxy-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]ph enyl]-1-methyl- imidazole-2-carboxylate A mixture of tert-butyl 2-[3-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]pyrazol-1-yl]acetate (3.7 g, 9.29 mmol)(isomer mixture), ethyl 5-bromo-1-methyl- imidazole-2-carboxylate (3.25 g, 13.93 mmol), potassium carbonate (2.57 g, 18.58 mmol), BrettPhos Pd G3 (843.03 mg, 0.93 mmol) in 1,4-dioxane (50 mL)/Water (5 mL) was stirred under N2 at 90 °C for 16 h. The mixture was concentrated in vacuum and purified by silica column (PE: EA=2:1) to afford ethyl 5-[4-[1-(2-tert-butoxy-2-oxo-ethyl)-3-methyl-pyrazol-4-yl] phenyl]-1-methyl-imidazole-2-carboxylate (1.2 g, 2.83 mmol, 30.43% yield)(isomer mixture) as yellow oil. MS [(M+H)+]: 425.1. Step 2: tert-butyl 4-[4-[[5-[4-[1-(2-tert-butoxy-2-oxo-ethyl)-3-methyl-pyrazol- 4-yl]phenyl]- 1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]pipera zine-1-carboxylate To a solution of tert-butyl 4-(4-amino-2-chloro-benzoyl)piperazine-1-carboxylate (800.54 mg, 2.36 mmol) and ethyl 5-[4-[1-(2-tert-butoxy-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]ph enyl]-1- methyl-imidazole-2-carboxylate (1.0 g, 2.36 mmol)(isomer mixture) in THF (20 mL) was added dropwise potassium bis(trimethylsilyl) amide (3.53 mL, 3.53 mmol, 1M in hexane) slowly at -35 °C and stirred for 0.5 h under N2. The solution was poured into sat.NH4Cl (100 ml) and extracted with EA (50 ml × 2), washed with brine (100 ml), dried by anhydrous Na ₂ SO ₄ , then concentrated in vacuum to afford a residue. The residue was purified by silica column (55% EtOAc in PE) to afford the isomer mixture. The isomer mixture was purified by SFC [Column: Chiralpak IG-350 × 4.6 mm I.D., 3 um Mobile phase: Phase A for CO2, and Phase B for MeOH+ACN(0.05% DEA); Gradient elution: 60% Methanol + ACN(0.05% DEA) in CO2 Flow rate: 3 mL/min; Detector: PDA Column Temp: 35°C; Back Pressure: 100 Bar] to afford tert- butyl 4-[4-[[5-[4-[1-(2-tert-butoxy-2-oxo-ethyl)-3-methyl-pyrazol- 4-yl]phenyl]-1-methyl- imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-ca rboxylate (470.0 mg, 0.65 mmol, 27.78% yield) as light yellow solid MS (ESI+) [(M+H)+]: 718.3. The following example were prepared in analogy to Intermediate O4.

Intermediates R16 and R16’ cis-1-(2-(tert-butoxy)-2-oxoethyl)-1-((1-(tert-butoxycarbony l)azetidin-3-yl)methyl)-4- carboxypiperidin-1-ium; 2,2,2-trifluoroacetate trans-1-(2-(tert-butoxy)-2-oxoethyl)-1-((1-(tert-butoxycarbo nyl)azetidin-3-yl)methyl)-4- carboxypiperidin-1-ium; 2,2,2-trifluoroacetate Intermediate R14 was purified by SFC (Column: DAICEL CHIRALCEL OD (250 mm × 30 mm,10 um); condition: 0.1% NH3H ₂ O MEOH; 20%B; Gradient Time(min): 6.5 min; FlowRate(ml/min): 50 mL/min) to give cis-1-(2-(tert-butoxy)-2-oxoethyl)-1-((1-(tert- butoxycarbonyl)azetidin-3-yl)methyl)-4-carboxypiperidin-1-iu m; 2,2,2-trifluoroacetate (4.6 g, 11.15 mmol, 28.65% yield) as a white solid, MS [(M)+]: 413.0 and trans-1-(2-(tert-butoxy)-2- oxoethyl)-1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-4 -carboxypiperidin-1-ium; 2,2,2- trifluoroacetate (4.6 g, 11.15 mmol, 28.65% yield) as a white solid MS [(M)+]: 413.0. Intermediate R17 (1-tert-butoxycarbonylazetidin-3-yl)methyl-(2-tert-butoxy-2- oxo-ethyl)-(3-carboxypropyl)- methyl-ammonium;2,2,2-trifluoroacetate

Step 1: tert-butyl 3-[[(4-benzyloxy-4-oxo-butyl)amino]methyl]azetidine-1-carbox ylate To a mixture of benzyl 4-aminobutanoate;hydrochloride (4.5 g, 19.59 mmol) and potassium carbonate (8.12 g, 58.77 mmol), sodium iodide (146.83 mg, 0.98 mmol) in ACN (45 mL) was added 1-BOC-3-(bromomethyl)azetidine (6.37 g, 25.47 mmol) at 20 °C. Then the mixture was stirred at 50 °C for 16 h. The mixture was filtered, the solid was washed with ACN (20 mL x 3). The combined filtrate was concentrated under vacuum to give tert-butyl 3-[[(4-benzyloxy-4-oxo- butyl)amino]methyl]azetidine-1-carboxylate (12.0 g, 33.11 mmol, 99.71% yield) as a light yellow oil. MS [(M+H)+]:363.2. Step 2: tert-butyl 3-[[(4-benzyloxy-4-oxo-butyl)-methyl-amino]methyl]azetidine- 1- carboxylate To a solution of tert-butyl 3-[[(4-benzyloxy-4-oxo-butyl)amino]methyl]azetidine-1-carbox ylate (12.0 g, 33.11 mmol) in MeCN (100 mL) was added acetic acid (397.63 mg, 6.62 mmol) and formaldehyde (13.44 g, 165.54 mmol, 37% in water) at 30 °C and stirred for 2 h. Sodium cyan borohydride (4.16 g, 66.21 mmol) was added into the mixture in five portions at 30 °C and stirred at 30 °C for another 16 h. The mixture was concentrated under vacuum to afford a residue. The residue was dissolved in ACN (100 mL), filtered through the celite pad, The filtrate was concentrated under vacuum and purified by reversed phase-HPLC (water (0.1% FA)-ACN) and lyophilized to give tert-butyl 3-[[(4-benzyloxy-4-oxo-butyl)-methyl-amino]methyl]azetidine- 1-carboxylate (1.9 g, 5.05 mmol, 15.24% yield) as light red oil. MS [(M+Na)+]:399.2. Step 3: (4-benzyloxy-4-oxo-butyl)-[(1-tert-butoxycarbonylazetidin-3- yl)methyl]-(2-tert- butoxy-2-oxo-ethyl)-methyl-ammonium;2,2,2-trifluoroacetate To a solution of tert-butyl 3-[[(4-benzyloxy-4-oxo-butyl)-methyl-amino]methyl]azetidine- 1- carboxylate (1.7 g, 4.52 mmol) and DIEA (1.57 mL, 9.03 mmol) in ACN (20 mL) was added sodium iodide (67.68 mg, 0.45 mmol) and tert-butyl bromoacetate (1.32 g, 6.77 mmol). The mixture was stirred at 50 °C for 16 h. The mixture was concentrated under vacuum to afford a residue, which was purified by revered phase-HPLC (0water (0.1% TFA)-ACN), lyophilized to give (4-benzyloxy-4-oxo-butyl)-[(1-tert-butoxycarbonylazetidin-3- yl)methyl]-(2-tert-butoxy-2- oxo-ethyl)-methyl-ammonium;2,2,2-trifluoroacetate (2.3 g, 3.8 mmol, 81.35% yield) as light yellow gum. MS [(M)+]:491.4. Step 4: (1-tert-butoxycarbonylazetidin-3-yl)methyl-(2-tert-butoxy-2- oxo-ethyl)-(3- carboxypropyl)-methyl-ammonium;2,2,2-trifluoroacetate To a solution of (4-benzyloxy-4-oxo-butyl)-[(1-tert-butoxycarbonylazetidin-3- yl)methyl]-(2-tert- butoxy-2-oxo-ethyl)-methyl-ammonium;2,2,2-trifluoroacetate (2.3 g, 3.8 mmol) in Methanol (30 mL) was added palladium on charcoal (460 mg, 0.43 mmol) and palladium hydroxide on charcoal (460.0 mg, 0.33 mmol) under N2. The mixture was degassed and then stirred at 30 °C for 3 h under hydrogen (760 mmHg). The mixture was filtered through celite pad, the solid was washed with MeOH (10 mL x 3). The filtrate was concentrated under vacuum to give (1-tert- butoxycarbonylazetidin-3-yl)methyl-(2-tert-butoxy-2-oxo-ethy l)-(3-carboxypropyl)-methyl- ammonium;2,2,2-trifluoroacetate (1.87 g, 3.63 mmol, 95.55% yield). MS [(M)+]:401.1. The following example was prepared in analogy to Intermediate R17. Intermediate R19 tert-butyl N-[3-[4-(3-aminopropyl)-2-pyridyl]propyl]carbamate;hydrochlo ride Step 1: benzyl N-prop-2-ynylcarbamate To a mixture of propargylamine (5.0 g, 90.78 mmol, 1.0 eq) and sodium hydrogen carbonate (38.13 g, 453.89 mmol, 5.0 eq) in EtOAc (100 mL)/water (100 mL) was added dropwise benzyl chloroformate (14.25 mL, 99.85 mmol, 1.1 eq) at 0 °C, then the mixture was stirred for 1 h at 0 °C. The solution was poured into water (50 mL) and extracted with EtOAc, washed with brine, dried over Na2SO ₄ , concentrated in vacuo and purified by flash chromatography to afford benzyl N-prop-2-ynylcarbamate (15.4 g, 81.39 mmol, 89.66% yield) as light yellow oil. MS [(M+H)+]:189.9 Step 2: benzyl N-[3-(2-bromo-4-pyridyl)prop-2-ynyl]carbamate A mixture of benzyl N-prop-2-ynylcarbamate (6.0 g, 31.7 mmol, 1.0 eq) , copper(I) iodide (0.32 mL, 9.51 mmol, 0.3 eq) and tetrakis(triphenylphosphine)palladium(0) (1.83 g, 1.59 mmol, 0.05 eq) in toluene (20 mL) and was added 2-bromo-4-iodopyridine (9.0 g, 31.7 mmol, 1.0 eq) , tetrabutylammonium fluoride in THF (31.7 mL, 31.7 mmol, 1.0 eq) and triethylamine (13.26 mL, 95.11 mmol, 3.0 eq) under N2 , then the mixture was stirred at 25 °C for 16 h. The reaction was no further work-up and purified by flash chromatography to obtain benzyl N-[3-(2-bromo- 4-pyridyl)prop-2-ynyl]carbamate (9.1 g, 26.36 mmol, 83.16% yield) as brown oil. MS [(M+H)+]:345.0 Step 3: tert-butyl N-[3-[4-[3-(benzyloxycarbonylamino)prop-1-ynyl]-2-pyridyl]pr op-2- ynyl]carbamate To a mixture of N-BOC-propargylamine (4.09 g, 26.36 mmol, 1.0 eq) , copper(I) iodide (0.16 mL, 4.78 mmol, 0.18 eq) and bis(triphenylphosphine)palladium(II) chloride (0.93 g, 1.32 mmol, 0.05 eq) in DMF (10 mL) was added benzyl N-[3-(2-bromo-4-pyridyl)prop-2-ynyl]carbamate (9.1 g, 26.36 mmol, 1.0 eq) and triethylamine (91.0 mL, 652.89 mmol, 24.77 eq) under N2 , then the mixture was stirred at 50 °C for 16 h. The reaction was concentrated under vacuum and purified by flash chromatography to obtain tert-butyl N-[3-[4-[3- (benzyloxycarbonylamino)prop-1-ynyl]-2-pyridyl]prop-2-ynyl]c arbamate (9.4 g, 22.41 mmol, 85.0% yield) as brown oil. MS [(M+H)+]:420.2 Step 4: tert-butyl N-[3-[4-(3-aminopropyl)-2-pyridyl]propyl]carbamate;hydrochlo ride To a mixture of tert-butyl N-[3-[4-[3-(benzyloxycarbonylamino)prop-1-ynyl]-2-pyridyl]pr op-2- ynyl]carbamate (4.0 g, 9.54 mmol, 1.0 eq) and ammonium hydroxide (1.0 mL, 9.54 mmol, 1.0 eq) in methanol (50 mL) was added wet palladium 10% on actived carbon (400.0 mg, 9.54 mmol, 1.0 eq) at 25°C. The mixture was degassed and purged with H ₂ for 3 times. Then the mixture was stirred under hydrogen for 48 h. The reaction was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC and lyophilized to obtain the white solid, then dissolved in HCl solution (5%, 100 mL) and lyophilized to afford tert-butyl N-[3-[4-(3-aminopropyl)-2- pyridyl]propyl]carbamate;hydrochloride (2090.86 mg, 6.34 mmol, 64.54% yield) as light yellow oil. MS [(M+H)+]:294.2 Intermediate R19 bis[4-(tert-butoxycarbonylamino)butyl]-(2-tert-butoxy-2-oxo- ethyl)-(3- carboxypropyl)ammonium;bromide Step1: benzyl 4-[bis[4-(tert-butoxycarbonylamino)butyl]amino]butanoate To a mixture of 4-(tert-butoxycarbonylamino)butyl 4-methylbenzenesulfonate (4934.05 mg, 14.37 mmol) and benzyl 4-aminobutanoate;hydrochloride (1.5 g, 6.53 mmol) in ACN (60 mL) was added potassium carbonate (2707.56 mg, 19.59 mmol). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was filtered, the filtrate was concentrated in vacuum to give the residue, which was purified by reversed phase-HPLC and lyophilized to afford benzyl 4- [bis[4-(tert-butoxycarbonylamino)butyl]amino]butanoate (2000.0 mg, 3.25 mmol, 57.17% yield) as yellow oil. MS [(M+H)+]: 536.4. Step 2: (4-benzyloxy-4-oxo-butyl)-bis[4-(tert-butoxycarbonylamino)bu tyl]-(2-tert-butoxy-2- oxo-ethyl)ammonium;bromide To a mixture of benzyl 4-[bis[4-(tert-butoxycarbonylamino)butyl]amino]butanoate (2000.0 mg, 3.25 mmol) and N-ethyl-N-isopropylpropan-2-amine (839.74 mg, 6.5 mmol) in ACN (10 mL) was added and tert-butyl bromoacetate (633.67 mg, 3.25 mmol) at 20 °C. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was filtered, the filtrate was concentrated in vacuum to give the residue, which was purified by reversed phase-HPLC and lyophilized to afford (4-benzyloxy-4-oxo-butyl)-bis[4-(tert-butoxycarbonylamino)bu tyl]-(2-tert-butoxy-2-oxo- ethyl)ammonium;bromide (400.0 mg, 0.55 mmol, 18.92% yield) as yellow solid. MS [(M)+]: 650.4. Step 3: bis[4-(tert-butoxycarbonylamino)butyl]-(2-tert-butoxy-2-oxo- ethyl)-(3- carboxypropyl)ammonium;bromide To a solution of (4-benzyloxy-4-oxo-butyl)-bis[4-(tert-butoxycarbonylamino)bu tyl]-(2-tert- butoxy-2-oxo-ethyl)ammonium;bromide (500.0 mg, 0.68 mmol) in Methanol (20 mL) was added wet palladium on active carbon (50.0 mg, 10%) at 30 °C under N2, then the reaction mixture was stirred at 30 °C for 16h under H ₂ (balloon, 15 psi). The reaction mixture was filtered, the filtrate was concentrated in vacuum to give bis[4-(tert-butoxycarbonylamino)butyl]-(2-tert- butoxy-2-oxo-ethyl)-(3-carboxypropyl)ammonium;bromide (250.0 mg, 0.39 mmol, 57.03% yield) as colorless oil. MS [(M)+]: 560.8. Intermediate R20 4-[bis[3-(tert-butoxycarbonylamino)propyl]amino]butanoic acid Step 1: benzyl 4-[bis[3-(tert-butoxycarbonylamino)propyl]amino]butanoate To a stirred mixture of benzyl 4-aminobutanoate;hydrochloride (4.5 g, 19.59 mmol) and potassium carbonate (5.42 g, 39.18 mmol) in ACN (100 mL) was added 3-(BOC-amino)propyl bromide (11.66 g, 48.98 mmol) at 20 °C, then the mixture was stirred at 60 °C for 16 h. The solution was cooled to room temperature and filtered. The filtrate was concentrated in vacuum, purified by reversed phase-HPLC and lyophilized to afford benzyl 4-[bis[3-(tert- butoxycarbonylamino)propyl]amino]butanoate (3.5 g, 6.89 mmol, 35.19% yield) as colorless oil. MS [(M+H)+]: 508.1. Step 2: 4-[bis[3-(tert-butoxycarbonylamino)propyl]amino]butanoic acid To a solution of benzyl 4-[bis[3-(tert-butoxycarbonylamino)propyl]amino]butanoate (1.3 g, 2.56 mmol) in Methanol (50 mL) was added wet palladium on active carbon (0.27 g, 0.26 mmol, 10%) at 20 °C under N2, then the mixture was stirred under H ₂ (balloon) at 20 °C for 16 h. The solution was filtered with diatomite and concentrated to afford 4-[bis[3-(tert- butoxycarbonylamino)propyl]amino]butanoic acid (706.0 mg, 1.69 mmol, 66.03% yield) as colorless oil. MS [(M+H)+]: 418.3. Intermediate R21 bis[2-(tert-butoxycarbonylamino)ethyl]-(2-tert-butoxy-2-oxo- ethyl)-(3- carboxypropyl)ammonium;bromide Step 1: benzyl 4-[bis[2-(tert-butoxycarbonylamino)ethyl]amino]butanoate To a solution of benzyl 4-aminobutanoate;hydrochloride (11.0 g, 47.89 mmol) in ACN (100 mL) was added tert-butyl N-(2-bromoethyl)carbamate (32.2 g, 143.67 mmol) and DIEA (33.36 mL, 191.55 mmol) at 10 °C, then the mixture was stirred at 50 °C for 48 h. The solution was concentrated, the residue was purified by reversed phase-HPLC and lyophilized to afford benzyl 4-[bis[2-(tert-butoxycarbonylamino)ethyl]amino]butanoate (6.5 g, 13.55 mmol, 28.3% yield) as light yellow oil. MS [(M+H)+]: 480.3. Step 2: (4-benzyloxy-4-oxo-butyl)-bis[2-(tert-butoxycarbonylamino)et hyl]-(2-tert-butoxy-2- oxo-ethyl)ammonium;bromide To a mixture of benzyl 4-[bis[2-(tert-butoxycarbonylamino)ethyl]amino]butanoate (5.0 g, 10.43 mmol) in ACN (50 mL) was added tert-butyl bromoacetate (12.2 g, 62.55 mmol) and DIEA (5.45 mL, 31.28 mmol) at 10 °C. The reaction mixture was stirred at 60 °C for 16 h. The mixture was concentrated under vacuum and the residue was purified by reversed phase-HPLC and lyophilized to afford (4-benzyloxy-4-oxo-butyl)-bis[2-(tert-butoxycarbonylamino)et hyl]-(2-tert- butoxy-2-oxo-ethyl)ammonium;bromide (5.5 g, 8.17 mmol, 78.33% yield) as white solid. MS [(M)+]: 594.3. Step 3: bis[2-(tert-butoxycarbonylamino)ethyl]-(2-tert-butoxy-2-oxo- ethyl)-(3- carboxypropyl)ammonium;bromide To a solution of (4-benzyloxy-4-oxo-butyl)-bis[2-(tert-butoxycarbonylamino)et hyl]-(2-tert- butoxy-2-oxo-ethyl)ammonium;formate (2.5 g, 3.91 mmol) in Methanol (50 mL) was added wet palladium on active carbon (250 mg, 10%) under N2. Then the mixture was stirred under Hydrogen (15 Psi) at 20 °C for 16 h. The mixture was filtered with diatomite and the filtrate was concentrated to afford bis[2-(tert-butoxycarbonylamino)ethyl]-(2-tert-butoxy-2-oxo- ethyl)-(3- carboxypropyl)ammonium;bromide (1.2 g, 2.05 mmol, 52.54% yield) as white solid. MS [(M)+]: 504.4. Intermediate R22 tert-butyl 2-[1-[3-(tert-butoxycarbonylamino)propyl]piperazin-1-ium-1-y l]acetate;formate Step 1: benzyl 4-[3-(tert-butoxycarbonylamino)propyl]piperazine-1-carboxyla te To a solution of 1-CBZ-piperazine (5.0 g, 22.7 mmol, 1.0 eq) in MeCN (100 mL) was added triethylamine (3.16 mL, 22.7 mmol, 1.0 eq) and 3-(BOC-amino)propyl bromide (5.68 g, 23.83 mmol, 1.05 eq) ,then the mixture was stirred at 25 °C for 16 h. The mixture was concentrated in vacuo and purified by flash chromatography to obtain benzyl 4-[3-(tert- butoxycarbonylamino)propyl]piperazine-1-carboxylate (5.2 g, 13.78 mmol, 60.69% yield) as light brown soild. MS [(M+H)+]: 378.3 Step 2: benzyl 4-[3-(tert-butoxycarbonylamino)propyl]piperazine-1-carboxyla te To a solution of benzyl 4-[3-(tert-butoxycarbonylamino)propyl]piperazine-1-carboxyla te (5.2 g, 13.78 mmol, 1 eq) in MeCN (100 mL) was added triethylamine (1.92 mL, 13.78 mmol, 1 eq) and tert-butyl bromoacetate (5.37 g, 27.55 mmol, 2 eq) ,then the mixture was stirred at 50 °C for 16 h. The mixture was concentrated in vacuo and purified by prep-HPLC to obtain benzyl 4-[3-(tert- butoxycarbonylamino)propyl]-4-(2-tert-butoxy-2-oxo-ethyl)pip erazin-4-ium-1- carboxylate;formate (4.0 g, 7.44 mmol, 58.94% yield) as light yellow oil. MS [(M+]: 492.4 Step 3: tert-butyl 2-[1-[3-(tert-butoxycarbonylamino)propyl]piperazin-1-ium-1- yl]acetate;formate To a solution of benzyl 4-[3-(tert-butoxycarbonylamino)propyl]-4-(2-tert-butoxy-2-ox o- ethyl)piperazin-4-ium-1-carboxylate (4.0 g, 8.12 mmol, 1.0 eq) in THF (40 mL) with palladium (0.39 mL, 0.38 mmol, 0.05 eq) was treated under Hydrogen (16.24 mg, 8.12 mmol, 1.0 eq) at 25 °C for 16 h. The cat. was filtered and washed. The filtrate was concentrated in vacuo and purified by prep- HPLC to obtain tert-butyl 2-[1-[3-(tert-butoxycarbonylamino)propyl]piperazin-1-ium-1- yl]acetate (1.5 g, 3.72 mmol, 51.53% yield)tert-butyl 2-[1-[3-(tert- butoxycarbonylamino)propyl]piperazin-1-ium-1-yl]acetate;form ate (1.5 g, 3.72 mmol, 51.53% yield) as white solid. MS [(M+]: 358.3 The following example was prepared in analogy to Intermediate R22. Intermediate R24 1-[2-(tert-butoxycarbonylamino)ethyl]-1-(2-tert-butoxy-2-oxo -ethyl)piperidin-1-ium-4- carboxylic acid;2,2,2-trifluoroacetate Step 1: benzyl 1-[2-(tert-butoxycarbonylamino)ethyl]piperidine-4-carboxylat e To a solution of benzyl piperidine-4-carboxylate; hydrochloride (6.0 g, 23.46 mmol, 1.0 eq) and potassium carbonate (6.48 g, 46.92 mmol) in DMF (120 mL) was added tert-butyl N-(2- bromoethyl)carbamate (6.31 g, 28.15 mmol) at 20 °C and stirred at 20 °C for 16 h. The mixture was poured into water (200 mL) and then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (80 mL × 3), dried over sodium sulfate, filtered, the filtrate was concentrated under vacuum to give benzyl 1-[2-(tert- butoxycarbonylamino)ethyl]piperidine-4-carboxylate (9.23 g, 25.46 mmol, 97.69% yield) as a light yellow oil. MS [(M+H)+]: 363.2. Step 2: benzyl 1-[2-(tert-butoxycarbonylamino)ethyl]-1-(2-tert-butoxy-2-oxo - ethyl)piperidin-1-ium-4-carboxylate;2,2,2-trifluoroacetate To a solution of benzyl 1-[2-(tert-butoxycarbonylamino)ethyl]piperidine-4-carboxylat e (9.23 g, 25.46 mmol), NaI (381.7 mg, 2.55 mmol) and DIEA (6.65 mL, 38.2 mmol) in DMF (90 mL) was added tert-butyl bromoacetate (5.96 g, 30.56 mmol) at 20 °C and stirred at 20 °C for 16 h. The mixture was concentrated under vacuum, the residue was purified by reversed phase-HPLC (water (0.1% TFA)-ACN) and lyophilized to give benzyl 1-[2-(tert-butoxycarbonylamino)ethyl]- 1-(2-tert-butoxy-2-oxo-ethyl)piperidin-1-ium-4-carboxylate;2 ,2,2-trifluoroacetate (5.7 g, 9.65 mmol, 46.87% yield) as a light yellow gum. MS [(M)+]: 477.2. Step 3: 1-[2-(tert-butoxycarbonylamino)ethyl]-1-(2-tert-butoxy-2-oxo -ethyl)piperidin-1- ium-4-carboxylic acid;2,2,2-trifluoroacetate To a solution of benzyl 1-[2-(tert-butoxycarbonylamino)ethyl]-1-(2-tert-butoxy-2-oxo - ethyl)piperidin-1-ium-4-carboxylate;2,2,2-trifluoroacetate (6.43 g, 10.89 mmol) in methanol (120 mL) was added palladium hydroxide on charcoal (1528.98 mg, 1.09 mmol, 10%) and palladium on charcoal (1.13 mL, 1.09 mmol, 10%) under N2. The mixture was degassed and then stirred under hydrogen (760 mmHg) at 25 °C for 4 h. The mixture was filtered through the celite pad, the solid was washed with MeOH (20 mL×4). The combined filtrate was concentrated under vacuum to give 1-[2-(tert-butoxycarbonylamino)ethyl]-1-(2-tert-butoxy-2-oxo - ethyl)piperidin-1-ium-4-carboxylic acid;2,2,2-trifluoroacetate (4.1 g, 8.19 mmol, 67.71% yield) as a white solid. MS [(M)+]: 387.2. Example L1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]- 5-[4-[1-[2-[(6-fluoropyridazin-3-yl)amino]-2-oxo-ethyl]-3-me thyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide;formate

Step 1: tert-butyl 2-[4-[4-[2-[[3-chloro-4-(piperazine-1-carbonyl)phenyl]carbam oyl]-3- methyl-imidazol-4-yl]phenyl]-3-methyl-pyrazol-1-yl]acetate;f ormic acid To a solution of tert-butyl 4-[4-[[5-[4-[1-(2-tert-butoxy-2-oxo-ethyl)-3-methyl-pyrazol- 4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-ben zoyl]piperazine-1-carboxylate (200.0 mg, 0.28 mmol) in DCM (5 mL) was added TFA (0.25 mL, 3.24 mmol) at 25 °C and for 16 h. The mixture was concentrated in vacuum and purified by reversed phase HPLC (water (0.1% FA)-ACN) and lyophilized to afford tert-butyl 2-[4-[4-[2-[[3-chloro-4-(piperazine-1- carbonyl) phenyl] carbamoyl]-3-methyl-imidazol-4-yl] phenyl]-3-methyl-pyrazol-1-yl] acetate;formic acid (70.0 mg, 0.11 mmol, 40.67% yield) as white solid. MS [(M+H)+]: 618.3 Step 2: tert-butyl 2-[4-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4- carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-im idazol-4-yl]phenyl]-3- methyl-pyrazol-1-yl]acetate;formate To a solution of tert-butyl 2-[4-[4-[2-[[3-chloro-4-(piperazine-1-carbonyl)phenyl]carbam oyl]-3- methyl-imidazol-4-yl]phenyl]-3-methyl-pyrazol-1-yl]acetate;f ormic acid (70.0 mg, 0.11 mmol), 1,1-dimethylpiperidin-1-ium-4-carboxylic acid;iodide (60.1 mg, 0.21 mmol), DIEA (0.09 mL, 0.53 mmol) in DMF (2 mL) was added HATU (60.11 mg, 0.16 mmol) at 0°C and stirred at 0°C for 0.5 h. The mixture was purified by reversed phase-HPLC (water (0.1% FA)-ACN) and lyophilized to afford tert-butyl 2-[4-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4- carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-im idazol-4-yl]phenyl]-3-methyl- pyrazol-1-yl]acetate;formate (60.0 mg, 0.08 mmol, 75.07% yield) as yellow solid. MS [(M) +]: 757.4. Step 3: 2-[4-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-ca rbonyl)piperazine-1- carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]phenyl]-3- methyl-pyrazol-1-yl]acetic acid;chloride To a solution of tert-butyl 2-[4-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4- carbonyl)piperazine-1-carbonyl]phenyl]carbamoyl]-3-methyl-im idazol-4-yl]phenyl]-3-methyl- pyrazol-1-yl]acetate;formate (60.0 mg, 0.07 mmol) in DCM (2 mL) was added TFA (2.0 mL, 25.96 mmol) at 25 °C and stirred for 0.5 h. The mixture was concentrated in vacuum and purified by reversed phase HPLC (water (0.1% HCl)-ACN), lyophilized to afford 2-[4-[4-[2-[[3- chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazi ne-1-carbonyl]phenyl]carbamoyl]- 3-methyl-imidazol-4-yl]phenyl]-3-methyl-pyrazol-1-yl]acetic acid;chloride (40.0 mg, 0.05 mmol, 76.27% yield) as white solid. MS [(M)+]: 701.4. Step 4: N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-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;formate To a solution of 2-[4-[4-[2-[[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-ca rbonyl)piperazine- 1-carbonyl]phenyl]carbamoyl]-3-methyl-imidazol-4-yl]phenyl]- 3-methyl-pyrazol-1-yl]acetic acid;chloride (70.0 mg, 0.09 mmol) in DMF (2 mL) was added DIEA (0.05 mL, 0.28 mmol) and 2-chloro-1-methylpyridinium iodide (36.36 mg, 0.14 mmol) at 25 °C and stirred for 20 min. Then 6-fluoropyridazin-3-amine (16.1 mg, 0.14 mmol) was added to the solution and stirred at 80 °C for 8 h. The mixture was purified by Prep-HPLC (Phenomenex Luna C1875 × 30 mm × 3 um, water (0.225% FA)-ACN, B= 19%-39%; FlowRat: 25 ml/min) to afford N-[3-chloro-4-[4- (1,1-dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbony l]phenyl]-5-[4-[1-[2-[(6- fluoropyridazin-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2- carboxamide;formate (28.9 mg, 0.03 mmol, 35.07% yield) as yellow solid. MS [(M)+]: 796.0. The following examples were prepared in analogy to Examples L1

Example L6 cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-4-[1-[2-[(6-fluoropyridazin- 3-yl)amino]-2-oxo-ethyl]-3-methyl-pyrazol-4-yl]phenyl]-1-met hyl-imidazole-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium -1-yl]acetic acid;formate

Step 1: 2-[4-[4-[2-[[4-(4-tert-butoxycarbonylpiperazine-1-carbonyl)- 3-chloro- phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluoro-pheny l]-3-methyl-pyrazol-1- yl]acetic acid To a solution of tert-butyl 4-[4-[[5-[4-[1-(2-tert-butoxy-2-oxo-ethyl)-3-methyl-pyrazol- 4-yl]-2,3- difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-chlo ro-benzoyl]piperazine-1- carboxylate (300.0 mg, 0.4 mmol) in Water (3 mL) and THF (3 mL) was added sodium hydroxide (47.7 mg, 1.19 mmol). The mixture was stirred at 10 °C and for 16 h. The reaction mixture was pour into water (10 mL), acidified with aq. HCl (1N) to pH= 6, extracted with EA (10 mL×2). The combined organic layer was washed with brine, dried over sodium sulfate, concentrated in vacuum to afford 2-[4-[4-[2-[[4-(4-tert-butoxycarbonylpiperazine-1-carbonyl)- 3- chloro-phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluor o-phenyl]-3-methyl-pyrazol-1- yl]acetic acid (220.0 mg, 79.2% yield) as off-white solid. MS [(M+H)+]: 698.3. Step 2: tert-butyl 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-carboxylate To a solution of 2-[4-[4-[2-[[4-(4-tert-butoxycarbonylpiperazine-1-carbonyl)- 3-chloro- phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-2,3-difluoro-pheny l]-3-methyl-pyrazol-1-yl]acetic acid (220.0 mg, 0.32 mmol) and 6-fluoropyridazin-3-amine (142.55 mg, 1.26 mmol) in DMF (3 mL) was added DIEA (0.16 mL, 0.95 mmol) and BopCl (120.33 mg, 0.47 mmol). The mixture was stirred at 30 °C and for 1 h. The mixture was purified by reversed phase-HPLC (water (0.1% FA)-ACN, B= 10%-60%) and lyophilized to afford tert-butyl 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-carboxylate (200.0 mg, 0.25 mmol, 69.1% yield) as light yelllow solid. MS [(M+H)+]:793.2 Step 3: N-[3-chloro-4-(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 To a solution of tert-butyl 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-methy l-imidazole-2- carbonyl]amino]benzoyl]piperazine-1-carboxylate (200.0 mg, 0.25 mmol) in DCM (2 mL) was added TFA (0.4 mL, 5.19 mmol) at 30 °C and stirred at 30 °C for 3 h. The reaction mixture was pour into water, basified with aq.NaHCO ₃ to pH= 8, extracted with EA (10 mL × 2). The combined organic layer was washed with brine, dry over sodium sulfate, concentrated in vacuum to afford N-[3-chloro-4-(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 (120.0 mg, 0.17 mmol, 63.3% yield) as light yellow solid. MS [(M+H)+]:693.2. Step 4: tert-butyl 3-[[1-(2-tert-butoxy-2-oxo-ethyl)-4-[4-[2-chloro-4-[[5-[2,3- difluoro-4-[1- [2-[(6-fluoropyridazin-3-yl)amino]-2-oxo-ethyl]-3-methyl-pyr azol-4-yl]phenyl]-1-methyl- imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]pip eridin-1-ium-1- yl]methyl]azetidine-1-carboxylate;formic acid To a mixture of N-[3-chloro-4-(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 (80.0 mg, 0.12 mmol) and (1s,4s)-1-(2-(tert-butoxy)-2-oxoethyl)-1-((1-(tert- butoxycarbonyl)azetidin-3-yl)methyl)-4-carboxypiperidin-1-iu m;2,2,2-trifluoroacetate (57.28 mg, 0.14 mmol) in DMF (1 mL) was added Bop-Cl (29.32 mg, 0.12 mmol) and DIEA (0.06 mL, 0.35 mmol). The reaction mixture was stirred at 30 °C for 1 h. The reaction mixture was purified by reversed phase HPLC (water (0.1% FA)-ACN, B=60%-90% ) and lyophilized to give tert- butyl 3-[[1-( 2-tert-butoxy-2-oxo-ethyl)-4-[4-[2-chloro-4-[[5-[2,3-difluor o-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]methyl]azetidine-1- carboxylate;formic acid (40.0 mg, 0.04 mmol, 25.5% yield) as light yellow solid. MS [(M)+]: 1087.5. Example M1 N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1-carbonyl]phenyl]- 5-[2,3-difluoro-4-[3-methyl-1-[2-[(6-methyl-3-pyridyl)carbam oylamino]ethyl]pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide formate 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-carbo xylate 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (4.61 g, 24 mmol, Eq: 1.05) and N-ethyl-N-isopropylpropan-2-amine (14.8 g, 20 ml, 114 mmol, Eq: 5) were added to a solution of 2-chloro-4-(5-(2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phen yl)-1- methyl-1H-imidazole-2-carboxamido)benzoic acid (10.8 g, 22.9 mmol, Eq: 1) and 1H- benzo[d][1,2,3]triazol-1-ol (3.25 g, 24 mmol, Eq: 1.05) in DMA (57.2 ml) and stirred for 18 hours at room temperature. The mixture was poured into 100 mL and extrated with EtOAc (50 mLx 4). The organic layer was washed with 50 mL with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was used in the next step without purification. Step 2: 4-[4-[[5-[4-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-met hyl-pyrazol-4-yl]-2,3- difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-chlo ro-benzoyl]piperazine-1- carboxylic acid tert-butyl ester 4-[2-chloro-4-[[5-[2,3-difluoro-4-(5-methyl-1H-pyrazol-4-yl) phenyl]-1-methyl-imidazole-2- carbonyl]amino]benzoyl]piperazine-1-carboxylic acid tert-butyl ester (1.9 g, 2.88 mmol, 1.000 eq) was dissolved in acetonitrile (60 mL). cesium carbonate (1.41 g, 4.32 mmol, 1.500 eq) was added followed by tert-butyl(2-iodoethoxy)dimethylsilane (1.07 g, 3.75 mmol, 1.300 eq). The mixture was heated at 70°C over night. The cesium carbonate was filtered off. The mixture was purified by flash chromatography (100% heptane to 100% EtOAc). The mixture of regioisomers was separated by Prep-SFC chiral. The structures of regioisomeres were elucitated by NMR. The title coumpound (814 mg, 32.9%) was isolated as colorless oil. MS [(M+H-Buten)+]:742.2. Step 3: 4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-hydroxyethyl)-3-meth yl-pyrazol-4-yl]phenyl]- 1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-car boxylic acid tert-butyl ester 4-[4-[[5-[4-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-met hyl-pyrazol-4-yl]-2,3-difluoro- phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoy l]piperazine-1-carboxylic acid tert-butyl ester (814 mg, 1.02 mmol, 1.000 eq) was dissolved in N,N-dimethylformamide (4 mL) and water (1 mL). Ammonium fluoride (377.61 mg, 10.2 mmol, 10.000 eq) was added at room temperature. The mixture was stirred at 60°C over two days. The reaction mixture was poured into 100mL brine and extracted two times with 100mL EtOAc. The organic layers were combined, dried with Na2SO ₄ , filtered and evaporated to dryness to afford the title coumpound (501.6 mg, 69.76%) as colorless waxy solid. MS [(M+H)+]:684.3. Step 4: 4-[2-chloro-4-[[5-[2,3-difluoro-4-[3-methyl-1-(2-methylsulfo nyloxyethyl)pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azine-1-carboxylic acid tert-butyl ester To 4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-hydroxyethyl)-3-meth yl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbo xylic acid tert-butyl ester (468 mg, 0.664 mmol, 1.000 eq) dissolved in dichloromethane (30 mL) was added methanesulfonic anhydride (173.39 mg, 188.46 uL, 0.995 mmol, 1.500 eq) and DIEA (171.52 mg, 231.78 uL, 1.33 mmol, 2.000 eq). The mixture was stirred at room temperature for 3h. The reaction mixture was poured into 30mL brine and extracted three times with 30mL DCM. The organic layers were combined, dried over MgSO ₄ and concentrated to dryness. The title compound was obtained as a light brown solid with an assumed purity of 85% and was used without further purification. MS [(M+H)+]:762.4. Step 5: 4-[4-[[5-[4-[1-(2-aminoethyl)-3-methyl-pyrazol-4-yl]-2,3-dif luoro-phenyl]-1-methyl- imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-ca rboxylic acid tert-butyl ester 4-[2-chloro-4-[[5-[2,3-difluoro-4-[3-methyl-1-(2-methylsulfo nyloxyethyl)pyrazol-4-yl]phenyl]- 1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-car boxylic acid tert-butyl ester (585 mg, 0.652 mmol, 1.000 eq) was treated with 2 M ammonia solution (2M in iPrOH) (12.61 g, 16.31 mL, 32.62 mmol, 50.000 eq) at 70°C over 2 days.The title compound was obtained as a light brown gum with an assumed purity of 89% and was used without further purification. MS [(M+H)+]:683.4 Step 6: tert-butyl 4-[2-chloro-4-[[5-[2,3-difluoro-4-[3-methyl-1-[2-[(6-methyl- 3- pyridyl)carbamoylamino]ethyl]pyrazol-4-yl]phenyl]-1-methyl-i midazole-2- carbonyl]amino]benzoyl]piperazine-1-carboxylate 4-[4-[[5-[4-[1-(2-aminoethyl)-3-methyl-pyrazol-4-yl]-2,3-dif luoro-phenyl]-1-methyl-imidazole- 2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carboxylic acid tert-butyl ester (33.7 mg, 0.044 mmol, 1.000 eq) was dissolved in N,N-dimethylformamide (1.5 mL).5-isocyanato-2- methyl-pyridine (8.83 mg, 0.066 mmol, 1.500 eq) and DIEA (28.37 mg, 38.34 uL, 0.220 mmol, 5.000 eq) were added and the mixture was stirred over night at room temperature. The mixture was concentrated to dryness and used crude for next step. Step 7: N-[3-chloro-4-(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 Crude tert-butyl 4-[2-chloro-4-[[5-[2,3-difluoro-4-[3-methyl-1-[2-[(6-methyl- 3- pyridyl)carbamoylamino]ethyl]pyrazol-4-yl]phenyl]-1-methyl-i midazole-2- carbonyl]amino]benzoyl]piperazine-1-carboxylate was treated with an excess of HCl 4N in dioxan (30 eq) at room temperature over night. The crude mixture was concentrated and purified by Prep-HPLC to afford the title coumpound (20 mg, 59.7%) as white amorph freeze-dried solid. MS [(M+H)+]:717.2. Step 8: N-[3-chloro-4-[4-(1,1-dimethylpiperidin-1-ium-4-carbonyl)pip erazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[3-methyl-1-[2-[(6-methyl -3- pyridyl)carbamoylamino]ethyl]pyrazol-4-yl]phenyl]-1-methyl-i midazole-2-carboxamide formate N-[3-chloro-4-(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-i midazole-2-carboxamide (20 mg, 0.028 mmol, 1.000 eq) was dissolved in dichloromethane (1 mL).1,1-dimethylpiperidin-1-ium- 4-carboxylic acid iodide (24 mg, 0.069 mmol, 2.500 eq), DIEA (36.04 mg, 48.7 uL, 0.279 mmol, 10.000 eq) and propylphosphonic anhydride (50% solution) (53.24 mg, 0.084 mmol, 3.000 eq) were added and the mixture was stirred at room temperature over night. The crude mixture was concentrated, dissolved in MeOH and purified by Prep-HPLC to afford N-[3-chloro-4-[4-(1,1- dimethylpiperidin-1-ium-4-carbonyl)piperazine-1-carbonyl]phe nyl]-5-[2,3-difluoro-4-[3-methyl- 1-[2-[(6-methyl-3-pyridyl)carbamoylamino]ethyl]pyrazol-4-yl] phenyl]-1-methyl-imidazole-2- carboxamide formate (1.2 mg, 4.5% yield) as white amorph freeze-dried solid. MS [M+]: 856.5. Example N1 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-im idazole-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-a mmonium;formic acid;formate

Step 1: N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[4-[1-[2-(dif luoromethoxy)ethyl]-5- methyl-pyrazol-4-yl]-3-fluoro-2-methyl-phenyl]-1-methyl-imid azole-2- carboxamide;hydrochloride To a mixture of tert-butyl 4-[2-chloro-4-[[5-[4-[1-[2-(difluoromethoxy)ethyl]-5-methyl- pyrazol- 4-yl]-3-fluoro-2-methyl-phenyl]-1-methyl-imidazole-2-carbony l]amino]benzoyl]piperazine-1- carboxylate (100.0 mg, 0.14 mmol) in 1,4-Dioxane (2 mL) was added HCl (0.5 mL, 2.0 mmol, 4M in 1,4-dioxane) at 30 °C and stirred at 30 °C for 4 h. The reaction mixture was concentrated in vacuum to afford crude N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[4-[1-[2- (difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-3-fluoro-2-me thyl-phenyl]-1-methyl-imidazole- 2-carboxamide;hydrochloride (90.0 mg, 0.14 mmol, 98.6% yield) as light yellow solid. MS [(M+H)+]:630.0. Step 2: (1-tert-butoxycarbonylazetidin-3-yl)methyl-(2-tert-butoxy-2- oxo-ethyl)-[4-[4-[2- chloro-4-[[5-[4-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyraz ol-4-yl]-3-fluoro-2-methyl- phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazi n-1-yl]-4-oxo-butyl]- methyl-ammonium;2,2,2-trifluoroacetate To a solution of N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[4-[1-[2- (difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-3-fluoro-2-me thyl-phenyl]-1-methyl-imidazole- 2-carboxamide;hydrochloride (90.0 mg, 0.14 mmol), (1-tert-butoxycarbonylazetidin-3- yl)methyl-(2-tert-butoxy-2-oxo-ethyl)-(3-carboxypropyl)-meth yl-ammonium;2,2,2- trifluoroacetate (115.79 mg, 0.23 mmol) and DIEA (0.1 mL, 0.6 mmol) in DMF (0.5 mL) was added HATU (85.57 mg, 0.23 mmol) at 0°C. The mixture was stirred at 0 °C for 0.5 h. The mixture was quenched with water (1 drop) and then concentrated under vacuum to afford a residue, which was purified by reversed phase and lyophilized to give (1-tert- butoxycarbonylazetidin-3-yl)methyl-(2-tert-butoxy-2-oxo-ethy l)-[4-[4-[2-chloro-4-[[5-[4-[1-[2- (difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-3-fluoro-2-me thyl-phenyl]-1-methyl-imidazole- 2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl -ammonium;2,2,2- trifluoroacetate (70 mg, 0.06 mmol, 41.4% yield) as a light yellow solid. MS [(M)+]: 1012.4. Step 3: azetidin-3-ylmethyl-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[4 -[1-[2- (difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-3-fluoro-2-me thyl-phenyl]-1-methyl- imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-but yl]-methyl- ammonium;formic acid;formate To a solution of (1-tert-butoxycarbonylazetidin-3-yl)methyl-(2-tert-butoxy-2- oxo-ethyl)-[4-[4- [2-chloro-4-[[5-[4-[1-[2-(difluoromethoxy)ethyl]-5-methyl-py razol-4-yl]-3-fluoro-2-methyl- phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazi n-1-yl]-4-oxo-butyl]-methyl- ammonium;2,2,2-trifluoroacetate (65.0 mg, 0.06 mmol) in DCM (0.5 mL) was added TFA (2.6 mL, 33.75 mmol) at 30 °C and stirred for 16h. The mixture was concentrated under vacuum, the residue was purified by prep-HPLC (Column: Unisil 3-100 C18 Ultra 150 × 50 mm × 3 um; Condition: water (0.225% FA)-ACN; Begin B= 16%, End B= 36%; Gradient Time(min) 10 min) and lyophilized to give azetidin-3-ylmethyl-(carboxymethyl)-[4-[4-[2-chloro-4-[[5-[4 -[1-[2- (difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-3-fluoro-2-me thyl-phenyl]-1-methyl-imidazole- 2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl -ammonium;formic acid;formate (33.1 mg, 0.03 mmol, 57.11% yield) as a white solid. MS [(M)+]: 856.1. The following examples were prepared in analogy to Example N1

Example N4 cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[4-[1-[2-(di fluoromethoxy)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

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-carbo xylate 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (4.61 g, 24 mmol, Eq: 1.05) and N-ethyl-N-isopropylpropan-2-amine (14.8 g, 20 ml, 114 mmol, Eq: 5) were added to a solution of 2-chloro-4-(5-(2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phen yl)-1- methyl-1H-imidazole-2-carboxamido)benzoic acid (10.8 g, 22.9 mmol, Eq: 1) and 1H- benzo[d][1,2,3]triazol-1-ol (3.25 g, 24 mmol, Eq: 1.05) in DMA (57.2 ml) and stirred for 18 hours at room temperature. The mixture was poured into 100 mL and extrated with EtOAc (50 mLx 4). The organic layer was washed with 50 mL with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was used in the next step without purification. Step 2: tert-butyl 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]ben zoyl]piperazine-1- carboxylate To a mixture of 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-car boxylate (700.0 mg, 1.09 mmol, 1.0 eq) and 2-(difluoromethoxy)ethyl 4-methylbenzenesulfonate (349.42 mg, 1.31 mmol, 1.2 eq) in DMF (10 mL) was added potassium carbonate (453.43 mg, 3.28 mmol, 3.0 eq). The reaction mixtrue was stirred at 60 °C for 16 h. The reaction mixture was filtered, the filtrate was purified by prep-HPLC (FA) to afford a mixture of isomers. The mixture was further purified by SFC to afford tert-butyl 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-carboxylate (125.0 mg, 0.17 mmol, 15.57% yield) as yellow solid and the title compound tert-butyl 4-[2- chloro-4-[[5-[4-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyraz ol-4-yl]-2,3-difluoro-phenyl]-1- methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbo xylate (125.0 mg, 0.17 mmol, 15.57% yield) as yellow solid. MS [(M+H)+]:734.3 Step 3: N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[4-[1-[2-(dif luoromethoxy)ethyl]-3- methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole -2- carboxamide;hydrochloride A mixture of tert-butyl 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- carboxylate (125.0 mg, 0.17 mmol, 1.0 eq) in HCl (4N in dioxane) (5.0 mL, 5.0 mmol, 29.37 eq) was stirred at 30 °C for 15 h. The reaction mixture was concetrated in vacuum to afford N-[3- chloro-4-(piperazine-1-carbonyl)phenyl]-5-[4-[1-[2-(difluoro methoxy)ethyl]-3-methyl-pyrazol- 4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; hydrochloride (100.0 mg, 0.15 mmol, 92.63% yield) as yellow solid. MS [(M+H)+]:634.1 Step 4: tert-butyl 3-[[1-(2-tert-butoxy-2-oxo-ethyl)-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]methyl]azetidine-1- carboxylate To a mixture of 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-but oxy-2-oxo- ethyl)piperidin-1-ium-4-carboxylic acid (156.54 mg, 0.38 mmol, 1.2 eq) and N-ethyl-N- isopropylpropan-2-amine (0.16 mL, 0.95 mmol, 3.0 eq) in DMF (3 mL) was added 2-chloro-1- methylpyridin-1-ium iodide (96.71 mg, 0.38 mmol, 1.2 eq). The reaction mixture was stirred at 30 °C for 0.5 h. Then, N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[4-[1-[2- (difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-2,3-difluoro- phenyl]-1-methyl-imidazole-2- carboxamide (200.0 mg, 0.32 mmol, 1.0 eq) was added to the above solution. The reaction mixture was stirred at 30 °C for another 3.5 h. The reaction mixture was purified by prep-HPLC (FA) to afford tert-butyl 3-[[1-(2-tert-butoxy-2-oxo-ethyl)-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]methyl]azetidine-1- carboxylate (170.0 mg, 0.17 mmol, 52.35% yield) as yellow solid. MS [(M+H)+]:1028.5 Step 5: cis 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[4-[1-[2-(di fluoromethoxy)ethyl]- 3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium -1-yl]acetate A solution of tert-butyl 3-[[1-(2-tert-butoxy-2-oxo-ethyl)-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]methyl]azetidine-1- carboxylate (150.0 mg, 0.15 mmol, 1.0 eq) in DCM (2 mL) was added trifluoroacetic acid (2.0 mL, 25.96 mmol, 178.18 eq). The reaction mixture was stirred at 30 °C for 16 h. The reaction mixture was concentrated in vacuum to give the residue, which was purified by prep-HPLC (FA) to afford 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[4-[1-[2-(di fluoromethoxy)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]acetic acid;formate (82.3 mg, 0.09 mmol, 58.8% yield) as white solid Cis and trans isomers were separated by SFC chiral to afford the cis title coumpound (15.2 mg, 42.57%) as white powder. MS [(M+H)+]:872.3 Example O1 2-[1-(azetidin-3-ylmethyl)-4-[[1-[2-chloro-4-[[5-[2,3-difluo ro-4-[1-(2-methoxyethyl)-5- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]am ino]benzoyl]-4-piperidyl]- methyl-carbamoyl]piperidin-1-ium-1-yl]acetic acid formate To N-[3-chloro-4-[4-(methylamino)piperidine-1-carbonyl]phenyl]- 5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide (8.7 mg, 0.014 mmol, 1 eq) dissolved in dichloromethane (2 mL), was added PyAOP reagent (9.49 mg, 0.018 mmol, 1.300 eq) and DIEA (7.24 mg, 9.8 uL, 0.056 mmol, 4.000 eq) followed by 1-[(1- tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2- keto-ethyl)piperidin-1-ium-4- carboxylic acid;2,2,2-trifluoroacetate (11.8 mg, 0.0224 mmol, 1.6 eq). The mixture was stirred at room temperature over night. The mixture weas then treated with an excess of HCl 4N in dioxane (15.31 mg, 12.76 uL, 0.420 mmol, 30.000 eq) over night at room temperature The mixture was then concentrated and directly purified by preparative HPLC to afford the title compound (1.7 mg, 13.3% yield). MS [M-]: 862.5. The following examples were prepared in analogy to Example O1 Example O11 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-methy l-pyrazol-4-yl]-2-methyl- phenyl]-1-methyl-imidazole-2-carboxamide 2,2,2-trifluoroacetate Step 1: (2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carboxylic acid trans-4-hydroxy-L-proline (8 g, 61.01 mmol, 1 eq) is dispensed in methanol (50 mL).1,3- diisopropyl-2-methyl-isourea (10.62 g, 67.11 mmol, 1.1 eq) was added and the suspension is stirred at 22°C for 18 hr. Motherliquor is evaporated to dryness to afford crude (2S,4R)-4- hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carboxylic acid (15.011 g, 99.8% yield, purity 65%) which was used crude for next step. MS [M+]: 160.1 Step 2: 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-m ethoxyethyl)-5-methyl- pyrazol-4-yl]-2-methyl-phenyl]-1-methyl-imidazole-2-carboxam ide 2,2,2-trifluoroacetate (2S,4R)-4-hydroxy-1,1-dimethyl-pyrrolidin-1-ium-2-carboxylic acid (13.9 mg, 0.039 mmol, 1.179 eq) was dissolved in N,N-dimethylformamide (1 mL), DIEA (12.58 mg, 17 uL, 0.097 mmol, 2.937 eq) and HATU (15 mg, 0.039 mmol, 1.190 eq) were added and the mixture was stirred for 2 min before N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[3-fluoro-4-[ 1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]-2-methyl-phenyl]-1-meth yl-imidazole-2-carboxamide .1:12,2,2-trifluoroacetic acid (24.7 mg, 0.033 mmol, 1.000 eq) was added. The reaction mixture was stirred at room temperature for 1.5 h. an excess of 4 M HCl in dioxane (1.03 g, 855.73 uL, 3.42 mmol, 42.82 eq) was added and the mixture was stirring for 5 h at room temperature. The crude reaction mixture was directly purified by preparative HPLC and lyophilized to afford the title compound (14.6 mg, 52% yield) a colourless lyoph powder. MS [M+]: 735.5. Example O12 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 formate Step 1: N-[3-[4-[3-[[1-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxy ethyl)-5-methyl-pyrazol- 4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]iso nipecotoyl]amino]propyl]-2- pyridyl]propyl]carbamic acid tert-butyl ester To a solution of 1-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-meth yl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]isoni pecotic acid (105.7 mg, 0.165 mmol, 1.000 eq) and N-[3-[4-(3-aminopropyl)-2-pyridyl]propyl]carbamic acid tert-butyl ester;hydrochloride (92 mg, 0.279 mmol, 1.691 eq) in N,N-dimethylformamide (1 mL) was added DIPEA (127.86 mg, 172.78 uL, 0.989 mmol, 6.000 eq) and HATU (81.5 mg, 0.214 mmol, 1.300 eq), the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue pruified via preparative HPLC to afford the title compound (95.7 mg, 63.33% yield) as off-white lyoph powder. MS [(M+H)+]: 916.9. Step 2: 2-[2-[3-(tert-butoxycarbonylamino)propyl]-4-[3-[[1-[2-chloro -4-[[5-[2,3-difluoro-4- [1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-i midazole-2- carbonyl]amino]benzoyl]isonipecotoyl]amino]propyl]pyridin-1- ium-1-yl]acetic acid tert- butyl ester To a solution of N-[3-[4-[3-[[1-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxy ethyl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2- carbonyl]amino]benzoyl]isonipecotoyl]amino]propyl]-2-pyridyl ]propyl]carbamic acid tert-butyl ester (95.7 mg, 0.104 mmol, 1.000 eq) in acetonitrile (2 mL) was added tert-butyl bromoacetate (162.94 mg, 123.44 uL, 0.835 mmol, 8.000 eq) and DIPEA (107.97 mg, 145.9 uL, 0.835 mmol, 8.000 eq), and the reaction mixture stirred at 50 °C overnight. The solvent was removed in vacuo to afford crude 2-[2-[3-(tert-butoxycarbonylamino)propyl]-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 tert-butyl ester (243.8 mg, 99.58%) as yellow viscous oil, which was used without further purification. MS [M+]: 1030.9. Step 3: 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 formate To a solution of 2-[2-[3-(tert-butoxycarbonylamino)propyl]-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 tert-butyl ester (243.8 mg, 0.104 mmol, 1.000 eq) in dichloromethane (2 mL) was added 4 M HCl in Dioxane (249.57 mg, 207.97 uL, 0.832 mmol, 8.000 eq) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified via preparative HPLC to afford the title compound as light yellow lyoph powder. MS [M+]: 874.8 Example P1 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-imidazo le-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-a mmonium;formate Step 1: tert-butyl N-[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]ben zoyl]piperazin-1-yl]-4-oxo- butyl]carbamate To a stirred mixture of N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[2,3-difluoro -4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide (633.0 mg, 1.0 mmol), DIEA (0.52 mL, 3.01 mmol) and BOC-gamma-abu-OH (0.2 g, 1.0 mmol) in DMF (10 mL) was added HATU (0.76 g, 2.01 mmol) at 15°C. The reaction mixture was stirred at 15°C for 1h. The mixture was poured into water, extracted with EtOAc, washed with brine, dried over Na2SO ₄ and concentrated in vacuum to afford crude tert-butyl N-[4-[4-[2-chloro-4-[[5- [2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]ph enyl]-1-methyl-imidazole-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]carbamate (500.0 mg, 0.64 mmol, 63.63% yield) as black oil. MS [(M+H)+]: 783.5. Step 2: N-[4-[4-(4-aminobutanoyl)piperazine-1-carbonyl]-3-chloro-phe nyl]-5-[2,3-difluoro- 4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl -imidazole-2-carboxamide A solution of tert-butyl N-[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]ben zoyl]piperazin-1-yl]-4-oxo- butyl]carbamate (500.0 mg, 0.64 mmol) in hydrochloric acid (6.0 mL, 4 M in 1,4-dioxane) was stirred at 15 °C for 1 h. The mixture was concentrated in vacuum, the residue was purified by reversed phase HPLC and lyophilized to afford N-[4-[4-(4-aminobutanoyl)piperazine-1- carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyet hyl)-5-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide (320.0 mg, 0.47 mmol, 73.38% yield) as white solid MS [(M+H)+]: 683.1. Step 3: tert-butyl 3-[[[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]ben zoyl]piperazin-1-yl]-4-oxo- butyl]amino]methyl]azetidine-1-carboxylate To a solution of N-[4-[4-(4-aminobutanoyl)piperazine-1-carbonyl]-3-chloro-phe nyl]-5-[2,3- difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl] -1-methyl-imidazole-2- carboxamide (110.0 mg, 0.16 mmol) in ACN (5 mL) was added 1-BOC-3- (bromomethyl)azetidine (40.28 mg, 0.16 mmol,), sodium iodide (24.14 mg, 0.16 mmol) and potassium carbonate (33.38 mg, 0.24 mmol, 1.5 eq) at 20 °C. Then the reaction mixture was heated to 50 °C and stirred for 16 h. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by Prep-HPLC, lyophilized to afford tert-butyl 3-[[[4-[4-[2- chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-py razol-4-yl]phenyl]-1-methyl- imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-but yl]amino]methyl]azetidine-1- carboxylate (40.0 mg, 0.05 mmol, 29.14% yield) as white solid. MS [(M+H)+]: 852.2. Step 4: tert-butyl 3-[[(2-tert-butoxy-2-oxo-ethyl)-[4-[4-[2-chloro-4-[[5-[2,3-d ifluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]amino]met hyl]azetidine-1-carboxylate To a solution of tert-butyl 3-[[[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl )-5- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]am ino]benzoyl]piperazin-1-yl]-4- oxo-butyl]amino]methyl]azetidine-1-carboxylate (40.0 mg, 0.05 mmol) and TEA (0.02 mL, 0.14 mmol)in ACN (5 mL) was added tert-butyl bromoacetate (0.01 mL, 0.06 mmol) at 20 °C, then the solution was stirred at 35 °C for 16 h. The reaction mixture was concentrated, purified by reversed phase-HPLC and concentrated to afford tert-butyl 3-[[(2-tert-butoxy-2-oxo-ethyl)-[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-but yl]amino]methyl]azetidine-1- carboxylate (40.0 mg, 0.04 mmol, 88.19% yield) as yellow oil. MS [(M+H)+]: 966.2. Step 5: (1-tert-butoxycarbonylazetidin-3-yl)methyl-(2-tert-butoxy-2- oxo-ethyl)-[4-[4-[2- chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-py razol-4-yl]phenyl]-1-methyl- imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-but yl]-methyl- ammonium;iodide To a solution of tert-butyl 3-[[(2-tert-butoxy-2-oxo-ethyl)-[4-[4-[2-chloro-4-[[5-[2,3-d ifluoro-4- [1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-i midazole-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]amino]met hyl]azetidine-1-carboxylate (40.0 mg, 0.04 mmol) and TEA (0.02 mL, 0.12 mmol) in ACN (2 mL) was added iodomethane (0.03 mL, 0.41 mmol) at 15 °C, then the solution was stirred at 15 °C for 2 h. The reaction mixture was concentrated in vacuum, the residue was purified by reversed phase HPLC and lyophilized to afford (1-tert-butoxycarbonylazetidin-3-yl)methyl-(2-tert-butoxy-2- oxo-ethyl)-[4- [4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1-methyl- imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-but yl]-methyl-ammonium;iodide (30.0 mg, 0.03 mmol, 98.47% yield) as white solid. MS [(M)+]: 980.2. Step 6: 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-imidazo le-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-a mmonium;formate A solution of (1-tert-butoxycarbonylazetidin-3-yl)methyl-(2-tert-butoxy-2- oxo-ethyl)-[4-[4-[2- chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-py razol-4-yl]phenyl]-1-methyl- imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-but yl]-methyl-ammonium;iodide (30.0 mg, 0.03 mmol) in DCM (1 mL) was added TFA (1.0 mL, 12.98 mmol) at 15 °C and stirred at 15 °C for 16 h. The reaction mixture was concentrated in vacuum, the residue was purified by Prep-HPLC and lyophilized to afford azetidin-3-ylmethyl-(carboxymethyl)-[4-[4-[2- chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-py razol-4-yl]phenyl]-1-methyl- imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-but yl]-methyl-ammonium;formate (13.7 mg, 0.02 mmol) as white solid. MS [(M)+]: 824.1. Example P2 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-imidazo le-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]ammonium; formate intermediate R19 intermediate H8 Step 1: bis[4-(tert-butoxycarbonylamino)butyl]-(2-tert-butoxy-2-oxo- ethyl)-[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-but yl]ammonium;formate To a mixture of bis[4-(tert-butoxycarbonylamino)butyl]-(2-tert-butoxy-2-oxo- ethyl)-(3- carboxypropyl)ammonium;bromide (128.55 mg, 0.2 mmol) and DIEA(64.83 mg, 0.5 mmol) in DMF (2 mL) was added CMPI (51.26 mg, 0.2 mmol) at 30°C and stirred at 30 °C for 0.5 h. Then, 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 (100.0 mg, 0.17 mmol) was added to the above solution and stirred at 30 °C for another 3.5 h. The reaction mixture was purified by reversed phase-HPLC (water (0.1% FA)-ACN, B=85%~90%) and lyophilized to afford bis[4-(tert-butoxycarbonylamino)butyl]-(2-tert-butoxy-2-oxo- ethyl)-[4-[4-[2-chloro-4-[[5- [2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]ph enyl]-1-methyl-imidazole-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]ammonium; formate (80.0 mg, 0.07 mmol, 41.94% yield) as yellow solid. MS [(M)+]: 1139.5. Step 2: 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-imidazo le-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]ammonium; formate To a mixture of bis[4-(tert-butoxycarbonylamino)butyl]-(2-tert-butoxy-2-oxo- ethyl)-[4-[4-[2- chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-py razol-4-yl]phenyl]-1-methyl- imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-but yl]ammonium;formate (60.0 mg, 0.05 mmol) in DCM (2 mL) was added TFA (2.0 mL, 25.96 mmol) at 30 °C and stirred for 16 h. The reaction mixture was concentrated in vacuum to give the residue, which was purified by prep-HPLC (Phenomenex Synergi C18150 × 25 mm × 10 um, water (0.225% FA)-ACN, B= 9%-39% FlowRat: 25 ml/min) to afford bis(4-aminobutyl)-(carboxymethyl)-[4-[4-[2-chloro-4- [[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-y l]phenyl]-1-methyl-imidazole-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]ammonium; formate (30.0 mg, 0.03 mmol) as white solid. MS [(M)+]: 883.5. Example P3 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]ben zoyl]piperazin-1-yl]-4-oxo- butyl]-methyl-ammonium;formate Step 1: tert-butyl N-[3-[3-(tert-butoxycarbonylamino)propyl-[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]amino]pro pyl]carbamate To a stirred mixture of N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[2,3-difluoro -4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide (100.0 mg, 0.17 mmol), DIEA (0.09 mL, 0.5 mmol) and 4-[bis[3-(tert- butoxycarbonylamino)propyl]amino]butanoic acid (69.82 mg, 0.17 mmol) in DMF (3 mL) was added HATU (0.13 g, 0.33 mmol) at 15 °C. Then the solution was stirred at 15 °C for 12 h. The mixture was poured into water (40 ml), extracted with EtOAc (40 ml), washed with brine (30 ml), dried over Na2SO ₄ and concentrated in vacuum to afford a residue. The residue was purified by reversed phase HPLC and lyophilized to afford tert-butyl N-[3-[3-(tert- butoxycarbonylamino)propyl-[4-[4-[2-chloro-4-[[5-[2,3-difluo ro-4-[1-(2-methoxyethyl)-5- methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]am ino]benzoyl]piperazin-1-yl]-4- oxo-butyl]amino]propyl]carbamate (60.0 mg, 0.06 mmol, 35.97% yield) as white solid. MS [(M+H)+]: 997.2. Step 2: bis[3-(tert-butoxycarbonylamino)propyl]-[4-[4-[2-chloro-4-[[ 5-[2,3-difluoro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-a mmonium;iodide To a solution of tert-butyl N-[3-[3-(tert-butoxycarbonylamino)propyl-[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]amino]pro pyl]carbamate (60.0 mg, 0.06 mmol) and TEA (0.03 mL, 0.18 mmol) in ACN (3 mL) was added iodomethane (0.04 mL, 0.6 mmol) at 15 °C and stirred for 16 h. The reaction mixture was concentrated in vacuum, purified by reversed phase and lyophilized to afford bis[3-(tert-butoxycarbonylamino)propyl]-[4-[4-[2- chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-py razol-4-yl]phenyl]-1-methyl- imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-but yl]-methyl-ammonium;iodide (25.0 mg, 0.02 mmol, 36.48% yield) as white solid. MS [(M)+]: 1011.3. Step 3: 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]am ino]benzoyl]piperazin-1- yl]-4-oxo-butyl]-methyl-ammonium;formate To a solution of bis[3-(tert-butoxycarbonylamino)propyl]-[4-[4-[2-chloro-4-[[ 5-[2,3-difluoro-4- [1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-i midazole-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-a mmonium;iodide (50.0 mg, 0.04 mmol) in DCM (3 mL) was added TFA (3.0 mL, 38.94 mmol), the solution was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuum and purified by Prep-HPLC, lyophilized to afford bis(3-aminopropyl)-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1- (2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-methyl-a mmonium;formate (15.7 mg, 0.02 mmol) as white solid. MS [(M)+]: 811.5. Example P4 carboxymethyl-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-me thoxyethyl)-5-methyl-pyrazol- 4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]pip erazin-1-yl]-4-oxo-butyl]- bis[2-(dimethylamino)ethyl]ammonium;2,2,2-trifluoroacetate Step 1: bis[2-(tert-butoxycarbonylamino)ethyl]-(2-tert-butoxy-2-oxo- ethyl)-[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-but yl]ammonium;formate To a solution of N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[2,3-difluoro -4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide (200.0 mg, 0.33 mmol), DIEA (0.17 mL, 1.0 mmol) and bis[2-(tert-butoxycarbonylamino)ethyl]-(2-tert- butoxy-2-oxo-ethyl)-(3-carboxypropyl)ammonium;bromide (195.49 mg, 0.33 mmol) in DMF (5 mL) was added HATU (0.25 g, 0.67 mmol) at 15 °C. Then the solution was stirred at 15 °C for 16 h. The mixture was purified by reversed phase-HPLC and lyophilized to afford bis[2-(tert- butoxycarbonylamino)ethyl]-(2-tert-butoxy-2-oxo-ethyl)-[4-[4 -[2-chloro-4-[[5-[2,3-difluoro-4- [1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-i midazole-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]ammonium; formate (300.0 mg, 0.27 mmol, 82.7% yield) as light brown solid. MS [(M)+]: 1083.5. Step 2: (2-tert-butoxy-2-oxo-ethyl)-[4-[4-[2-chloro-4-[[5-[2,3-diflu oro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-bis[2- (dimethylamino)ethyl]ammonium;formate To a solution of bis[2-(tert-butoxycarbonylamino)ethyl]-(2-tert-butoxy-2-oxo- ethyl)-[4-[4-[2- chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-methyl-py razol-4-yl]phenyl]-1-methyl- imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-but yl]ammonium;formate (245.0 mg, 0.22 mmol) and formaldehyde (1.0 mL, 37% in water) in DCM (4 mL) was added TFA (1.0 mL, 12.98 mmol) and stirred at 20 °C for 16 h. NaBH(OAc)3 (229.82 mg, 1.08 mmol) was added to the solution and stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuum and the residue was purified by reversed phase-HPLC and lyophilized to obtain (2-tert- butoxy-2-oxo-ethyl)-[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]ben zoyl]piperazin-1-yl]-4-oxo- butyl]-bis[2-(dimethylamino)ethyl]ammonium;formate (60.0 mg, 0.06 mmol, 28.07% yield) as light brown solid. MS [(M)+]: 939.6. Step 3: carboxymethyl-[4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-me thoxyethyl)-5-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]ben zoyl]piperazin-1-yl]-4-oxo- butyl]-bis[2-(dimethylamino)ethyl]ammonium;2,2,2-trifluoroac etate To a solution of (2-tert-butoxy-2-oxo-ethyl)-[4-[4-[2-chloro-4-[[5-[2,3-diflu oro-4-[1-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2- carbonyl]amino]benzoyl]piperazin-1-yl]-4-oxo-butyl]-bis[2- (dimethylamino)ethyl]ammonium;formate (60.0 mg, 0.06 mmol) in DCM (1 mL) was added TFA (1.0 mL, 12.98 mmol) and stirred at 20 °C for 16 h. The reaction mixture was concentrated in vacuum and the residue was purified by prep-HPLC to obtain 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;2,2,2-trifluoroacetate (11.86 mg, 0.01 mmol) as white solid. MS [(M)+]: 883.6. Example P5 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]ben zoyl]piperazino]-5-keto- pentanoyl]piperazin-1-ium-1-yl]acetic acid formate Step 1: 5-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-m ethyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azino]-5-keto-valeric acid methyl ester 5-keto-5-methoxy-valeric acid (35.93 mg, 0.246 mmol, 1.300 eq), HATU (107.87 mg, 0.284 mmol, 1.500 eq) and DIEA (122.21 mg, 165.15 uL, 0.946 mmol, 5.000 eq) are dissolved in N,N- dimethylformamide (1.2 mL). The mixture is stirred for 10 min. N-[3-chloro-4-(piperazine-1- carbonyl)phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide;hydrochloride (120 mg, 0.189 mmol, 1.000 eq) is then added and the mixture was stirred at room temperature over night.. The mixture was poured into 50mL water and extracted 2x with EtOAc. The organic phases were combined and evaporated to dryness to give 5-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-m ethyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azino]-5-keto-valeric acid methyl ester .1:1 hydrogen chloride (299.5 mg, 99.67%) as light brown solid and used crude for next step. [(M+H)+]: 726.3 Step 2: 5-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-m ethyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azino]-5-keto-valeric acid 5-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-m ethyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carbonyl]amino]benzoyl]piperazino]-5-keto -valeric acid methyl ester (299.5 mg, 0.189 mmol, 1.000 eq) was dissolved in methanol (5 mL) and water (2 mL). lithium hydroxide monohydrate (79.1 mg, 1.89 mmol, 10.000 eq) was added and the reaction is stirred at 22°C for 18 hr. The clear solution was acidified with 4M aq. HCl solution. The product is extracted two times with ethylacetate. Both organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. The crude product purified via prep HPLC to afford after lyophilization 5-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-m ethyl-pyrazol- 4-yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]pip erazino]-5-keto-valeric acid (50.6 mg, 37.32%) as white solid. [(M+H)+]: 712.2 Step 3: 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]am ino]benzoyl]piperazino]-5- keto-pentanoyl]piperazin-1-ium-1-yl]acetic acid formate To a solution of 5-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-m ethyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azino]-5-keto-valeric acid (12.5 mg, 0.017 mmol, 1.000 eq) and 2-[1-[3-(tert-butoxycarbonylamino)propyl]piperazin-1-ium-1- yl]acetic acid tert-butyl ester;formate (10.37 mg, 0.024 mmol, 1.477 eq) in dichloromethane (1.04 mL) was added DIEA (10.68 mg, 14.44 uL, 0.083 mmol, 5.000 eq) and then PyAOP reagent (11.2 mg, 0.021 mmol, 1.300 eq). The reaction mixture was stirred at room temprature for 2 hr. Boc and t-butyl were then deprotected with 4N HCl in dioxane (247.96 mg, 206.64 uL, 0.827 mmol, 50.000 eq) over night at room temprature. Volatils were removed in vacuo and the residue was purified via prep HPLC to yield the desired compound 2-[1-(3-aminopropyl)-4-[5- [4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-5-met hyl-pyrazol-4-yl]phenyl]-1-methyl- imidazole-2-carbonyl]amino]benzoyl]piperazino]-5-keto-pentan oyl]piperazin-1-ium-1-yl]acetic acid formate (5.8 mg, 37.27%) as white powder. MS [M-]: 940.5 The following example was prepared in analogy to Example P5 Example Q1 N-[3-chloro-4-[4-(4-oxo-3-aza-6-azoniaspiro[5.5]undecane-9-c arbonyl)piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetate Intermediate I2 Step 1 :tert-butyl 2-[1-[2-(tert-butoxycarbonylamino)ethyl]-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]acetate;2,2,2- trifluoroacetate To a solution 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-imidazo le-2-carboxamide;hydrochloride (200.0 mg, 0.32 mmol), DIEA (0.16 mL, 0.95 mmol) and 1-[2-(tert- butoxycarbonylamino)ethyl]-1-(2-tert-butoxy-2-oxo-ethyl)pipe ridin-1-ium-4-carboxylic acid;2,2,2-trifluoroacetate (205.09 mg, 0.41 mmol) in DMF (4 mL) was added HATU (179.78 mg, 0.47 mmol, 1.5 eq) at 0 °C and stirred at 0 °C for 1 h. The solution was purified by reversed phase-HPLC and lyophilized to afford tert-butyl 2-[1-[2-(tert-butoxycarbonylamino)ethyl]-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]pip eridin-1-ium-1-yl]acetate;2,2,2- trifluoroacetate (251.0 mg, 0.23 mmol, 73.7% yield) as white solid. MS [(M)+]: 966.6. Step 2: N-[3-chloro-4-[4-(4-oxo-3-aza-6-azoniaspiro[5.5]undecane-9-c arbonyl)piperazine-1- carbonyl]phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-met hyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetate To a solution of tert-butyl 2-[1-[2-(tert-butoxycarbonylamino)ethyl]-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]acetate;2,2,2- trifluoroacetate (51.0 mg, 0.05 mmol) in DCM (2 mL) was added TFA (4.0 mL, 51.92 mmol) in one portion at 10 °C and stirred at 10 °C for 16 h. The solution was concentrated, purified by Prep-HPLC and lyophilized to afford N-[3-chloro-4-[4-(4-oxo-3-aza-6- azoniaspiro[5.5]undeACNe-9-carbonyl)piperazine-1-carbonyl]ph enyl]-5-[2,3-difluoro-4-[1-(2- methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imidazo le-2-carboxamide;2,2,2- trifluoroacetate (17.4 mg, 0.02 mmol) as white solid. MS [(M)+]: 792.3. Example Q2 N-[4-[4-(3-benzyl-3-aza-6-azoniaspiro[5.5]undecane-9-carbony l)piperazine-1-carbonyl]-3- chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methy l-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carboxamide Step 1: 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-m ethyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piper azine-1- carbonyl]piperidine-1-carboxylic acid tert-butyl ester To a solution of 1-tert-butoxycarbonylisonipecotic acid (20.93 mg, 91.3 umol, 1.200 eq), 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 (50 mg, 76.08 umol, 1.000 eq), HATU (43.39 mg, 114.12 umol, 1.500 eq) and N,N-dimethylformamide, extra dry (400 uL) was added DIEA (29.5 mg, 39.86 uL, 228.25 umol, 3.000 eq) and the reaction mixture was stirred at room temperature for 2h. The reaction mixture was diluted in EtOAc, and then washed with water and brine, filtered over MgSO ₄ and then concentrated under vacuo. The crude material was purified by flash chromatography to yield 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-ca rboxylic acid tert-butyl ester (41.8 mg, 67.89%) as yellow waxy solid. MS [(M+H)+]: 809.4 Step 2: N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]- 5-[2,3-difluoro-4-[1- (2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-1-methyl-imid azole-2-carboxamide hydrochloride 4-[4-[2-chloro-4-[[5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-m ethyl-pyrazol-4-yl]phenyl]-1- methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbo nyl]piperidine-1-carboxylic acid tert-butyl ester (41.8 mg, 0.052 mmol, 1.000 eq) was treated with an excess of 4 M HCl in dioxane (129.12 uL, 516.5 umol, 10.000 eq) in 1,4-dioxane (1.0 mL) and was stirred at room temperature over 4 days. Diethyl ether was added so the product was crash out. The solvent was evaporated to yield N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]- 5-[2,3- difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl] -1-methyl-imidazole-2- carboxamide hydrochloride (40.8 mg, 100%) as white solid. MS [(M+H)+]: 709.3. Step 3: N-[4-[4-(3-benzyl-3-aza-6-azoniaspiro[5.5]undecane-9-carbony l)piperazine-1- carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyet hyl)-3-methyl-pyrazol-4- yl]phenyl]-1-methyl-imidazole-2-carboxamide Benzyl-bis(2-bromoethyl)amine (9.47 mg, 6.06 uL, 29.5 umol, 1.100 eq), N-[3-chloro-4-(4- isonipecotoylpiperazine-1-carbonyl)phenyl]-5-[2,3-difluoro-4 -[1-(2-methoxyethyl)-3-methyl- pyrazol-4-yl]phenyl]-1-methyl-imidazole-2-carboxamide (20 mg, 26.82 umol, 1.000 eq), potassium carbonate (12.23 mg, 88.51 umol, 3.300 eq) and potassium iodide (890.51 ug, 5.36 umol, 0.200 eq) were combined in N,N-dimethylformamide (500 uL). The reaction mixture was then stirred at room temperature over night. The mixture was purified over prep HPLC to afford N-[4-[4-(3-benzyl-3-aza-6-azoniaspiro[5.5]undecane-9-carbony l)piperazine-1-carbonyl]-3- chloro-phenyl]-5-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methy l-pyrazol-4-yl]phenyl]-1-methyl- imidazole-2-carboxamide (5.1 mg, 20.56%) as colorless solid. MS [(M)+]: 868.5. The following examples were prepared in analogy to Example O1

Assay procedures Antimicrobial susceptibility testing: 90% Growth Inhibitory Concentration (IC90) determination The in vitro antimicrobial activity of the compounds was determined according to the following procedure: The assay used a 10-points Iso-Sensitest broth medium to measure quantitatively the in vitro activity of the compounds against Acinetobacter baumannii ATCC17961. Stock compounds in DMSO were serially twofold diluted (e.g. range from 50 to 0.097 µM final concentration) in 384 wells microtiter plates and inoculated with 49 µl the bacterial suspension in Iso-Sensitest medium to have a final cell concentration of ~ 5x10 ⁽⁵⁾ CFU/ml in a final volume/well of 50 ul/well. Microtiter plates were incubated at 35 ± 2 °C. Bacterial cell growth was determined with the measurement of optical density at λ=600nm each 20 minutes over a time course of 16h. Growth inhibition was calculated during the logarithmic growth of the bacterial cells with determination of the concentration inhibiting 50% (IC50) and 90% (IC90) of the growth. Table 1 provides the 90% growth inhibitory concentrations (IC90) in micromoles per liter of the compounds of present invention obtained against the strain Acinetobacter baumannii ATCC17961. Particular compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17961) ≤ 25 µmol/l. More particular compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17961) ≤ 5 µmol/l. Most particular compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17961) ≤ 1 µmol/l. Table 1 Minimal Inhibitory Concentration Protocol (MIC) Assay: Table 2 provides the in vitro potency of the compounds of present invention obtained against the strain Acinetobacter baumannii ATCC17978, which was assessed by an MIC (Minimal Inhibitory Concentration) assay as follows. Test compounds were prepared from 10 mM DMSO stock solutions. The top dose was diluted from 10 mM to 2.5 mM by DMSO, followed by serial 2-fold 11 points dilutions in DMSO in a master plate (Greiner, Cat No: 651201).2 µL compounds were transferred from the master plate into a new 96-well assay plate (Costar, 3599). The growth medium Caution-Adjusted Mueller Hinton Broth (CAMHB) was prepared by adding 22 g powder (BD, 212322) in 1L purified water, autoclaved, and supplemented with sterilized CaCl ₂ (20 mg per liter) and MgCl ₂ (10 mg per liter). Vials of each of the test microorganisms were maintained frozen in the vapor phase of a liquid nitrogen freezer. Took out the bacterial strain ATCC 17978 from liquid nitrogen freezer, thawed it at room temperature, and diluted the bacterial in the CAMHB medium to achieve a final inoculum of 2 × 10 ⁵ CFU/ mL.98 µL of the adjusted bacteria suspension was dispensed to the assay plate and pipetted 5 times. Then the assay plates were incubated for 20 hours at 35 ±2 °C in ambient air with humidity. Following incubation, MIC (µg/mL) value, the lowest concentration of drug that inhibits visible growth of the microorganism, was recorded by visual judgment of bacterial growth through magnification mirror of MIC reader, and the assay plates were photographed with Qcount system as image raw data. Meanwhile, the OD600 of assay plates was recorded with SpectraMax Plus384 as OD raw data. Table 2 Example 1 A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Example 2 A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg Example 3 A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of an infusion solution of the following composition: Active ingredient 100 mg Lactic acid 90% 100 mg NaOH q.s. or HCl q.s. for adjustment to pH 4.0 Sodium chloride q.s. or glucose q.s. for adjustment of the osmolality to 290 mOsm/kg Water for injection (WFI) ad 100 ml Example 4 A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of an infusion solution of the following composition: Active ingredient 100 mg Hydroxypropyl-beta-cyclodextrin 10 g NaOH q.s. or HCl q.s. for adjustment to pH 7.4 Sodium chloride q.s. or glucose q.s. for adjustment of the osmolality to 290 mOsm/kg Water for injection (WFI) ad 100 ml