Zwitterionic antibacterial compounds

Abstract

The present invention provides novel imidazole-pyrazole derivatives having the general formula (I), and pharma- ceutically acceptable salts thereof, wherein A, X, R 1 ~R 9 , R 12 and R 13 is as described herein. TIFF2025508473000297.tif67102 Pharmaceutical compositions comprising the compounds, methods of making the compounds, and methods of using the compounds as medicines, particularly methods of using the compounds as antibiotics for the treatment or prevention of bacterial infections and resultant diseases, are further provided.

Description

[Technical field]

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

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

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

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

[0005] A. baumannii has a remarkable ability to upregulate and acquire resistance determinants and exhibits environmental persistence that allows its survival and spread in the nosocomial environment, making the organism a frequent cause of infectious disease outbreaks and a healthcare-associated pathogen endemic to that environment.

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

[0007] According to the Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA), Acinetobacter baumannii has been and still is considered to be "a prime example of the mismatch that exists between unmet medical need and the current antibiotic research and development pipeline. Therefore, there is a strong demand and need to identify suitable compounds for the treatment of diseases and infections caused by Acinetobacter baumannii. The present invention provides novel compounds that exhibit activity against drug-susceptible and drug-resistant strains of Acinetobacter baumannii. Summary of the Invention

[0008] In a first aspect, the present invention provides a compound of formula (I) [ka] (In the formula, A, X, R 1 -R 9 , R 12 and R 13 or a pharma- ceutically acceptable salt thereof, wherein:

[0009] In one aspect, the present invention provides methods for preparing compounds of formula (I) as described herein, the methods being as depicted in Schemes 1-12 below, in particular as depicted in Scheme 4. In a further aspect, the present invention provides a compound of formula (I) as described herein when prepared according to the methods described herein.

[0010] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

[0011] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, and a therapeutically inert carrier.

[0012] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use as an antibiotic. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] definition It should be understood that features, integers, characteristics, compounds, chemical moieties or groups described in connection with a particular aspect, embodiment or example of the invention are applicable to any other aspect, embodiment or example described herein, except where inconsistent therewith. All of the features disclosed herein (including any accompanying claims, abstracts and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel or any novel combination of features disclosed herein (including any accompanying claims, abstracts and drawings), or any novel or any novel combination of steps of any method or process so disclosed.

[0014] The term "alkyl" refers to a monovalent or polyvalent, e.g., monovalent or divalent, linear or branched, saturated hydrocarbon group of 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms ("C 1 -C 6 In some embodiments, an alkyl group includes 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred, but non-limiting example of alkyl is methyl.

[0015] The term "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Unless otherwise specified, an alkoxy group contains 1 to 6 carbon atoms ("C 1 -C 6 In some preferred embodiments, the alkoxy group contains 1-4 carbon atoms. In still other embodiments, the alkoxy group contains 1-3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred, but non-limiting example of alkoxy is methoxy.

[0016] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred, but non-limiting examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0017] The term "aminoalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by an amino group. Preferably, "aminoalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group are replaced by an amino group. Preferred but non-limiting examples of aminoalkyl are aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl and 6-aminohexyl. Particularly preferred but non-limiting examples of aminoalkyl are 3-aminopropyl, 4-aminobutyl and 6-aminohexyl.

[0018] The term "heterocyclylalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by a heterocycle. Preferably, "heterocyclylalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group are replaced by a heterocycle. Most preferably, "heterocyclylalkyl" refers to an alkyl group in which one hydrogen atom of the alkyl group is replaced by a heterocycle. A preferred, but non-limiting example of a heterocyclylalkyl is azetidinylmethyl, e.g., azetidin-3-ylmethyl.

[0019] The term "aminoalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group is replaced with an amino group. Preferably, "aminoalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkoxy group are replaced with an amino group. Most preferably, "aminoalkoxy" refers to an alkoxy group in which one hydrogen atom of the alkoxy group is replaced with an amino group. Preferred, but non-limiting examples of aminoalkoxy are aminomethoxy and 2-aminoethoxy. The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated, monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms ("C 3-10"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 a cycloalkyl moiety consisting of two saturated carbocyclic rings 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 a spirocyclic moiety, i.e., a cycloalkyl moiety in which the two rings are joined through one common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[1.1.1]pentanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl. Particularly preferred, but non-limiting, examples of cycloalkyl are cyclopropyl and cyclopentyl.

[0020] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, ring system of 3 to 14 ring atoms, preferably 3 to 10 ring atoms, preferably 3 to 8 ring atoms, in which 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. "Bicyclic heterocyclyl" refers to a heterocyclic moiety consisting of two rings having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., the two rings are joined via one common ring atom. Some non-limiting examples of heterocyclyl groups include morpholine, thiomorpholine, piperazine, pyrrolidinyl, piperidyl, pyridyl, cyclopropyl, cyclopentyl, 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrole, 9-oxa-3,7-diazabicyclo[3.3.1]nonane, 7-oxa-2-azaspiro[3.5]nonane, and 2,6-dioxa-9-azaspiro[4.5]decane.

[0021] The term "aryl" refers to a group having 6 to 14 total ring members ("C 6 -C 14 -aryl"), preferably a monocyclic, bicyclic, or tricyclic carbocyclic ring system having 6 to 12 ring members, more preferably 6 to 10 ring members, in which at least one ring of the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g., 9H-fluoren-9-yl). A particularly preferred, but non-limiting example of aryl is phenyl.

[0022] The term "heteroaryl" refers to a mono- or polyvalent, monocyclic or bicyclic, preferably bicyclic, ring system having a total of 5-14 ring members, preferably 5-12 ring members, more preferably 5-10 ring members, in which at least one ring of the system is aromatic and at least one ring of the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Preferably, "heteroaryl" refers to a 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from O and N. Most preferably, "heteroaryl" refers to a 5-6 membered heteroaryl containing 1-2 heteroatoms independently selected from O and N. Some preferred, but non-limiting examples of heteroaryl include thiazolyl, isothiazolyl, pyridyl, 1H-pyrrolo[3,2-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1,3-benzothiazole, benzothiophene, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-indazolyl, furo[3,2-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine. A particularly preferred, but non-limiting example of heteroaryl is pyridyl.

[0023] The term "hydroxy" refers to an --OH group.

[0024] The term "amino" means -NH 2 Refers to the base.

[0025] The term "carboxy" refers to the group -COOH.

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

[0027] The term "oxo" refers to the group ═O.

[0028] The term "imino" refers to the group =NH.

[0029] The term "carbamoyl" refers to the group -C(O)NH2 Refers to...

[0030] The term "hydroxycarbamoyl" refers to the group -C(O)-NH-OH.

[0031] The term "carboxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced with a carboxy group. Preferably, "carboxyalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group are replaced with a carboxy group. A preferred, but non-limiting example of a carboxyalkyl is carboxymethyl.

[0032] The term "alkoxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced with an alkoxy group. Preferably, "alkoxyalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group are replaced with an alkoxy group. Most preferably, "alkoxyalkyl" refers to an alkyl group in which one hydrogen atom of the alkyl group is replaced with an alkoxy group. Particular, but non-limiting, examples of alkoxyalkyl groups are methoxymethyl and 2-methoxyethyl, especially 2-methoxyethyl.

[0033] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a hydroxy group. Preferably, "hydroxyalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group, most preferably one hydrogen atom, are replaced by a hydroxy group. Preferred, but non-limiting examples of hydroxyalkyl are hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), hydroxypropyl (e.g., 3-hydroxypropyl), 2-hydroxy-2-methyl-propyl, 2,3-dihydroxypropyl, 2-hydroxy-1-(hydroxymethyl)-ethyl, 3-hydroxy-3-methyl-butyl, 1,2-dihydroxyethyl.

[0034] The term "halohydroxyalkyl" refers to a hydroxyalkyl group in which at least one of the hydrogen atoms of the hydroxyalkyl group is replaced with a halogen atom. Preferably, "halohydroxyalkyl" refers to a hydroxyalkyl group in which one, two or three hydrogen atoms of the hydroxyalkyl group are replaced by halogen atoms. A preferred, but non-limiting example of a halohydroxyalkyl is 3,3,3 trifluoro-2-hydroxypropyl.

[0035] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids, such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, lactic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. Furthermore, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium and magnesium salts, etc. Salts that may be derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc. Particular pharma- ceutically acceptable salts of the compounds of formula (I) are the hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid) and trifluoroacetate.

[0036] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0037] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom may be of the "R" or "S" configuration.

[0038] The term "treatment" as used herein includes: (1) suppressing the condition, disorder or state (e.g., in the case of maintenance treatment, arresting, reducing or delaying the onset or recurrence of at least one clinical symptom or subclinical disease thereof), and / or (2) alleviating the state (i.e., causing regression of the condition, disorder or state, or at least one of its clinical symptoms or subclinical symptoms). The benefit to the patient to be treated is either statistically significant or at least perceptible to the patient or the physician. However, it will be understood that when a pharmaceutical agent is administered to a patient to treat a disease, the result may not necessarily be an effective treatment.

[0039] As used herein, the term "prophylaxis" or "prevention" includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition developing in a mammal, particularly a human who may be afflicted with or predisposed to the condition, disorder or condition, but has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder or condition.

[0040] The term "mammal" as used herein includes both humans and non-humans, including, but not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. In a particularly preferred embodiment, the term "mammal" refers to humans.

[0041] The term "nosocomial infection" refers to a hospital-acquired infection (HAI), which is an infection acquired in a hospital or other health care facility. To emphasize both hospital and non-hospital settings, it may alternatively be called a healthcare-associated infection (HAI or HCAI). Such infections may be acquired in hospitals, nursing homes, rehabilitation facilities, outpatient clinics, or other clinical settings.

[0042] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I) [ka] (In the formula, X and Y are each independently selected from N and CH; n is selected from 0 to 6, A is a 5- to 14-membered heteroaryl and C 6 -C 14 -aryl, B is 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl and C 3 -C 10 -cycloalkyl, L is a covalent bond, carbonyl, NHC(O), C(O)NH, or CH 2 NH, NHCH 2 and NH; L 1 is -O- or a covalent bond, R 1 teeth, (i) C substituted with one amino and one carboxy substituent 1 -C 6 -alkyl, (ii) one amino and one carboxy-C 1 -C 6 -C substituted with alkyl-NH-substituents 1 -C 6 -alkyl, (iii) C 1 -C 6 -Alkyl-N(R 1a R 1b ), (iv)-L 1 -C 1 -C 6 -Alkyl-N + (R 1c R 1d R 1e ), (v) group [ka] and (vi) Group [ka] is selected from R 1a is amino-C 1 -C 6 -alkyl, R 1b is carboxy-C 1 -C 6 -alkyl, R 1c is amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl, R 1d is carboxy-C 1 -C 6 -alkyl, R 1e is C 1 -C 6 -Alkyl, Amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl-, R 1f is C 1 -C 6 -Alkyl, Hydroxy-C 1 -C 6 -Alkyl, Amino-C 1 -C 6 -Alkyl, C 1 -C 6 -Alkyl-NH-C 1 -C6 -alkyl, (C 1 -C 6 -alkyl) 2 NC 1 -C 6 -alkyl, and (3- to 14-membered heterocyclyl)-C 1 -C 6 -alkyl-, R 1g is carboxy-C 1 -C 6 -alkyl, R 1h is carboxy-C 1 -C 6 -alkyl, R 1i is amino-C 1 -C 6 -alkyl, R 2 is hydrogen, C 1 -C 6 -Alkyl and C 1 -C 6 -alkoxy; R 3 and R 7 are both hydrogen, or R 2 and R 7 together with the atoms to which they are attached form a 4- to 14-membered heterocycle or C 4 -C 10 - forms a cycloalkyl, R 3 is hydrogen, or R 2 and R 3 together with the carbon atom to which they are attached, C 3 -C 10 - forms a cycloalkyl, R 7 is hydrogen, R 4 is hydrogen and C 1 -C 6 -alkyl; R 5 and R 6 are both hydrogen, or R 4 and R 6together with the atoms to which they are attached form a 4- to 14-membered heterocyclic ring; R 5 is hydrogen, or R 4 and R 5 together with the carbon atom to which they are attached, C 3 -C 10 - forms a cycloalkyl, R 6 is hydrogen, R 8 is hydrogen, cyano, hydroxy, amino, C 1 -C 6 -alkyl-NH-, (C 1 -C 6 -alkyl) 2 N-, (C 1 -C 6 -alkyl) 2 N-SO 2 -, (C 1 -C 6 -alkyl) 2 NC 1 -C 6 -Alkyl-, Amino-C 1 -C 6 -Alkyl, Amino-C 1 -C 6 -Alkoxy, Amino-C 1 -C 6 -Alkyl-NH-, (amino-C 1 -C 6 -alkyl) 2 N-, (amino-C 1 -C 6 -alkyl) 2 NC 1 -C 6 -Alkyl-NH-, C 1 -C 6 -Alkyl-NH-C 1 -C 6 -Alkyl-NH-, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl-NH-, Halo-C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl-NH-, C 3 -C10 -Cycloalkyl-NH-, C 1 -C 6 -Alkoxy, C 1 -C 6 -Alkyl, Cyano-C 1 -C 6 -Alkyl-, Hydroxy-C 1 -C 6 -Alkyl-, Hydroxy-C 1 -C 6 -Alkyl-NH-, Hydroxy-C 1 -C 6 -Alkyl-NHC(O)-, halo-hydroxy-C 1 -C 6 -Alkyl-NHC(O)-, carbamoyl, hydroxycarbamoyl, C 1 -C 6 -alkyl-NHC(O)-, (C 1 -C 6 -alkyl) 2 NC(O)-, Carbamoyl-C 1 -C 6 -alkyl-, and groups [ka] is selected from R 9 is hydrogen, halogen, amino, C 1 -C 6 -Alkyl and Hydroxy-C 1 -C 6 -alkyl-, R 10 is hydrogen, C 1 -C 6 - selected from alkyl, halogen, hydroxy, oxo, imino and amino, R 11 is selected from hydrogen and halogen; R 12 is halogen and C 1 -C 6 -alkyl, R 13 Halo-C 1 -C 6-alkyl), or a pharma- ceutically acceptable salt thereof.

[0043] In one embodiment, the present invention relates to a compound wherein L is a covalent bond, a carbonyl, an NHC(O), a CH 2 Provided is a compound of formula (I) as described herein, selected from NH and NH, or a pharma- ceutically acceptable salt thereof.

[0044] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1f C 1 -C 6 -Alkyl, Hydroxy-C 1 -C 6 -Alkyl, Amino-C 1 -C 6 -alkyl, (C 1 -C 6 -alkyl) 2 NC 1 -C 6 -alkyl, and (3- to 14-membered heterocyclyl)-C 1 -C 6 -alkyl- or a pharma- ceutically acceptable salt thereof.

[0045] In a preferred embodiment, the present invention comprises: R 1 but, (I C 1 -C 6 -Alkyl-N + (R 1c R 1d R 1e ), and (ii) group [ka] is selected from Y is CH; R 1c and R 1e All of these are amino-C 1 -C 6 -alkyl, R 1d and R 1g All of them are carboxy-C1 -C 6 -alkyl, R 1f But Amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl- or a pharma- ceutically acceptable salt thereof.

[0046] In a preferred embodiment, the present invention comprises: R 1 Based on [ka] and Y is CH; R 1g Carboxy-C 1 -C 6 -alkyl, R 1f But Amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl- or a pharma- ceutically acceptable salt thereof.

[0047] In a preferred embodiment, the present invention comprises: R 1 C 1 -C 6 -Alkyl-N + (R 1c R 1d R 1e )) and R 1c and R 1e But independently, C 1 -C 6 -alkyl, R 1d Carboxy-C 1 -C 6 or a pharma- ceutically acceptable salt thereof.

[0048] In a particularly preferred embodiment, the present invention comprises: R 1 but, (i)-(CH 2 ) 3 -N + (R 1c R 1d R 1e ), and (ii) group [ka] is selected from Y is CH; R 1c and R 1e are all 4-aminobutyl, R 1d and R 1g are all carboxymethyl, R 1f is selected from 3-aminopropyl and azetidin-3-ylmethyl, or a pharma- ceutically acceptable salt thereof.

[0049] In a particularly preferred embodiment, the present invention comprises: R 1 Based on [ka] and Y is CH; R 1g is carboxymethyl, R 1f is selected from 3-aminopropyl and azetidin-3-ylmethyl, or a pharma- ceutically acceptable salt thereof.

[0050] In a particularly preferred embodiment, the present invention comprises: R 1 Ga-(CH 2 ) 3 -N + (R 1c R1d R 1e ) and R 1c and R 1e are all 4-aminobutyl, R 1d is carboxymethyl, or a pharma- ceutically acceptable salt thereof.

[0051] In a preferred embodiment, the present invention provides a 2 , R 3 , R 4 , R 5 , R 6 and R 7 are all hydrogen, or a pharma- ceutically acceptable salt thereof.

[0052] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein A is selected from thiazolyl; isothiazolyl; pyridyl; 1H-pyrrolo[3,2-b]pyridine; 1H-imidazo[4,5-b]pyridine; 1,3-benzothiazole; benzothiophene; 1H-pyrazolo[4,3-b]pyridine; 1H-pyrrolo[3,2-c]pyridine; 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 2H-pyrazolo[4,3-c]pyridine, 1H-pyrrolo[3,2-d]pyrimidine, 1H-indazolyl; furo[3,2-b]pyridine; 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine; and phenyl.

[0053] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein B is selected from morpholine, thiomorpholine, piperazine, pyrrolidinyl, piperidyl, pyridyl, cyclopropyl, cyclopentyl, 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrole, 9-oxa-3,7-diazabicyclo[3.3.1]nonane, 7-oxa-2-azaspiro[3.5]nonane, and 2,6-dioxa-9-azaspiro[4.5]decane.

[0054] In a preferred embodiment, the present invention comprises: A is 5-14 membered heteroaryl and C 6 -C 14 -aryl, B is 3-14 membered heterocyclyl; L is a covalent bond; R 8 is hydrogen, amino, hydroxy, C 1 -C 6 -Alkyl-NH-, Amino-C 1 -C 6 -Alkyl-NH-, Hydroxy-C 1 -C 6 -Alkyl-, Hydroxy-C 1 -C 6 -Alkyl-NH-, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl-NH-, Carbamoyl-C 1 -C 6 -alkyl-, (C 1 -C 6 -alkyl) 2 NC(O)- and groups [ka] is selected from R 9 is selected from hydrogen and halogen; R 10 is amino, R 11 is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0055] In a particularly preferred embodiment, the present invention comprises: A is selected from pyridyl, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrrolo[3,2-c]pyridine, 2H-pyrazolo[4,3-c]pyridine and phenyl; B is pyrrolidine; L is a covalent bond; R 8is hydrogen, hydroxy, amino, CH 3 -NH-, amino-(CH 2 ) 3 -NH-, hydroxymethyl, 2-hydroxyethyl, hydroxy-(CH 2 ) 2 -NH-, methoxy-(CH 2 ) 2 -NH-, H 2 NC(O)-CH 2 -, (CH 3 ) 2 NC(O)- and groups [ka] is selected from R 9 is selected from hydrogen and fluoro; R 10 is amino, R 11 is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0056] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein X is N.

[0057] In a preferred embodiment, the present invention provides a 12 is selected from chloro and methyl; R 13 But CHF 2 and CF 3 or a pharma- ceutically acceptable salt thereof.

[0058] In a particularly preferred embodiment, the present invention provides 12 is selected from chloro and methyl; R 13 CF 3 or a pharma- ceutically acceptable salt thereof.

[0059] In a particularly preferred embodiment, the present invention provides 12is selected from chloro and methyl, or a pharma- ceutically acceptable salt thereof.

[0060] In a particularly preferred embodiment, the present invention provides 12 is chloro; or a pharma- ceutically acceptable salt thereof.

[0061] In a particularly preferred embodiment, the present invention provides 12 is methyl, or a pharma- ceutically acceptable salt thereof.

[0062] In a particularly preferred embodiment, the present invention provides 13 CF 3 or a pharma- ceutically acceptable salt thereof.

[0063] In one embodiment, the present invention provides X and Y are each independently selected from N and CH; n is selected from 0 to 6; A is 5-14 membered heteroaryl and C 6 -C 14 -aryl, B is 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl and C 3 -C 10 -cycloalkyl, L is a covalent bond, carbonyl, NHC(O), CH 2 selected from NH and NH; L 1 is -O- or a covalent bond, R 1 but, (i) C substituted with one amino and one carboxy substituent 1 -C 6 -alkyl, (ii) one amino and one carboxy-C 1 -C 6 -C substituted with alkyl-NH-substituents1 -C 6 -alkyl, (iii) C 1 -C 6 -Alkyl-N(R 1a R 1b ), (iv)-L 1 -C 1 -C 6 -Alkyl-N + (R 1c R 1d R 1e ), (v) group [ka] and (vi) Group [ka] is selected from R 1a Amino-C 1 -C 6 -alkyl, R 1b Carboxy-C 1 -C 6 -alkyl, R 1c But Amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl, R 1d Carboxy-C 1 -C 6 -alkyl, R 1e But, C 1 -C 6 -Alkyl, Amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl-, R 1f But, C 1 -C 6 -Alkyl, Hydroxy-C1 -C 6 -Alkyl, Amino-C 1 -C 6 -alkyl, (C 1 -C 6 -alkyl) 2 NC 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl-, R 1g Carboxy-C 1 -C 6 -alkyl, R 1h Carboxy-C 1 -C 6 -alkyl, R 1i Amino-C 1 -C 6 -alkyl, R 2 But hydrogen, C 1 -C 6 -Alkyl and C 1 -C 6 -alkoxy; R 3 and R 7 are both hydrogen, or R 2 and R 7 together with the atoms to which they are attached form a 4- to 14-membered heterocycle or C 4 -C 10 - forms a cycloalkyl, R 3 is hydrogen, or R 2 and R 3 together with the carbon atom to which they are attached, C 3 -C 10 - forms a cycloalkyl, R 7 is hydrogen, R 4 But hydrogen and C 1 -C 6 -alkyl; R 5 and R 6 are both hydrogen, or R4 and R 6 together with the atoms to which they are attached form a 4- to 14-membered heterocyclic ring, R 5 is hydrogen, or R 4 and R 5 together with the carbon atom to which they are attached, C 3 -C 10 - forms a cycloalkyl, R 6 is hydrogen, R 8 is hydrogen, cyano, amino, hydroxy, C 1 -C 6 -alkyl-NH-, (C 1 -C 6 -alkyl) 2 N-, (C 1 -C 6 -alkyl) 2 N-SO 2 -, (C 1 -C 6 -alkyl) 2 NC 1 -C 6 -Alkyl-, Amino-C 1 -C 6 -Alkyl, Amino-C 1 -C 6 -Alkoxy, Amino-C 1 -C 6 -Alkyl-NH-, (amino-C 1 -C 6 -alkyl) 2 N-, (amino-C 1 -C 6 -alkyl) 2 NC 1 -C 6 -Alkyl-NH-, C 1 -C 6 -Alkyl-NH-C 1 -C 6 -Alkyl-NH-, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl-NH-, Halo-C 1 -C 6 -Alkoxy-C 1 -C 6-Alkyl-NH-, C 3 -C 10 -Cycloalkyl-NH-, C 1 -C 6 -Alkoxy, C 1 -C 6 -Alkyl, Cyano-C 1 -C 6 -Alkyl-, Hydroxy-C 1 -C 6 -Alkyl-, Hydroxy-C 1 -C 6 -Alkyl-NH-, Hydroxy-C 1 -C 6 -Alkyl-NHC(O)-, halo-hydroxy-C 1 -C 6 -Alkyl-NHC(O)-, carbamoyl, hydroxycarbamoyl, C 1 -C 6 -alkyl-NHC(O)-, (C 1 -C 6 -alkyl) 2 NC(O)-, Carbamoyl-C 1 -C 6 -alkyl-, and groups [ka] is selected from R 9 However, hydrogen, halogen, amino, C 1 -C 6 -Alkyl and Hydroxy-C 1 -C 6 -alkyl-, R 10 But hydrogen, C 1 -C 6 - selected from alkyl, halogen, hydroxy, oxo, imino and amino, R 11 is selected from hydrogen and halogen; R 12 But halogens and C 1 -C 6 -alkyl, R 13 But, Halo-C 1 -C 6or a pharma- ceutically acceptable salt thereof.

[0064] In a preferred embodiment, the present invention comprises: A is 5-14 membered heteroaryl and C 6 -C 14 -aryl, B is 3-14 membered heterocyclyl; L is a covalent bond; X is N, Y is CH; R 1 but, (I C 1 -C 6 -Alkyl-N + (R 1c R 1d R 1e ), and (ii) group [ka] is selected from R 1c and R 1e All of these are amino-C 1 -C 6 -alkyl, R 1d and R 1g All of them are carboxy-C 1 -C 6 -alkyl, R 1f But Amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl-, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are all hydrogen, R 8 is hydrogen, amino, hydroxy, C 1 -C 6-Alkyl-NH-, Amino-C 1 -C 6 -Alkyl-NH-, Hydroxy-C 1 -C 6 -Alkyl-, Hydroxy-C 1 -C 6 -Alkyl-NH-, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl-NH-, Carbamoyl-C 1 -C 6 -alkyl-, (C 1 -C 6 -alkyl) 2 NC(O)- and groups [ka] is selected from R 9 is selected from hydrogen and halogen; R 10 is amino, R 11 is hydrogen, R 12 But halogens and C 1 -C 6 -alkyl, R 13 But, Halo-C 1 -C 6 or a pharma- ceutically acceptable salt thereof.

[0065] In a particularly preferred embodiment, the present invention comprises: A is selected from pyridyl, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrrolo[3,2-c]pyridine, 2H-pyrazolo[4,3-c]pyridine and phenyl; B is pyrrolidine; L is a covalent bond; R 1 but, (i)-(CH 2 ) 3 -N + (R 1c R1d R 1e ), and (ii) group [ka] is selected from R 1c and R 1e are all 4-aminobutyl, R 1d and R 1g are all carboxymethyl, R 1f is selected from 3-aminopropyl and azetidin-3-ylmethyl; R 8 is hydrogen, hydroxy, amino, CH 3 -NH-, amino-(CH 2 ) 3 -NH-, hydroxymethyl, 2-hydroxyethyl, hydroxy-(CH 2 ) 2 -NH-, methoxy-(CH 2 ) 2 -NH-, H 2 NC(O)-CH 2 -, (CH 3 ) 2 NC(O)- and groups [ka] is selected from R 9 is selected from hydrogen and fluoro; R 10 is amino, R 11 is hydrogen, R 12 is selected from chloro and methyl; R 13 CF 3 or a pharma- ceutically acceptable salt thereof.

[0066] In one embodiment, the present invention provides a method for the preparation of a compound according to the present invention, wherein A is 5-14 membered heterocyclyl and C 6 -C14 -aryl, or a pharma- ceutically acceptable salt thereof.

[0067] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein B is 3-14 membered heterocyclyl.

[0068] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein L is a covalent bond.

[0069] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein X is N.

[0070] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein Y is CH.

[0071] In a preferred embodiment, the present invention comprises: R 1 but, (I C 1 -C 6 -Alkyl-N + (R 1c R 1d R 1e ), and (ii) group [ka] or a pharma- ceutically acceptable salt thereof.

[0072] In a preferred embodiment, the present invention provides a 1c Amino-C 1 -C 6 or a pharma- ceutically acceptable salt thereof.

[0073] In a preferred embodiment, the present invention provides a 1e Amino-C 1 -C 6 or a pharma- ceutically acceptable salt thereof.

[0074] In a preferred embodiment, the present invention provides a 1f But Amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl- or a pharma- ceutically acceptable salt thereof.

[0075] In a preferred embodiment, the present invention provides a 2 is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0076] In a preferred embodiment, the present invention provides a 3 is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0077] In a preferred embodiment, the present invention provides a 4 is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0078] In a preferred embodiment, the present invention provides a 5 is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0079] In a preferred embodiment, the present invention provides a 6 is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0080] In a preferred embodiment, the present invention provides a 7is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0081] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 8 is hydrogen, amino, hydroxy, C 1 -C 6 -Alkyl-NH-, Amino-C 1 -C 6 -Alkyl-NH-, Hydroxy-C 1 -C 6 -Alkyl-, Hydroxy-C 1 -C 6 -Alkyl-NH-, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl-NH-, Carbamoyl-C 1 -C 6 -alkyl-, (C 1 -C 6 -alkyl) 2 NC(O)- and groups [ka] or a pharma- ceutically acceptable salt thereof.

[0082] In a preferred embodiment, the present invention provides a 9 is selected from hydrogen and halogen, or a pharma- ceutically acceptable salt thereof.

[0083] In a preferred embodiment, the present invention provides a 10 is amino; or a pharma- ceutically acceptable salt thereof.

[0084] In a preferred embodiment, the present invention provides a 11 is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0085] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein A is selected from pyridyl, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrrolo[3,2-c]pyridine, 2H-pyrazolo[4,3-c]pyridine and phenyl.

[0086] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein A is pyridyl.

[0087] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein A is 1H-pyrrolo[3,2-b]pyridine.

[0088] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein A is 1H-pyrrolo[3,2-c]pyridine.

[0089] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein A is 2H-pyrazolo[4,3-c]pyridine.

[0090] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein A is phenyl.

[0091] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein B is pyrrolidine.

[0092] In a particularly preferred embodiment, the present invention comprises: R 1 but, (i)-(CH 2 ) 3 -N + (R 1c R 1d R 1e ), and (ii) group [ka] or a pharma- ceutically acceptable salt thereof.

[0093] In a particularly preferred embodiment, the present invention provides 1c and R 1e and R are each 4-aminobutyl; or a pharma- ceutically acceptable salt thereof.

[0094] In a particularly preferred embodiment, the present invention provides 1d is carboxymethyl, or a pharma- ceutically acceptable salt thereof.

[0095] In a particularly preferred embodiment, the present invention provides 1g is carboxymethyl, or a pharma- ceutically acceptable salt thereof.

[0096] In a particularly preferred embodiment, the present invention provides 1f is selected from 3-aminopropyl and azetidin-3-ylmethyl, or a pharma- ceutically acceptable salt thereof.

[0097] In a particularly preferred embodiment, the present invention provides 8 is hydrogen, hydroxy, amino, CH 3 -NH-, amino-(CH 2 ) 3 -NH-, hydroxymethyl, 2-hydroxyethyl, hydroxy-(CH 2 ) 2 -NH-, methoxy-(CH 2 ) 2 -NH-, H 2 NC(O)-CH 2 -, (CH 3 ) 2 NC(O)- and groups [ka] or a pharma- ceutically acceptable salt thereof.

[0098] In a particularly preferred embodiment, the present invention provides 9 is selected from hydrogen and fluoro, or a pharma- ceutically acceptable salt thereof.

[0099] In one embodiment, the present invention provides a compound of formula (I), which has the formula (Ia): [ka] (In the formula, X and Y are each independently selected from N and CH; n is selected from 0 to 6, A is a 5- to 14-membered heteroaryl and C 6 -C 14 -aryl, B is 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl and C 3 -C 10 -cycloalkyl, L is a covalent bond, CH 2 NH, NHCH 2 and NH; R 1 teeth, (i) C substituted with one amino and one carboxy substituent 1 -C 6 -alkyl, (ii) one amino and one carboxy-C 1 -C 6 -C substituted with alkyl-NH-substituents 1 -C 6 -alkyl, (iii) C 1 -C 6 -Alkyl-N(R 1a R 1b ), (iv) C1 -C 6 -Alkyl-N + (R 1c R 1d R 1e ), (v) group [ka] and (vi) Group [ka] is selected from R 1a is amino-C 1 -C 6 -alkyl, R 1b is carboxy-C 1 -C 6 -alkyl, R 1c is amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl, R 1d is carboxy-C 1 -C 6 -alkyl, R 1e is C 1 -C 6 -Alkyl, Amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl-, R 1f is amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl-, R 1g is carboxy-C 1 -C 6 -alkyl, R 1his carboxy-C 1 -C 6 -alkyl, R 1i is amino-C 1 -C 6 -alkyl, R 2 is hydrogen, C 1 -C 6 -Alkyl and C 1 -C 6 -alkoxy; R 3 and R 7 are both hydrogen, or R 2 and R 7 together with the atoms to which they are attached form a 4- to 14-membered heterocycle or C 4 -C 10 - forms a cycloalkyl, R 3 is hydrogen, or R 2 and R 3 together with the carbon atom to which they are attached, C 3 -C 10 - forms a cycloalkyl, R 7 is hydrogen, R 4 is hydrogen and C 1 -C 6 -alkyl; R 5 and R 6 are both hydrogen, or R 4 and R 6 together with the atoms to which they are attached form a 4- to 14-membered heterocyclic ring, R 5 is hydrogen, or R 4 and R 5 together with the carbon atom to which they are attached, C 3 -C 10 - forms a cycloalkyl, R 6 is hydrogen, R 8 is hydrogen, cyano, amino, C 1 -C 6 -alkyl-NH-, (C 1 -C6 -alkyl) 2 N-, (C 1 -C 6 -alkyl) 2 NC 1 -C 6 -Alkyl-, Amino-C 1 -C 6 -Alkyl, Amino-C 1 -C 6 -Alkoxy, Amino-C 1 -C 6 -Alkyl-NH-, C 1 -C 6 -Alkyl-NH-C 1 -C 6 -Alkyl-NH-, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl-NH-, C 3 -C 10 -Cycloalkyl-NH-, C 1 -C 6 -Alkoxy, C 1 -C 6 -Alkyl, Hydroxy-C 1 -C 6 -Alkyl-, Hydroxy-C 1 -C 6 -alkyl-NH- and groups [ka] is selected from R 9 is selected from hydrogen, halogen and amino; R 10 is selected from hydrogen, halogen and amino; R 11 is selected from hydrogen and a halogen.

[0100] In a preferred embodiment, the present invention provides a compound of formula (Ia) as described herein, or a pharma- ceutically acceptable salt thereof, said compound of formula (I) having the formula (II): [ka] (In the formula, R 1 , R 8 , R 9 and A is as defined herein.

[0101] In one embodiment, the present invention provides a compound wherein L is a covalent bond, CH 2 Provided is a compound of formula (I) as described herein, selected from NH and NH, or a pharma- ceutically acceptable salt thereof.

[0102] In one embodiment, the invention provides a compound of formula (I) as described herein, wherein B is selected from morpholine, piperazine, pyrrolidinyl, piperidyl, pyridyl, cyclopropyl, and cyclopentyl.

[0103] In one embodiment, the present invention provides L is a covalent bond, CH 2 selected from NH and NH; Provided herein is a compound of formula (Ia) as described herein, or a pharma- ceutically acceptable salt thereof, wherein B is selected from morpholinyl, piperazinyl, pyrrolidinyl, piperidyl, pyridyl, cyclopropyl, and cyclopentyl.

[0104] In a preferred embodiment, the present invention comprises: R 1 but, (I C 1 -C 6 -Alkyl-N + (R 1c R 1d R 1e ), and (ii) group [ka] is selected from Y is CH; R 1c and R 1e All of these are amino-C 1 -C 6 -alkyl, R 1d and R 1gAll of them are carboxy-C 1 -C 6 -alkyl, R 1f But Amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl- or a pharma- ceutically acceptable salt thereof.

[0105] In a particularly preferred embodiment, the present invention comprises: R 1 but, (i)-(CH 2 ) 3 -N + (R 1c R 1d R 1e ), and (ii) group [ka] is selected from Y is CH; R 1c and R 1e are all 4-aminobutyl, R 1d and R 1g are all carboxymethyl, R 1f is selected from 3-aminopropyl and azetidin-3-ylmethyl, or a pharma- ceutically acceptable salt thereof.

[0106] In a particularly preferred embodiment, the present invention provides 2 , R 3 , R 4 , R 5 , R 6 and R 7 are all hydrogen, or a pharma- ceutically acceptable salt thereof.

[0107] In a preferred embodiment, the present invention provides a compound of formula (Ia) as described herein, or a pharma- ceutically acceptable salt thereof, wherein A is selected from thiazolyl, isothiazolyl; pyridyl; 1H-pyrrolo[3,2-b]pyridine; 1H-imidazo[4,5-b]pyridine; 1,3-benzothiazole; benzothiophene; 1H-pyrazolo[4,3-b]pyridine; 1H-pyrrolo[3,2-c]pyridine; 1H-indazolyl; furo[3,2-b]pyridine; 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine; and phenyl.

[0108] In a particularly preferred embodiment, the present invention provides compounds of formula (Ia) as described herein, or a pharma- ceutically acceptable salt thereof, wherein A is selected from pyridyl, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrrolo[3,2-c]pyridine and phenyl.

[0109] In a preferred embodiment, the present invention comprises: R 8 But hydrogen, amino, C 1 -C 6 -Alkyl-NH-, Amino-C 1 -C 6 -Alkyl-NH-, Hydroxy-C 1 -C 6 -Alkyl- and hydroxy-C 1 -C 6 -alkyl-NH-, R 9 is selected from hydrogen and halogen, or a pharma- ceutically acceptable salt thereof.

[0110] In a particularly preferred embodiment, the present invention comprises: R 8 is hydrogen, amino, CH 3 -NH-, amino-(CH 2 ) 3 -NH-, hydroxymethyl and hydroxy-(CH 2 ) 2 -NH-, R 9is selected from hydrogen and fluoro, or a pharma- ceutically acceptable salt thereof.

[0111] In a preferred embodiment, the present invention comprises: A is 5-14 membered heteroaryl and C 6 -C 14 -aryl, R 8 But hydrogen, amino, C 1 -C 6 -Alkyl-NH-, Amino-C 1 -C 6 -Alkyl-NH-, Hydroxy-C 1 -C 6 -Alkyl- and hydroxy-C 1 -C 6 -alkyl-NH-, R 9 is selected from hydrogen and halogen, or a pharma- ceutically acceptable salt thereof.

[0112] In a particularly preferred embodiment, the present invention comprises: A is selected from pyridyl, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrrolo[3,2-c]pyridine and phenyl; R 8 is hydrogen, amino, CH 3 -NH-, amino-(CH 2 ) 3 -NH-, hydroxymethyl and hydroxy-(CH 2 ) 2 -NH-, R 9 is selected from hydrogen and fluoro, or a pharma- ceutically acceptable salt thereof.

[0113] In a preferred embodiment, the present invention provides compounds of formula (Ia) as described herein, or a pharma- ceutically acceptable salt thereof, wherein X is N.

[0114] In one embodiment, the present invention provides X and Y are each independently selected from N and CH; n is selected from 0 to 6; A is 5-14 membered heteroaryl and C 6 -C 14 -aryl, B is 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl and C 3 -C 10 -cycloalkyl, L is a covalent bond, CH 2 selected from NH and NH; R 1 but, (i) C substituted with one amino and one carboxy substituent 1 -C 6 -alkyl, (ii) one amino and one carboxy-C 1 -C 6 -C substituted with alkyl-NH-substituents 1 -C 6 -alkyl, (iii) C 1 -C 6 -Alkyl-N(R 1a R 1b ), (iv) C 1 -C 6 -Alkyl-N + (R 1c R 1d R 1e ), (v) group [ka] and (vi) Group [ka] is selected from R 1a Amino-C 1 -C 6 -alkyl, R 1b Carboxy-C 1 -C6 -alkyl, R 1c But Amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl, R 1d Carboxy-C 1 -C 6 -alkyl, R 1e But, C 1 -C 6 -Alkyl, Amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl-, R 1f But Amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl-, R 1g Carboxy-C 1 -C 6 -alkyl, R 1h Carboxy-C 1 -C 6 -alkyl, R 1i Amino-C 1 -C 6 -alkyl, R 2 But hydrogen, C 1 -C 6 -Alkyl and C 1 -C 6 -alkoxy; R 3 and R 7 are both hydrogen, or R 2 and R 7 together with the atoms to which they are attached form a 4- to 14-membered heterocycle or C 4 -C 10 - forms a cycloalkyl, R3 is hydrogen, or R 2 and R 3 together with the carbon atom to which they are attached, C 3 -C 10 - forms a cycloalkyl, R 7 is hydrogen, R 4 But hydrogen and C 1 -C 6 -alkyl; R 5 and R 6 are both hydrogen, or R 4 and R 6 together with the atoms to which they are attached form a 4- to 14-membered heterocyclic ring, R 5 is hydrogen, or R 4 and R 5 together with the carbon atom to which they are attached, C 3 -C 10 - forms a cycloalkyl, R 6 is hydrogen, R 8 is hydrogen, cyano, amino, C 1 -C 6 -alkyl-NH-, (C 1 -C 6 -alkyl) 2 N-, (C 1 -C 6 -alkyl) 2 NC 1 -C 6 -Alkyl-, Amino-C 1 -C 6 -Alkyl, Amino-C 1 -C 6 -Alkoxy, Amino-C 1 -C 6 -Alkyl-NH-, C 1 -C 6 -Alkyl-NH-C 1 -C 6 -Alkyl-NH-, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl-NH-, C3 -C 10 -Cycloalkyl-NH-, C 1 -C 6 -Alkoxy, C 1 -C 6 -Alkyl, Hydroxy-C 1 -C 6 -Alkyl-, Hydroxy-C 1 -C 6 -alkyl-NH- and groups [ka] is selected from R 9 is selected from hydrogen, halogen and amino; R 10 is selected from hydrogen, halogen and amino; R 11 is selected from hydrogen and halogen, or a pharma- ceutically acceptable salt thereof.

[0115] In a preferred embodiment, the present invention comprises: X is N, Y is CH; A is 5-14 membered heteroaryl and C 6 -C 14 -aryl, R 1 but, (I C 1 -C 6 -Alkyl-N + (R 1c R 1d R 1e ), and (ii) group [ka] is selected from R 1c and R 1e All of these are amino-C 1 -C 6 -alkyl, R 1d and R 1gAll of them are carboxy-C 1 -C 6 -alkyl, R 1f But Amino-C 1 -C 6 -Alkyl and (3-14 membered heterocyclyl)-C 1 -C 6 -alkyl-, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are all hydrogen, R 8 But hydrogen, amino, C 1 -C 6 -Alkyl-NH-, Amino-C 1 -C 6 -Alkyl-NH-, Hydroxy-C 1 -C 6 -Alkyl- and hydroxy-C 1 -C 6 -alkyl-NH-, R 9 is selected from hydrogen and halogen, or a pharma- ceutically acceptable salt thereof.

[0116] In a preferred embodiment, the present invention comprises: X is N, Y is CH; A is selected from pyridyl, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrrolo[3,2-c]pyridine and phenyl; R 1 but, (i)-(CH 2 ) 3 -N + (R 1c R 1d R 1e ), and (ii) group [ka] is selected from R1c and R 1e are all 4-aminobutyl, R 1d and R 1g are all carboxymethyl, R 1f is selected from 3-aminopropyl and azetidin-3-ylmethyl; R 8 is hydrogen, amino, CH 3 -NH-, amino-(CH 2 ) 3 -NH-, hydroxymethyl and hydroxy-(CH 2 ) 2 -NH-, R 9 is selected from hydrogen and fluoro, or a pharma- ceutically acceptable salt thereof.

[0117] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is Bis(4-aminobutyl)-(carboxymethyl)-[4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazino]-4-keto-butyl]ammonium; cis-2-[4-[4-[4-[[5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; Bis(4-aminobutyl)-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)ammonium; 2-[4-[4-[4-[[5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; Bis(3-aminopropyl)-(carboxymethyl)-[4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazino]-4-keto-butyl]ammonium; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-c]pyridin-6-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[5-(3-aminopropylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-[5-[[(2S)-2-aminopropyl]amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; Bis(4-aminobutyl)-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)ammonium; 2-[4-[4-[4-[[5-[1-[5-(aminomethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-[5-(2-aminoethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-[5-(2-aminoethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[5-(2-pyridylmethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-[5-[(1-aminocyclopentyl)methylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-(5-morpholino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-[5-[[(2S)-pyrrolidin-2-yl]methylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[5-(2-methoxyethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; trans-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-(5-piperazino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-[5-[2-(methylamino)ethylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; Bis(3-aminopropyl)-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)ammonium; Bis(4-aminobutyl)-[4-[4-[4-[[5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)ammonium; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(4-methoxyphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[5-(2-hydroxyethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1-methylpyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]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-[1-[5-(isopropylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-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-[[1-methyl-5-[1-[5-(2-pyridylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrazolo[4,3-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-thiazol-2-yl-3-(trifluoromethyl)pyrazol-4-yl]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-[1-[5-(cyclopropylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-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-[1-[5-(dimethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-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-[1-[4-(dimethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-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-[[1-methyl-5-[1-[5-[[(3S)-morpholin-3-yl]methylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[6-(dimethylamino)-3-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; [4-[4-[4-[[5-[1-(5-aminopyridin-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chlorobenzoyl]piperazin-1-yl]-4-oxobutyl]-bis(azetidin-3-ylmethyl)-(carboxymethyl)azanium; 2-[4-[4-[4-[[5-[1-[5-(6-aminohexylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[4-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-[5-(4-methylpiperazino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]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-[1-(5-hydroxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(1H-imidazo[4,5-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-(6-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[5-(4-piperidylmethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]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-[1-[5-[[(2S,4S)-4-fluoropyrrolidin-2-yl]methylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-(5-amino-3-fluoro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 4-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]butyric acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]-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-[1-(1H-indazol-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]-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-[1-furo[3,2-b]pyridin-5-yl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; trans-2-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[5-[(2,2-difluorocyclopropyl)methylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 3-Aminopropyl-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)-methyl-ammonium; Bis(3-aminopropyl)-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)ammonium; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(5,6-diamino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-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-[[1-methyl-5-[1-[6-(methylamino)-3-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]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-[1-[5-(cyclobutylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[2-(3-aminopropyl)-4-[3-[[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]amino]propyl]pyridin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-(4-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[3-aminopropyl-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]amino]acetic acid; cis-2-[4-[4-[4-[[5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-(2-amino-4-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[1-(3-aminopropyl)-4-[1-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperidine-4-carbonyl]piperazin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(5-cyano-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[4-[(2S)-4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-2-methyl-piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[4-[(3R)-4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-3-ethyl-piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[4-[(3S)-4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-3-methyl-piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-(1,3-benzothiazol-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[[(5S)-5-amino-6-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-6-keto-hexyl]amino]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(6-methoxy-3-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; (2S) 2-amino-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyric acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[5-[(dimethylamino)methyl]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; (3R)-3-amino-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyric acid; 2-[4-[7-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-4,7-diazaspiro[2.5]octane-4-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[4-[1-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperidine-4-carbonyl]-1-(azetidin-3-ylmethyl)piperazin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-(methylamino)-4-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-(6-amino-3-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[4-[8-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-3,8-diazabicyclo[3.2.1]octane-3-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; (2S)-2-amino-5-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-5-keto-valeric acid; (3S)-3-amino-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyric acid; 2-[4-[4-[4-[[5-[1-[6-(2-aminoethylamino)-3-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[4-[3-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-3,9-diazabicyclo[3.3.1]nonane-9-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-4,7-diazaspiro[2.5]octane-7-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-(4-aminoisothiazol-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-(benzothiophen-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[2-(3-aminopropyl)-4-[3-[[1-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperidine-4-carbonyl]amino]propyl]pyridin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-2-(methoxymethyl)piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[5-[1-[2-(3-hydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[2-(3-amino-3-oxo-propyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(3-aminopropyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[5-[1-(2-fluoro-4-morpholino-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-[2-[(1S)-1-hydroxyethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[5-[1-[2-[2-hydroxy-1-(hydroxymethyl)ethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[1-methyl-2-(morpholine-4-carbonyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[5-[1-[2-(2-hydroxyethylcarbamoyl)-1-methyl-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-[(1S)-1,2-dihydroxyethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-[(1R)-1,2-dihydroxyethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-[2-fluoro-4-(methylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-fluoro-4-[[5-[1-[2-fluoro-4-(methylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-[4-(dimethylamino)-2-fluorophenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-fluoro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(2-fluoro-4-hydroxyphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-[2-fluoro-4-(2-methoxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[2-[(3aS,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-(7-oxa-2-azaspiro[3.5]nonane-2-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(1-imino-1-keto-1,4-thiazinane-4-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(2-hydroxyethylcarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-(9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-[(3,3,3 trifluoro-2-hydroxy-propyl)carbamoyl]-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-(piperazine-1-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(2,2-difluoromorpholine-4-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-[(2-ketopyrrolidin-3-yl)carbamoyl]-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-[(5R)-2,6-dioxa-9-azaspiro[4.5]decane-9-carbonyl]-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-(thiomorpholine-4-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(dimethylcarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-fluoro-4-[[5-[1-[2-fluoro-4-(2-methoxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(hydroxycarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[4-[2-(difluoromethoxy)ethylamino]-2-fluorophenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-[2-(2-hydroxyethyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(difluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[2-(2-aminoethyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]oxyethyl-bis(3-aminopropyl)-(carboxymethyl)ammonium; cis-2-[1-(3-aminopropyl)-4-[4-[2-fluoro-4-[[5-[1-(2-fluoro-4-hydroxy-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-methyl-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-fluoro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[1-(3-aminopropyl)-4-[1-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]isonipecotoyl]piperazin-1-ium-1-yl]acetic acid; 2-[4-[1-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]isonipecotoyl]-1-(3-aminopropyl)piperazin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-fluoro-4-[[5-[1-(2-fluoro-4-hydroxyphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[4-[[(2S)-2,3-dihydroxypropyl]amino]-2-fluoro-phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[1-(2-amino-1,1-dimethyl-2-oxo-ethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperazin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(3-aminopropyl)piperazin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[2-(2-aminoethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[1-(methylcarbamoyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperazin-1-ium-1-yl]acetic acid; 2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperazin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[3-(2-hydroxyethylcarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[3-(piperazine-1-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[3-(4-methylpiperazine-1-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[2-(2-amino-2-keto-ethyl)pyrazolo[4,3-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-[(1R)-1-hydroxyethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-fluoro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-methyl-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(2-hydroxyethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[3-[(3S)-3-hydroxypyrrolidine-1-carbonyl]-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[3-(methylcarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-(3-carbamoyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(dimethylsulfamoyl)-2-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(3-hydroxypropyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-[(2S)-2,3-dihydroxypropyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-[1-(3-amino-2-methyl-3-oxo-propyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(2-hydroxyethyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(2-fluoro-4-hydroxy-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-[(2-hydroxy-2-methyl-propyl)amino]phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(5H-pyrrolo[3,2-d]pyrimidin-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-[5-[2-[bis(2-aminoethyl)amino]ethylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[2-(2-amino-2-oxo-ethyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[1-(2-amino-2-keto-ethyl)pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(cyanomethyl)-2-methylol-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(3-aminopropyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[3-(dimethylcarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(2-hydroxyethyl)-2-methylol-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-(methylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-(2-hydroxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[3-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 4-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]butanoic acid; [4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazin-1-yl]-4-oxo-butyl]-bis(3-aminopropyl)-(3-carboxypropyl)ammonium; [4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazin-1-yl]-4-oxo-butyl]-bis(3-aminopropyl)-(carboxymethyl)ammonium; cis-2-[4-[4-[4-[[5-[1-[2-(aminomethyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-(2-methoxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[4-(3-aminopropylamino)-2-fluorophenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; trans-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-[2-(dimethylamino)ethyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-[2-(dimethylamino)ethyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[2-(aminomethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[1-(2-aminoethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-(6-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-methyl-piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[3-(2-hydroxyethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazin-1-yl]-4-oxo-butyl]-(azetidin-3-ylmethyl)-methyl-ammonio]acetate; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-[5-[bis(2-aminoethyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(cyanomethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(2-hydroxyethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[1-(2-amino-2-keto-ethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[2,3-c]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; 2-[4-[4-[4-[[5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-methyl-piperidin-1-ium-1-yl]acetate; and cis-2-[4-[4-[4-[[5-[1-[5-[(3S)-3-aminopyrrolidin-1-yl]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid.

[0118] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is Bis(4-aminobutyl)-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)ammonium; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-c]pyridin-6-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[5-(3-aminopropylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; trans-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[5-(2-hydroxyethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(2-fluoro-4-hydroxyphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-methyl-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[2-(2-amino-2-keto-ethyl)pyrazolo[4,3-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-methyl-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(2-hydroxyethyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[3-(dimethylcarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-(2-hydroxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-(2-methoxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid; cis-2-[4-[4-[4-[[5-[1-[1-(2-amino-2-keto-ethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid; and cis-2-[4-[4-[4-[[5-[1-[5-[(3S)-3-aminopyrrolidin-1-yl]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid.

[0119] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is bis(4-aminobutyl)-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)ammonium, or a pharma- ceutically acceptable salt thereof.

[0120] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-c]pyridin-6-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid.

[0121] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is cis-2-[4-[4-[4-[[5-[1-[5-(3-aminopropylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid.

[0122] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid.

[0123] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, or a pharma- ceutically acceptable salt thereof.

[0124] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is trans-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, or a pharma- ceutically acceptable salt thereof.

[0125] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, or a pharma- ceutically acceptable salt thereof.

[0126] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is cis-2-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid.

[0127] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[5-(2-hydroxyethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, or a pharma- ceutically acceptable salt thereof.

[0128] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, or a pharma- ceutically acceptable salt thereof.

[0129] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(2-fluoro-4-hydroxyphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid.

[0130] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-methyl-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid.

[0131] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is cis-2-[4-[4-[4-[[5-[1-[2-(2-amino-2-keto-ethyl)pyrazolo[4,3-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid.

[0132] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid.

[0133] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-methyl-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid.

[0134] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(2-hydroxyethyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, or a pharma- ceutically acceptable salt thereof.

[0135] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[3-(dimethylcarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, or a pharma- ceutically acceptable salt thereof.

[0136] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, or a pharma- ceutically acceptable salt thereof.

[0137] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-(2-hydroxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, or a pharma- ceutically acceptable salt thereof.

[0138] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-(2-methoxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, or a pharma- ceutically acceptable salt thereof.

[0139] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is cis-2-[4-[4-[4-[[5-[1-[1-(2-amino-2-keto-ethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid.

[0140] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is cis-2-[4-[4-[4-[[5-[1-[5-[(3S)-3-aminopyrrolidin-1-yl]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid.

[0141] In some instances, the compounds of formula (I) according to the present invention contain a quaternary ammonium cation and are therefore permanently positively charged.

[0142] In one embodiment, the associated negatively charged counterion is selected from the group consisting of trifluoroacetate, formate, chloride, and bromide.

[0143] In one embodiment, the invention provides a compound of formula (I) as described herein, wherein when said compound of formula (I) comprises a quaternary ammonium cation, the associated negatively charged counterion is selected from the group consisting of trifluoroacetate, formate, chloride, and bromide.

[0144] In one embodiment, the present invention provides a pharma- ceutically acceptable salt of a compound of formula (I) as described herein, in particular a pharma- ceutically acceptable salt selected from the hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid) and trifluoroacetate salts.

[0145] In further specific embodiments, the present invention provides compounds of formula (I) as described herein (i.e., as the "free base" or "free acid", respectively).

[0146] In some embodiments, the compound of formula (I) is isotopically labeled by replacing one or more atoms therein with atoms having different atomic masses or mass numbers. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that may be incorporated into the compound of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, e.g. 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125Certain isotopically labeled compounds of formula (I), for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H and carbon-14, i.e. 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (I) may be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0147] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may confer greater metabolic stability and may confer certain therapeutic advantages, for example through increased in vivo half-life or reduced dosage requirements.

[0148] 1 1 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes such as N can be useful in positron emission tomography (PET) studies to examine 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 methods analogous to those described in the Examples set forth below, substituting the appropriate isotopically labeled reagent for the non-isotopically labeled reagent previously used.

[0149] Manufacturing method In one aspect, the present invention provides a method of making a compound of formula (I) described herein.

[0150] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, when prepared according to the processes described herein.

[0151] The preparation of the compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. The synthesis of the compounds of the present invention is shown in the following scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following method descriptions have the meanings given earlier in the specification, unless otherwise indicated. More specifically, the compounds of formula (I) may be prepared by the methods given below, the methods given in the examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. Also, for reaction conditions described in the literature that affect the reactions described, see, for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition, Richard C. Larock. John Wiley and Sons, New York, NY. 2018). The inventors have found it convenient to carry out the reaction in the presence or absence of a solvent. There is no particular restriction regarding the nature of the solvent used, provided that it does not adversely affect the reaction or the reagents involved, and that it can dissolve the reagents at least to some extent. The reactions described can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reactions described at a temperature range between -78°C and reflux temperature. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days will usually be sufficient to obtain the intermediates and compounds described. The reaction sequence is not limited to that shown in the scheme, but depending on the starting materials and their respective reactivities, the order of the reaction steps can be freely changed. The starting materials are commercially available or can be prepared by methods similar to those shown below, methods described in the references or examples cited herein, or methods known in the art.

[0152] The following abbreviations are used herein: Å: Angstrom (10 -10 m) ACN or MeCN: Acetonitrile aq: aqueous solution BINAP: (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) BOC or Boc: tert-butyloxycarbonyl CDI: Carbonyldiimidazole CFU: colony forming unit d:day DCM: dichloromethane DEA: Diethylamine DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide EDTA: Ethylenediaminetetraacetic acid EtOAc or EA: Ethyl acetate EtOH: Ethanol eq: equivalent FA: Formic acid FMOC or Fmoc: Fluorenylmethoxycarbonyl h or hr: hours HATU: 1-[bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC: High-performance liquid chromatography HPLC-UV: High-performance liquid chromatography with ultraviolet detector HV: High vacuum IC50: half-maximal inhibitory concentration IC90: 90% inhibitory concentration LED: Light Emitting Diode [M]:Molecular weight M: Molar concentration MeOH: Methanol Minute:Minute mL: milliliter MS: Mass spectrometry NaBH 3 CN: Sodium cyanoborohydride O / N: Overnight, about 16 hours 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 PyAOP: (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate quantitative: quantitative rac: racemic RP: Reverse phase RPHPLC: Reversed-phase high-performance liquid chromatography Rt: retention time RT: Room temperature, approximately 23℃ sat: saturation SEM: 2-Methoxyethyl(trimethyl)silane SFC: Supercritical Fluid Chromatography T3P: Propylphosphonic anhydride solution TEMPO: (2,2,6,6-tetramethylpiperidin-1-yl)oxyl TFA: Trifluoroacetic acid THF: tetrahydrofuran wt: weight XANTPHOS: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0153] In the following schemes, the variables are as defined herein unless otherwise defined. 8’ is R as defined herein. 8 In some cases, R 8’ is R as defined herein. 8 is a protected version of, for example, R 8 is amino, R 8’ is a Boc-protected amine. In some instances, R 8’ is a group R as defined herein. 8 For example, R 8 is amino, R8’ may represent a nitro group, which may then be reduced to the amino group. 8’ may be fluoro, which is the group R 8 By or R 8 Similar considerations apply to R 9’ This also applies to the definition of

[0154] Scheme 1 [ka]

[0155] In Scheme 1, LG represents a leaving group suitable for substitution or coupling reactions, such as a halide or boronic acid.

[0156] Scheme 1 summarizes synthetic routes for preparing intermediates B and C, which may be produced from intermediate AB (e.g., methyl 2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoate, CAS 2489205-78-7, or as described in WO 2020 / 182648) and intermediate A. Intermediate A may be a commercially available compound or may be modified by, for example, an alkylation reaction or the attachment of a protecting group, e.g., Boc, to a substituent R. 8’ and / or R 9’ Further routes for preparing intermediate A are summarized in Schemes 5 and 6. Intermediate A can be prepared by, for example, S N Coupling to intermediate AB via an Ar reaction or a coupling reaction, such as an Ullmann or Chan-Lam reaction, provides intermediate B. Hydrolysis of the methyl ester group of intermediate B provides the carboxylic acid intermediate C. Optionally, the substituent R 8’ and / or R 9’ Further modification of S, such as nitro group reduction followed by reductive amination with various aldehydes, orN The Ar reaction, or the Buchwald-Hartwig reaction may be carried out.

[0157] Scheme 2 [ka]

[0158] In Scheme 2, PG represents a suitable protecting group, such as Boc or Fmoc.

[0159] Intermediates D and E can be prepared according to Scheme 2. Similar to the route outlined in Scheme 1, intermediate A can be prepared by reacting, for example, with S N Intermediate AA (e.g., tert-butyl 4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate, CAS2489206-18-8) is coupled via Ar reaction or coupling reaction, such as Ullmann or Chan-Lam reaction, to give intermediate D. Intermediate AA can then be prepared according to Scheme 7. Alternatively, intermediate C can be coupled with various amines in the presence of a condensing agent such as HATU / DIPEA in a solvent such as DMF to give intermediate D. In another route, intermediate D can be prepared by aminolysis reaction of intermediate CC and intermediate BB, for example, using a base such as NaHMDS in a solvent such as THF. Intermediate CC can then be prepared from intermediate BA (e.g., ethyl 1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxylate, CAS 2489206-33-7) and intermediate A by the reaction of S NIntermediate BB may then be prepared from 4-aminobenzoic acid derivatives coupled with various amines in the presence of a condensing agent such as HATU / DIPEA in a solvent such as DMF. The protecting group PG of intermediate D is then removed to give intermediate E. Optionally, the substituent R may be removed before carrying out the removal of the protecting group PG. 8’ and / or R 9’ Further modification of S can be carried out, such as nitro group reduction followed by reductive amination with various aldehydes, or S N The Ar reaction, or the Buchwald-Hartwig reaction may be carried out.

[0160] Scheme 3 [ka]

[0161] In Scheme 3, PG' represents a suitable protecting group such as tert-Bu.

[0162] Intermediate F may be prepared according to Scheme 3. Intermediate C is coupled with an amine containing a carboxylic acid ester group in the presence of a condensing agent such as HATU / DIPEA in a solvent such as DMF. Subsequent removal of the protecting group PG' provides intermediate F.

[0163] Scheme 4 [ka]

[0164] In Scheme 4, R 1’ is R as defined herein. 1 In some cases, R 1’ is R as defined herein. 1 Thus, for example, R 1 When contains an amino group, R 1’ can be its Boc-protected analogue.

[0165] The compounds of formula (I) according to the invention may be prepared according to various synthetic routes, summarized in scheme 4. Thus, intermediate C is coupled with amine intermediate I in the presence of a condensing agent such as HATU / DIPEA in a solvent such as DMF to give intermediate G. Alternatively, intermediate E can be coupled with carboxylic acid intermediate H in the presence of a condensing agent such as HATU / DIPEA in a solvent such as DMF to give intermediate G, or intermediate E can be coupled with amine intermediate J or K in the presence of a coupling agent such as CDI in a solvent such as DMF, or with alcohol intermediate L to give intermediate G. Alternatively, intermediate F is coupled with amine intermediate J or K in the presence of a condensing agent such as HATU / DIPEA in a solvent such as DMF to give intermediate G. In another route, intermediate AAA (e.g., N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; hydrochloride, CAS2489198-91-4) can be coupled with carboxylic acid intermediate H in the presence of a condensing agent such as HATU / DIPEA in a solvent such as DMF to give intermediate AAAA. Intermediate AAA can also be coupled with amine intermediate J or K, or alcohol intermediate L in the presence of a coupling reagent such as CDI in a solvent such as DMF to give intermediate AAAA. Thereafter, for example, S N Coupling of intermediate A with Ar or a coupling reaction such as, for example, the Ullmann reaction or the Chan-Lam reaction can provide intermediate G. 1’ , R 8’ and R 9’ Subsequent removal of the protecting group of finally gives the compound of formula (I) of the present invention. Intermediate AAA can then be prepared according to the route outlined in Scheme 7.

[0166] Optionally, the route outlined in Scheme 4 may be carried out as a one-pot procedure, which does not require isolation of intermediate G and allows subsequent reactions leading to compounds of formula (I) (e.g., R 1’ , R 8’ and R 9’ This means that further modification of intermediate G can be carried out directly based on the required substitution pattern, such as, for example, alkylation reaction or reductive amination. 1’ , R 8’ and R 9’ This may be carried out before or after removal of the protecting group.

[0167] When a compound of formula (I) contains a quaternary ammonium cation and is therefore permanently positively charged, the associated negatively charged counterion (not shown in the scheme) can optionally be, for example, trifluoroacetate, formate, chloride or bromide.

[0168] Scheme 5 [ka]

[0169] In Scheme 5, R ’ are R 8’ or R 9’ or H, R ’’ are suitable protecting groups such as Boc or SEM, or R 8’ Or R 9’ or H, R ’’’ and R ’’’’ are the CONR ’’ R ’’’’ As R 8’ or R 9’ is a substituent corresponding to

[0170] Intermediate A, consisting of a fused bicyclic heteroaromatic scaffold, may be prepared according to the route depicted in Scheme 5. The route depicted also applies to the preparation of related bicyclic heteroaromatic rings, including positional isomers.

[0171] As shown in Scheme 5, aminopyridine derivative 1 is converted to iodo-substituted aminopyridine derivative 2 in the presence of a reagent such as N-iodosuccinimide in a solvent such as DMF. Compound 2 is then converted to iodo-substituted aminopyridine derivative 2 in a solvent such as THF using CuI / [(dppf)PdCl 2 ], catalysts such as Et 3 N in a Sonogashira reaction with a variety of alkynes to give the alkynyl-substituted aminopyridine derivatives 3. Cyclization of compound 3 in the presence of a base, e.g., KOtBu, in a solvent, e.g., NMP, affords the bicyclic heteroaromatic intermediates A. In an alternative route, commercially available azaindole derivatives 4 can be converted to bicyclic heteroaromatic intermediates A by cyclization with Cs in a solvent, e.g., DMF. 2 CO 3 or in the presence of a condensing agent such as CDI in a solvent such as ACN, R ’’ Optionally, a further substituent R ’ For example, the 2-position substituent can be introduced by the addition of Pd(PhCN) in a solvent such as DMF. 2 Cl 2 / norbornene or in the presence of a strong base such as LDA in a solvent such as THF. For example, the 3-position substituent can be introduced with AlCl 3 The substituent R may be introduced in the presence of a Lewis acid such as ethyl oxalyl chloride or similar reagent such as acyl chloride. ’’ and R ’ The order of introduction of the substituents R may be permuted as necessary. ’’ and R ’ Further modifications of, for example, addition or removal of protecting groups, substitution reactions, Wittig reactions, or reduction reactions, may be carried out as necessary.

[0172] In another route, the iodo-substituted aminopyridine derivative 2 can be catalyzed by the addition of a reagent such as pyruvic acid and Pd(OAc) in a solvent such as DMF. 2 The carboxylic acid derivative 5 can be further converted to intermediate A via a variety of routes. For example, the carboxylic acid derivative 5 can be reacted with a reducing agent such as DIBAL-H in a solvent such as THF to give the intermediate R ’ Alternatively, carboxylic acid derivative 5 can be converted to intermediate A by an esterification reaction. In another route, carboxylic acid derivative 5 or 6 (e.g., 6-chloro-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid, CAS1000341-67-2), respectively, can be coupled with various amines in the presence of a condensing agent such as HATU / DIPEA in a solvent such as DMF to give intermediate A in the form of R ’ It is possible to obtain intermediate A in which the substituent R ’’ and R ’ can be further modified, such as by attachment of a protecting group, or for example by conversion of an amide substituent to a ketone, which is then reduced to an alcohol.

[0173] Scheme 6 [ka]

[0174] In Scheme 6, A ’ are nitrogen, CH, or R 8’ or R 9’ any other C substituted with R ’ and R ’’ are NR ’ R ’’ ~R 8’ or R 9’ is a substituent corresponding to R ’’’ is R ’ However, the terminal methylene (CH 2 ) group.

[0175] Intermediate A consisting of a monocyclic (hetero)aromatic scaffold can be prepared according to the route shown in Scheme 6. The route shown also applies to the preparation of related monocyclic (hetero)aromatic rings, including positional isomers.

[0176] In one route shown in Scheme 6, a monocyclic (hetero)aromatic amine is reacted with a condensing agent, e.g., HATU / Et in a solvent such as DMF. 3 The coupling can be carried out with a variety of carboxylic acids in the presence of NMP such as N. 3 Subsequent reduction of the amide group in the presence of a reducing agent such as -THF gives intermediate A. Alternatively, monocyclic (hetero)aromatic amines can be converted to intermediates R via an alkylation reaction carried out in the presence of a base such as KOtBu in a solvent such as tBuOH. ’ and / or R ’’ to intermediate A. In another route, monocyclic (hetero)aromatic iodides can be coupled with various amines, for example via Ullmann reaction using catalysts / ligands such as CuI / L-proline in a solvent such as DMSO, to give intermediate A. In some cases, further modifications of intermediate A, such as protecting group modifications or reductive amination, can be performed based on the required substitution pattern.

[0177] Scheme 7 [ka]

[0178] In Scheme 7, PG is as defined above. ’’’ is a suitable protecting group, such as trityl.

[0179] Intermediates AA and AAA may be prepared according to the route shown in Scheme 7. The general route to these intermediates is also described in WO2020 / 182648. Commercially available substituted aniline carboxylate derivatives are coupled with 1-methyl-imidazole-2-carboxylate derivatives via aminolysis reaction in the presence of a base such as LiHMDS in a solvent such as THF. The ester group is then hydrolyzed to give a carboxylic acid intermediate, which is then coupled with a monoprotected piperazine derivative in the presence of a condensing agent such as HATU / DIPEA in a solvent such as DMF. This is followed by condensation with a catalyst such as cataCXium A Pd G2, Na in a solvent such as 1,4-dioxane / water 10:1. 2 CO 3 Suzuki reaction with a pyrazole boronic acid derivative in the presence of a base such as to give intermediate AA.

[0180] Intermediate AAA is accessible from intermediate AA by removal of the protecting group PG. Alternatively, intermediate AAA can be prepared via a similar route to intermediate AA, where the Suzuki reaction is carried out with a pyrazole boronic acid derivative protected with PG'''. This protected pyrazole boronic acid derivative can then be commercially available or prepared by protection of the boronic acid derivative or its synthetic precursor, for example from 1H-pyrazole-3-carbaldehyde. Finally, both protecting groups PG and PG'' are removed to give intermediate AAA.

[0181] Scheme 8 [ka]

[0182] In Scheme 8, PG is a suitable protecting group such as Boc or Bn, or H; PG' is as defined above, PG ’’ is a suitable protecting group such as Bn, and optionally R 1’ Other protecting groups such as PG or PG ’can be selectively removed in the presence of LG is a suitable leaving group, such as, for example, a halide or a tosylate. R ’ and R ’’ is R 1’ is a substituent corresponding to the partial structure of, for example, an alkyl or aminoalkyl or hydroxyalkyl group.

[0183] Intermediate H may be prepared according to the route shown in Scheme 5. It is a commercially available compound that contains an amine as well as a carboxylic acid moiety, where the amine is unprotected and can be either a primary or secondary amine, and the carboxyl group is protected by the protecting group PG ’’ and on the amino group, a substituent R having a protecting group PG is ’ and R ’’ Each of these substituents R ’ and R ’’ The introduction of 2 CO 3 or by reductive amination in the presence of a reducing agent such as sodium cyanoborohydride in a solvent such as MeOH. ’ and then alkylation with an alkylating reagent containing a carboxy group protected by the protecting group PG ’’ is removed to give the carboxylic acid intermediate H. In some cases, further modification of intermediate H can be performed based on the required substitution pattern, such as, for example, reductive amination, by adding R 1’ This may be carried out before or after removal of the protecting group.

[0184] Scheme 9 [ka]

[0185] In Scheme 9, R 1’ and P.G. ’’ is defined above, and R 1f’ and R1g’ is as defined in Scheme 10.

[0186] Intermediate I can be prepared according to Scheme 9. Carboxylic acid intermediate H is coupled with various amines in the presence of a condensing agent such as HATU / DIPEA in a solvent such as DMF. The subsequent protecting group PG ’’ Removal of the protecting group PG gives intermediate I. In an alternative route, intermediate J is coupled with a variety of amines in the presence of coupling reagents such as triphosgene / DIPEA in a solvent such as DCM to form the urea-linked structure. ’’ Removal of the aryl group gives intermediate I. In an alternative route, intermediate J can be cleaved by HATU / Et 3 The coupling is performed with a carboxylic acid derivative in the presence of a condensing agent such as N. The subsequent protecting group PG ’’ Removal of gives intermediate I.

[0187] Scheme 10 [ka]

[0188] In Scheme 10, LG is a suitable leaving group such as a halide or a tosylate; R 1f’ is R having a protecting group such as Boc 1f and R 1g’ is R having a protecting group such as tBu. 1g It is. Intermediate J may be prepared according to Scheme 10. Monoprotected piperazines can be reacted with a suitably protected alkylating reagent R in the presence of a base such as triethylamine in a solvent such as MeCN. 1f’ and R 1g’ Then, the protecting group PG is ’’ Removal of gives intermediate J.

[0189] Scheme 11 [ka]

[0190] In Scheme 11, PG ’’ is a protecting group, which may be removed in the presence of other protecting groups such as PG or PG'. For example, PG'' is a Bn group, LG is a group that can be used for coupling with alkynes, such as bromides or iodides; R 1i’ is R having a protecting group such as Boc 1i and R 1i’* is R 1i’ However, the terminal ethylene (CH 2 ) 2 It has no group.

[0191] Intermediate K may be prepared according to Scheme 11. The amino group of the aminoalkyne starting material is protected by the protecting group PG ’’ The protected aminoalkyne is then coupled with pyridine, which is then reacted with, for example, CuI / [Pd(PPh 3 ) 4 ], catalysts such as Et 3 The intermediate is then disubstituted, for example with iodide and bromide, by a Sonogashira reaction carried out in the presence of a base such as N and a solvent such as toluene. A second alkynyl substituent is then attached to the pyridine intermediate, for example via another Sonogashira reaction. Finally, a hydrogenation reaction removes the protecting group PG ’’ is removed and the two alkyne groups are reduced to give intermediate K.

[0192] Scheme 12 [ka]

[0193] In Scheme 12, PG ’’ is a suitable protecting group, PG or PG ’ R 1’’The protecting groups may be selectively removed in the presence of other protecting groups such as PG ’’ is Bn; PG ’ is as defined above, PG is a suitable protector such as Boc or H; LG is a leaving group such as a halide or a tosylate; R ’ and R ’’ is R 1’’ is a substituent, for example an alkyl or aminoalkyl group, corresponding to the moiety R ’’’ is a substituent containing an alkyl group, R 1’’ is R 1’ but does not have a terminal hydroxyl group.

[0194] Intermediate L may be prepared according to the route shown in Scheme 12. Each (amino)alkyl substituent R ’ and R ’’ Commercially available compounds containing a secondary amine substituted with PG are protected with the protecting group PG. Alternatively, this intermediate may be prepared by methods such as reductive amination or alkylation reactions from suitable commercially available starting materials. Subsequently, PG is reacted with PG in the presence of a base such as triethylamine in a solvent such as ACN. ’’ Alkylation is carried out with an alkylating reagent containing a hydroxyl group protected by PG' to give a tertiary amine. Subsequently, alkylation is carried out with an alkylating reagent containing a carboxyl group protected by PG'. Finally, the protecting group PG ’’ is removed to give the alcohol intermediate L.

[0195] When intermediates H, I, J, K, or L contain a quaternary ammonium cation and thus a permanently positively charged group, the associated negatively charged counterion (not shown in the scheme) can be, for example, trifluoroacetate, formate, chloride, or bromide, as appropriate. Reactions with these intermediates H, I, J, K, or L shown in Scheme 4 can be carried out in the presence of various counterions, such as trifluoroacetate, formate, chloride, or bromide. Those skilled in the art will recognize that for some of the reactions depicted in Scheme 4, the outcome can depend on the particular counterion present in the intermediate used. For example, in the case of amide coupling reactions, intermediates with formate counterions have been found to have lower conversions than similar intermediates with trifluoroacetate counterions. The examples shown below for the preparation of various intermediates and examples generally refer to intermediates H, I, J, K, or L without specifying the exact counterion or salt form used, and various salt forms can typically be used interchangeably in these reactions.

[0196] In one aspect, the present invention provides a method for preparing a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, the method being as described in any one of Schemes 1 to 12 above.

[0197] Uses of the Compounds of the Invention As shown in the experimental section, the compounds of formula (I) and their pharma- ceutically acceptable salts possess valuable pharmacological properties for the treatment or prevention of infections and resultant diseases caused by pathogens, in particular by bacteria, more particularly by Acinetobacter species, most particularly by Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0198] The compounds of formula (I) and their pharma- ceutically acceptable salts exhibit activity as antibiotics, particularly as antibiotics against Acinetobacter species, more particularly as antibiotics against Acinetobacter baumannii, and most particularly as pathogen-specific antibiotics against Acinetobacter baumannii.

[0199] The compounds of formula (I) and their pharma- ceutically acceptable salts may be used as antibiotics, i.e. as suitable antibacterial pharmaceutical ingredients in the treatment and prevention of bacterial infections, in particular bacterial infections caused by species, more particularly bacterial infections caused by Acinetobacter baumannii.

[0200] The compounds of the invention may be used, alone or in combination with other drugs, for the treatment or prevention of infections and resultant diseases caused by pathogens, particularly bacteria, more particularly by Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0201] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

[0202] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use as an antibiotic.

[0203] In a further aspect, the present invention provides a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis of hospital-acquired infections and resulting diseases.

[0204] In certain embodiments, the hospital-acquired infection and resulting disease is selected from bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, or combinations thereof.

[0205] In a further aspect, the present invention provides a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis of infections and resulting diseases caused by Gram-negative bacteria.

[0206] In certain embodiments, the infection and resulting disease caused by gram-negative bacteria is selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections or combinations thereof.

[0207] In a further aspect, the present invention provides a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or combinations thereof.

[0208] In a further aspect, the present invention provides a method for the treatment or prevention of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or combinations thereof, comprising administering to a mammal a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof.

[0209] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, as an antibiotic.

[0210] In a further aspect, the present invention provides the use of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for the treatment or prophylaxis of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or combinations thereof.

[0211] In a further aspect, the present invention provides the use of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment or prevention of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or combinations thereof.

[0212] In certain embodiments, the infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof, is selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, or a combination thereof.

[0213] In a further aspect, the present invention provides a compound of formula (I) as defined above or a pharma- ceutically acceptable salt thereof for use in the treatment or prevention of infections and resultant diseases caused by pathogens, in particular bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0214] In a further aspect, the present invention provides a method for the treatment or prevention of infections and resultant diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infections and wound infections caused by pathogens, particularly bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, which comprises administering to a mammal a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0215] In a further aspect, the present invention provides the use of a compound of formula (I) as defined above or a pharma- ceutically acceptable salt thereof for the treatment or prophylaxis of infections and resulting diseases caused by pathogens, in particular bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0216] In a further aspect, the present invention provides the use of a compound of formula (I) as defined above or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of infections and resulting diseases caused by pathogens, particularly bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections. Such a medicament comprises a compound of formula (I) as defined above or a pharma- ceutically acceptable salt thereof.

[0217] Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.Exemplary pharmaceutical compositions are described in Examples 203-206.

[0218] In a further aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients for the treatment or prevention of infections and resulting diseases caused by pathogens, in particular bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0219] The compounds of formula (I) and their pharma- ceutically acceptable salts can be used as medicines (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, liquids, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration can also be carried out parenterally, for example, intramuscularly or intravenously (e.g., in the form of injections or infusions).

[0220] The compound of formula (I) and its pharma- ceutically acceptable salts can be processed with pharma- ceutically inert inorganic or organic additives for the preparation of tablets, coated tablets, dragees, and hard gelatin capsules.Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., can be used as such additives for tablets, dragees, and hard gelatin capsules.

[0221] Suitable excipients for soft gelatine capsules are, by way of example, vegetable oils, waxes, fats, semisolid and liquid polyols etc.

[0222] Suitable excipients for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose etc.

[0223] Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0224] Suitable excipients for suppositories are, by way of example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0225] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. They may also contain still other therapeutically valuable substances.

[0226] The dosage can vary widely and will of course be adapted to the individual requirements in each particular case. In general, for oral administration, a daily dosage of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (e.g., about 300 mg / person), preferably divided into 1 to 3 individual dosages, for example of the same amount, will be appropriate. However, it is clear that the upper limit given in this specification may be exceeded in indicated cases.

[0227] Co-administration of compounds of formula (I) with other drugs The compound of formula (I) or its salt or the compound disclosed herein or its pharmaceutically acceptable salt can be used alone or in combination with other drugs for treatment.For example, the second drug of the combined pharmaceutical preparation or administration regimen can have complementary activity to the compound of formula (I) so that they do not adversely affect each other.The compounds can be administered together in a single pharmaceutical composition or separately. In one embodiment, the compound or pharma- ceutically acceptable salt may be co-administered with an antibiotic, particularly for the treatment or prevention of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, or E. coli, or combinations thereof.

[0228] The term "simultaneous administration" refers to simultaneous administration or any manner of separate sequential administration of the compound of formula (I) or its salt or the compound disclosed herein or its pharma-ceutically acceptable salt and additional active pharmaceutical ingredients, including antibiotics.When administration is not simultaneous, the compounds are administered close in time to each other.Furthermore, it is not important whether the compounds are administered in the same dosage form, for example, one compound may be administered intravenously and another compound may be administered orally. Typically, drugs with antibacterial activity can be co-administered.Specific examples of such drugs are carbapenem (meropenem), fluoroquinolone (ciprofloxacin), aminoglycoside (amikacin), tetracycline (tigecycline), colistin, sulbactam, sulbactam + durrobactam, cefiderocol (fetroja), macrocyclic peptides, and macrolides (erythromycin), as exemplified in, for example, WO2017072062, WO2019185572 and WO2019206853.

[0229] In one aspect, the invention provides a pharmaceutical composition as described herein, further comprising an additional therapeutic agent.

[0230] In one aspect, the present invention provides a pharmaceutical combination comprising a compound of formula (I) as described herein and an additional therapeutic agent.

[0231] In one embodiment, the additional therapeutic agent is an antibiotic agent.

[0232] In one embodiment, the additional therapeutic agent is an antibiotic formulation useful for the treatment or prevention of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, or E. coli, or combinations thereof.

[0233] In one embodiment, the additional therapeutic agent is an antibiotic agent selected from a carbapenem (meropenem), a fluoroquinolone (ciprofloxacin), an aminoglycoside (amikacin), a tetracycline (tigecycline), colistin, sulbactam, sulbactam plus durrobactam, cefiderocol (fetroja), a macrocyclic peptide, and a macrolide (erythromycin), as exemplified in WO2017072062, WO2019185572, and WO2019206853. EXAMPLES

[0234] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the claims to the examples.

[0235] Where the preparations are obtained as a mixture of enantiomers, the pure enantiomers may be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (eg chiral SFC) or crystallization.

[0236] Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere.

[0237] Intermediate A1 5-Bromopyrazolo[4,3-b]pyridine-1-carboxylic acid tert-butyl ester A mixture of 5-bromo-1H-pyrazolo[4,3-b]pyridine (150 mg, 0.758 mmol, 1 equiv) in ultra-dry dichloromethane (3.5 mL) / ultra-dry tetrahydrofuran, (3.5 mL) was treated with triethylamine (114.98 mg, 158.15 μL, 1.14 mmol, 1.5 equiv), di-tert-butyl dicarbonate (214.92 mg, 226.23 μL, 0.985 mmol, 1.3 equiv), and 4-dimethylaminopyridine (12 mg, 0.098 mmol, 0.130 equiv). The mixture was stirred at room temperature for 2 h and then quenched by the addition of water (50 mL). The layers were separated and the aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were washed with brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated. Purification by column chromatography (0-30% DCM / MeOH in DCM) afforded the title compound Intermediate A1 (151 mg, 64%) as a white solid. MS[M+H] + 298.1.

[0238] Intermediate A2 2-[(3-iodoindazol-1-yl)methoxy]ethyl-trimethyl-silane A solution of 3-iodo-1H-indazole (2.0 g, 8.2 mmol, 1 equiv) in DMF (20 mL) was treated with 60% sodium hydride in oil (0.36 g, 9.02 mmol, 1.1 equiv) at 0° C., stirred for 1 h, and treated with 2-(trimethylsilyl)ethoxymethyl chloride (1.6 mL, 9.02 mmol, 1.1 equiv). The reaction mixture was stirred at 0° C. for 1 h and then diluted with NH 4 The combined organic layers were washed with brine (100 mL) and extracted with EtOAc (2×50 mL). 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. Purification by column chromatography (petroleum ether / EtOAc 3:1) afforded the title compound intermediate A2 (2.2 g, 5.88 mmol, 72%) as a colorless oil. MS [M+H] + 375.0.

[0239] Intermediate A7 2-[[5-bromo-2-(2,2-dimethyl-1,3-dioxan-5-yl)pyrrolo[3,2-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane [ka] Step 1: 2,2-Dimethyl-1,3-dioxane-5-carbaldehyde To a solution of oxalyl chloride (10.42 g, 82.09 mmol, 1.2 equiv.) in DCM (100 mL), dimethyl sulfoxide (14.56 mL, 205.23 mmol, 3.0 equiv.) was added N 2 The mixture was added under reduced pressure at −78° C. and stirred for 15 min. To the mixture was added (2,2-dimethyl-1,3-dioxan-5-yl)methanol (10.0 g, 68.41 mmol, 1.0 equiv) in DCM (50 mL) with N 2 The mixture was added at -78°C under reduced pressure and stirred for 1.5 h. Triethylamine (47.67 mL, 342.04 mmol, 5.0 equiv) was then added and stirred for 1 h. Water (200 mL) was added, the layers were separated and the mixture was then extracted with DCM (2 x 100 mL). The combined extracts were washed with brine (300 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the title compound 2,2-dimethyl-1,3-dioxane-5-carbaldehyde (8.1 g, 56.18 mmol, 82.1%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ = 9.85 (s, 1H), 4.22-4.13 (m, 4H), 2.36-2.32 (m, 1H), 1.45 (s, 3H), 1.35 (s, 3H). Step 2: 5-ethynyl-2,2-dimethyl-1,3-dioxane To a solution of 2,2-dimethyl-1,3-dioxane-5-carbaldehyde (7.0 g, 48.55 mmol, 1.0 equiv) in methanol (200 mL) and THF (100 mL) was added 1-diazonio-1-dimethoxyphosphorylprop-1-en-2-oleate (18.66 g, 97.11 mmol, 2.0 equiv) and potassium carbonate (26.84 g, 194.22 mmol, 4.0 equiv). The mixture was stirred at 25° C. for 17 h. Water (500 mL) and PE (300 ml) were added, the layers were separated, and the mixture was then extracted with PE (2×30 mL). The combined extracts were washed with brine (1 L) and diluted with Na 2 SO 4 Drying at 400 rpm, filtering and concentrating under reduced pressure gave the title compound 5-ethynyl-2,2-dimethyl-1,3-dioxane (4.3 g, 30.67 mmol, 63.2%) as a yellow oil which was used without further purification. 1H NMR (400 MHz, chloroform-d) δ = 3.97-3.91 (m, 2H), 3.88-3.79 (m, 2H), 2.85-2.76 (m, 1H), 2.10 (d, J = 2.4 Hz, 1H), 1.46 (s, 3H), 1.38 (s, 3H). Step 3: 6-Bromo-2-iodo-pyridin-3-amine To a solution of 5-amino-2-bromopyridine (20.0 g, 115.6 mmol, 1.0 equiv) in DMF (200 mL) was added N-iodosuccinimide (31.21 g, 138.72 mmol, 1.2 equiv) in one portion at 20° C. and the reaction was stirred at 20° C. for 16 h. The mixture was diluted with EtOAc (500 mL), washed with saturated Na2SO3 solution (500 mL) and brine (500 mL), and then diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by silica column chromatography (70% PE in EtOAc) to give the title compound 6-bromo-2-iodo-pyridin-3-amine (31.0 g, 103.71 mmol, 89.7%) as a red solid. MS[M+H] + 298.9. Step 4: 6-Bromo-2-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethynyl]pyridin-3-amine A mixture of 6-bromo-2-iodo-pyridin-3-amine (5.0 g, 16.73 mmol, 1.0 equiv.), 5-ethynyl-2,2-dimethyl-1,3-dioxane (2.46 g, 17.54 mmol, 1.05 equiv.), triethylamine (6.99 mL, 50.18 mmol, 3.0 equiv.), copper(I) iodide (0.06 mL, 1.67 mmol, 0.1 equiv.) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1223.97 mg, 1.67 mmol, 0.1 equiv.) in THF (50 mL) was evacuated and purified with N. 2 (3x). The yellow mixture was charged with N 2 The mixture was stirred at 60° C. for 16 h under reduced pressure. The reaction mixture was poured into water (100 mL) and extracted with EA (3×100 mL), and the combined organic layers were washed with brine and 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure. The residue was purified by column chromatography (30% EA in PE) to give the title compound 6-bromo-2-[2-(2,2-dimethyl-1,3-dioxane-5-yl)ethynyl]pyridin-3-amine (2.8 g, 9.0 mmol, 44.4%) as a yellow solid. MS[M+H] + 311.2. Step 5: 5-Bromo-2-(2,2-dimethyl-1,3-dioxan-5-yl)-1H-pyrrolo[3,2-b]pyridine To a yellow solution of 6-bromo-2-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethynyl]pyridin-3-amine (2.8 g, 9.0 mmol, 1.0 equiv) in 1-methyl-2-pyrrolidinone (50 mL) was added potassium tert-butoxide (2.52 g, 22.5 mmol, 2.5 equiv) in one portion at 20° C. The mixture was stirred at 50° C. for 2 h. The mixture was poured slowly into a cooled HCl solution (0.05 M, 5 mL) and water (100 ml), extracted with EtOAc (3×60 mL), washed with brine (100 mL×2), and purified with NaCl. 2 SO 4The crude product was purified by silica column (50-100% EA in PE) and concentrated to give the title compound 5-bromo-2-(2,2-dimethyl-1,3-dioxan-5-yl)-1H-pyrrolo[3,2-b]pyridine (2.5 g, 8.03 mmol, 78.8%) as a yellow solid. MS[M+H] + 311.2. Step 6: 2-[[5-bromo-2-(2,2-dimethyl-1,3-dioxan-5-yl)pyrrolo[3,2-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane To a solution of 5-bromo-2-(2,2-dimethyl-1,3-dioxan-5-yl)-1H-pyrrolo[3,2-b]pyridine (2.15 g, 6.91 mmol, 1.0 equiv.) in ACN (15 mL) and DMF (15 mL) was added cesium carbonate (4.5 g, 13.82 mmol, 2.0 equiv.). The reaction mixture was cooled to 5° C. for 2 h and cooled to 3° C. for 1 h. 2 The mixture was stirred at 0° C. for 1 h under reduced pressure. Then, 2-(trimethylsilyl)ethoxymethyl chloride (1.47 mL, 8.29 mmol, 1.2 equiv.) was added. The mixture was then diluted with N 2 The mixture was stirred at 0° C. for 1 h under reduced pressure. EtOAc (50 mL) and water (50 mL) were added, the layers were separated, and the mixture was then extracted with EtOAc (2×50 mL). The combined extracts were washed with brine (100 mL) and diluted with Na 2 SO 4 The crude product was purified by silica gel chromatography eluting with 25% EA in PE to give the title compound 2-[[5-bromo-2-(2,2-dimethyl-1,3-dioxan-5-yl)pyrrolo[3,2-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (2.5 g, 5.66 mmol, 76.6%) as a yellow oil. MS[M+H] + 443.2.

[0240] Intermediate A8 (5-Chloro-1-methyl-pyrrolo[3,2-b]pyridin-2-yl)-morpholino-methanone [ka] Step 1: (5-Chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)-morpholino-methanone To a solution of 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (intermediate A6 step 1; 1.0 g, 5.09 mmol, 1.0 equiv), morpholine (0.47 g, 5.34 mmol, 1.05 equiv) and N,N-diisopropylethylamine (1.06 mL, 6.1 mmol, 1.2 equiv) in DMF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.13 g, 5.6 mmol, 1.1 equiv) at 0° C. The mixture was stirred at 0° C. for 2 h. The mixture was poured into water (30 mL) and then extracted with EA (3×40 mL). The combined organic layers were washed with brine (3×60 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0-100% ACN (FA) in water) and then concentrated under reduced pressure to give the title compound (5-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)-morpholino-methanone (1.2 g, 4.52 mmol, 88.8%) as a pale yellow solid. MS[M+H] + 266.1. Step 2: (5-Chloro-1-methyl-pyrrolo[3,2-b]pyridin-2-yl)-morpholino-methanone To a solution of (5-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)-morpholino-methanone (1.2 g, 4.52 mmol, 1.0 equiv) in DMF (15 mL) was added 60% sodium hydride in oil (0.27 g, 6.77 mmol, 1.5 equiv). The mixture was stirred at 25° C. for 0.5 h. To this solution was added iodomethane (0.42 mL, 6.77 mmol, 1.5 equiv) and stirred at 25° C. for an additional 16 h. The mixture was poured into water (80 mL) and then extracted with EA (3×40 mL). The combined organic layers were washed with brine (3×60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (5-chloro-1-methyl-pyrrolo[3,2-b]pyridin-2-yl)-morpholino-methanone (1.2 g, 4.29 mmol, 84.5%) as a pale yellow solid, which was used without further purification. MS [M+H] + 280.0.

[0241] The following examples were prepared similarly to Intermediate A8. [Table 1]

[0242] Intermediate A12 N-[2-(difluoromethoxy)ethyl]-3-fluoro-4-iodo-aniline [ka] Step 1: Benzyl 2-(difluoromethoxy)acetate To a mixture of benzyl glycolate (20.0 g, 120.36 mmol, 1.0 equiv) in MeCN (50 mL) was added copper(I) iodide (5.73 g, 30.09 mmol, 0.25 equiv). The reaction mixture was stirred at 50° C. Then, 2,2-difluoro-2-(fluorosulfonyl)acetic acid (32.15 g, 180.54 mmol, 1.5 equiv) in MeCN (250 mL) was added dropwise to the above solution over 20 min. After addition, the reaction mixture was immersed in N 2The mixture was stirred at 50° C. for 1 h under reduced pressure. The mixture was concentrated under reduced pressure and the crude product was purified by silica column (5% EA in PE) to give the title compound benzyl 2-(difluoromethoxy)acetate (7.8 g, 36.08 mmol, 30%) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ=7.41-7.38 (m, 5H), 6.38 (t, J=73.6, 1H), 5.25 (s, 2H), 4.49 (s, 2H). Step 2: 2-(Difluoromethoxy)acetic acid To a mixture of benzyl 2-(difluoromethoxy)acetate (7.8 g, 36.08 mmol, 1.0 equiv) in THF (50 mL) was added lithium hydroxide (1.7 mL, 180.41 mmol, 5.0 equiv). The reaction mixture was stirred at 25° C. for 16 h. EtOAc (100 mL) and water (50 mL) were added and the layers were separated. The aqueous layer was washed with EtOAc (2×100 mL). The aqueous layer was adjusted to pH=6 with 1 M HCl, then the mixture was extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (100 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the title compound 2-(difluoromethoxy)acetic acid (3.3 g, 26.18 mmol, 72.6%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ=6.35 (t, J=73.2, 1H), 4.47 (s, 2H). Step 3: 2-(Difluoromethoxy)-N-(3-fluoro-4-iodo-phenyl)acetamide To a mixture of 3-fluoro-4-iodoaniline (4.0 g, 16.88 mmol, 1.0 equiv), 2-(difluoromethoxy)acetic acid (3.19 g, 25.32 mmol, 1.5 equiv), triethylamine (7.06 mL, 50.63 mmol, 3.0 equiv) in DMF (50 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10.91 g, 28.69 mmol, 1.7 equiv) at 25° C. and stirred for 16 h at 25° C. The solution was poured into water (80 mL), extracted with EtOAc (50 mL×2), washed with brine (100 mL), and concentrated to give a residue, which was purified by silica column (20% EA in PE) and concentrated. The resulting material was purified again by RPHPLC (50-80% ACN in water, 0.1% FA) and lyophilized to give the title compound 2-(difluoromethoxy)-N-(3-fluoro-4-iodo-phenyl)acetamide (3.5 g, 10.14 mmol, 60.1%) as a pale yellow solid. 1H NMR (400 MHz, chloroform-d) δ = 8.02 (br s, 1H), 7.69 (dd, J = 7.2, 8.4 Hz, 1H), 7.59 (dd, J = 2.4, 9.6 Hz, 1H), 7.04 (dd, J = 2.0, 8.4 Hz, 1H), 6.41 (t, J = 72.4, 1H), 4.48 (s, 2H). Step 4: N-[2-(difluoromethoxy)ethyl]-3-fluoro-4-iodo-aniline A mixture of 2-(difluoromethoxy)-N-(3-fluoro-4-iodo-phenyl)acetamide (2.0 g, 5.8 mmol, 1.0 equiv) in THF (30 mL) was cooled to 0° C., then borane-tetrahydrofuran complex (16.0 mL, 16.0 mmol, 2.76 equiv) was added dropwise. The reaction was stirred at 50° C. for 14 h. The resulting mixture was cooled to 0° C., and methanol (30 mL) was added. The reaction mixture was then stirred at 80° C. for 2 h. The reaction mixture was poured into water (60 mL), extracted with EtOAc (2×40 mL), washed with brine (80 mL), and concentrated. The crude material was purified by silica column (20% EA in PE) and concentrated to give the title compound intermediate A12 (800.0 mg, 2.42 mmol, 36%) as a yellow oil. MS [M+H] + 332.2.

[0243] Intermediate A4 Methyl 3-[5-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]propanoate [ka] Step 1: Methyl 3-(5-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)propanoate 5-Bromo-4-azaindole (2.0 g, 10.15 mmol, 1.0 equiv), methyl 3-bromopropionate (2.03 g, 12.18 mmol, 1.2 equiv), Pd(PhCN) 2 Cl 2 (0.39g, 1.02mmol, 0.1eq), norbornene (1.91g, 20.3mmol, 2.0eq), NaHCO 3 A mixture of (3.41 g, 40.6 mmol, 4.0 equiv) and water (0.18 mL, 10.15 mmol, 1.0 equiv) in DMF (20 mL) was diluted with N 2The mixture was stirred at 80° C. under reduced pressure for 15 h. The reaction mixture was cooled to room temperature. EtOAc (30 mL) and water (80 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (40 mL), dried over MgSO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography eluting with PE:EA=1:1 (TLC, PE:EA=1:1, Rf=0.2, UV) and concentrated in vacuo to give the title compound (600.0 mg, 2.12 mmol, 20.88%) as a yellow oil. MS[M+H] + 283.0. Step 2: Methyl 3-[5-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]propanoate To a solution of methyl 3-(5-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)propanoate (600.0 mg, 2.12 mmol, 1.0 equiv.) and cesium carbonate (1.38 g, 4.24 mmol, 2.0 equiv.) in ACN (8 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (0.45 mL, 2.54 mmol, 1.2 equiv.) at 0° C. The mixture was diluted with N 2 The mixture was stirred at 0° C. for 1 hour under reduced pressure. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE / EA 5:1) to give the title compound intermediate A4 (400.0 mg, 0.97 mmol, 45.7%) as a yellow oil. MS[M+H] + 414.8.

[0244] Intermediate A3 3-(5-Bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)propoxy-tert-butyl-dimethyl-silane [ka] In a vial, 5-bromo-4-azaindole (600.0 mg, 3.05 mmol, 1.0 equiv.), (3-bromopropoxy)-tert-butyldimethylsilane (1156.8 mg, 4.57 mmol, 1.5 equiv.), Pd(PhCN) 2Cl 2 (587.07 mg, 1.52 mmol, 0.5 equiv), norbornene (573.44 mg, 6.09 mmol, 2.0 equiv), potassium carbonate (420.87 mg, 3.05 mmol, 1.0 equiv), water (0.01 mL, 0.76 mmol, 0.25 equiv) and DMF (10 mL). The mixture was charged with N 2 The mixture was stirred at 80° C. under reduced pressure for 15 h. The reaction mixture was cooled to room temperature. EtOAc (20 mL) and water (30 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (20 mL×2) and the combined organic layers were washed with brine (40 mL), dried over MgSO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE / EA 1:1) to give the title compound intermediate A3 (200.0 mg, 0.54 mmol, 17.8%) as a yellow solid. MS[M+H] + 369.2.

[0245] Intermediate A5 4-(4-Bromo-3-fluoro-phenyl)morpholine [ka] A mixture of 1-bromo-2-fluoro-4-iodobenzene (2.0 g, 6.65 mmol, 1.0 equiv.), morpholine (0.58 g, 6.65 mmol, 1.0 equiv.), (2S)-pyrrolidine-2-carboxylic acid (0.15 g, 1.33 mmol, 0.2 equiv.) and copper(I) iodide (0.05 mL, 1.33 mmol, 0.2 equiv.) in DMSO (20 mL) was evacuated and purified with N. 2 (3x). The mixture was then filled with N 2 The mixture was stirred at 40° C. for 16 h under reduced pressure. EtOAc (40 mL) and water (40 mL) were added and the mixture was filtered. The filtrate was then separated. The aqueous layer was extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (100 mL) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by column chromatography (45% EA in PE) to give the title compound Intermediate A5 (330.0 mg, 1.27 mmol, 19.1%) as a yellow solid. MS [M+H] + 261.9.

[0246] Intermediate A14 2-[[2-(2-azidoethyl)-5-bromo-pyrrolo[3,2-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane [ka] Step 1: 2-[(5-bromopyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane A solution of 5-bromo-4-azaindole (3.5 g, 17.76 mmol, 1.0 equiv) in THF (30 mL) was cooled to 0° C., then 60% sodium hydride in oil (1.07 g, 26.65 mmol, 1.5 equiv) was added in several portions. The mixture was diluted with N 2 The mixture was stirred at 0° C. for 0.5 h under reduced pressure. The reaction mixture was treated with 2-(trimethylsilyl)ethoxymethyl chloride (3.77 mL, 21.32 mmol, 1.2 equiv) in portions, stirred at 0° C. for 2 h, and warmed to 20° C. for 4 h. Water (100 mL) was added to the reaction mixture, EtOAc (200 mL) and additional water (200 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (4×80 mL). The combined extracts were concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EA 4:1). The resulting material was further purified by RP column chromatography (80-90% ACN in water, 0.1% TFA) to give the title compound 2-[(5-bromopyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (5.8 g, 17.72 mmol, 99.8%) as a light brown oil. MS[M+H] + 329.1. Step 2: 2-[5-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethanol A solution of 2-[(5-bromopyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (3.8 g, 11.61 mmol, 1.0 equiv.) in THF (80 mL) was diluted with N 2 The mixture was stirred at −78° C. for 30 min under reduced pressure. To the mixture was added LDA (7.55 mL, 15.09 mmol, 1.3 equiv) dropwise and the mixture was stirred at −78° C. for 1 h. The mixture was then treated with 1,3,2-dioxathiolane 2,2-dioxide (1.87 g, 15.09 mmol, 1.3 equiv) in THF (10 mL) and stirred at −78° C. for 1 h. Finally, the mixture was treated with 12 M HCl (4.07 mL, 48.86 mmol, 4.21 equiv) at 0° C., followed by stirring at 25° C. for 16 h. The reaction mixture was diluted with EtOAc (200 mL) and diluted with NaHCO 3 The aqueous layer was poured into 100 mL of EtOAc. The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers were washed with water (2×300 mL), brine (300 mL) and sodium chloride. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified by column chromatography (20-80% EtOAc in PE) to give 2-[5-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethanol (600.0 mg, 1.62 mmol, 13.9%) as a pale yellow solid. MS[M+H] + 373.1. Step 3: 2-[5-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethyl 4-methylbenzenesulfonate To a solution of 2-[5-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethanol (1.2 g, 3.23 mmol, 1.0 equiv) in DCM (10 mL) was added triethylamine (0.9 mL, 6.46 mmol, 2.0 equiv) and the mixture was stirred at 0° C. Then p-toluenesulfonyl chloride (739.31 mg, 3.88 mmol, 1.2 equiv) was added and the mixture was stirred at 0° C. for 1 h and warmed to 25° C. for 16 h. The reaction mixture was then diluted with EtOAc (20 mL) and diluted with NaHCO 3The aqueous layer was poured into EtOAc (20 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL) and sodium 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by column chromatography (17-33% EA in PE) to give the title compound 2-[5-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethyl 4-methylbenzenesulfonate (1.2 g, 2.28 mmol, 70.7%) as a pale yellow solid. MS[M+H] + 527.0. Step 4: 2-[[2-(2-azidoethyl)-5-bromo-pyrrolo[3,2-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane To a solution of 2-[5-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethyl 4-methylbenzenesulfonate (1.2 g, 2.28 mmol, 1.0 equiv.) in DMF (20 mL) was added sodium azide (0.19 g, 2.92 mmol, 1.28 equiv.) and the mixture was stirred at 25° C. for 16 h. The reaction mixture was cooled to 10° C. with NaHCO 3 (50 mL) and then extracted with EA (3×30 mL). The combined extracts were washed with brine (50 mL) and Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by RP column chromatography (90-100% ACN in water, 0.1% FA) to give the title compound intermediate A14 (740.0 mg, 1.87 mmol, 81.8%) as a pale yellow oil. MS[M+H] + 398.0.

[0247] Intermediate A44 (5-Bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol [ka] 5-Bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester (CAS1255098-82-8; 1790 mg, 6.65 mmol, 1 equiv) in THF (40 mL) was treated dropwise with 1M DIBAL-H in THF (25.28 mL, 25.28 mmol, 3.8 equiv) and stirred at -78 °C for 1 h. The reaction mixture was then warmed to room temperature and stirred for an additional 2 h. The reaction mixture was then cooled to 0 °C and quenched with EtOAc (5 mL) followed by the addition of Rochelle's salt (25 mL). The mixture was stirred overnight and the organic solvents were removed under reduced pressure. The reaction mixture was diluted with water (60 mL) and brine (20 mL) and extracted with EtOAc (4 x 100 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated to give the title compound intermediate A44 (917 mg, 83.3%) as a light brown solid. MS[M+H] + 227.04.

[0248] Intermediate A15 (2S)-3-(3-fluoro-4-iodo-anilino)propane-1,2-diol [ka] To a solution of 3-fluoro-4-iodoaniline (CAS656-66-6; 2.0 g, 8.44 mmol, 1.0 equiv) in methanol (30 mL), (R)-(+)-glycidol (1.06 g, 14.35 mmol, 1.7 equiv) was added and stirred at 90° C. for 16 h. The mixture was then treated with triethylamine (1.76 mL, 12.66 mmol, 1.5 equiv) and stirred at 90° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (50% EA in PE) to give the title compound intermediate A15 (1.8 g, 5.79 mmol, 68.6%) as a yellow solid. MS[M+H] + 312.2.

[0249] Intermediate A31 1-(3-Fluoro-4-iodo-anilino)-2-methyl-propan-2-ol [ka] To a pale yellow solution of 3-fluoro-4-iodoaniline (2.0 g, 8.44 mmol, 1.0 equiv) in tert-butanol (10 mL), potassium tert-butoxide (2.84 g, 25.32 mmol, 3.0 equiv) and isobutylene oxide (3.04 g, 42.19 mmol, 5.0 equiv) were added at 10° C., and the solution was heated to 80° C. and stirred for 16 h. The mixture was concentrated under reduced pressure. The crude material was purified by column chromatography (30% EA in PE) and concentrated under reduced pressure to give the title compound intermediate A31 (650.0 mg, 2.1 mmol, 24.9%) as a yellow solid. MS [M+H] + 310.0.

[0250] Intermediate A17 (6-Bromo-1H-pyrrolo[3,2-c]pyridin-2-yl)-morpholino-methanone [ka] A mixture of 6-bromo-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (Intermediate A11 step 2; 250 mg, 622.3 μmol, 1 equiv.) in N,N-dimethylformamide (1.75 mL) and DIPEA (402.16 mg, 543.46 μL, 3.11 mmol, 5 equiv.) was treated with morpholine (70.48 mg, 70.48 μL, 808.99 μmol, 1.3 equiv.) and HATU (283.94 mg, 746.76 μmol, 1.2 equiv.) and the reaction mixture was stirred at room temperature for 60 min. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were washed twice with 5% lithium chloride and brine, dried over sodium sulfate, filtered and evaporated to give the title compound intermediate A17 (100.3 mg, 46.8%) as a yellow solid, which was used directly in the next step without further purification. MS [M+H] + 310.06.

[0251] Intermediate A19 5-Bromo-N-methyl-pyrrolo[3,2-b]pyridine-1-carboxamide [ka] 5-Bromo-1H-pyrrolo[3,2-b]pyridine (120 mg, 609.04 μmol, 1 equiv) was dissolved in ultra-dry acetonitrile (1 mL). DMAP (7.44 mg, 60.9 μmol, 0.1 equiv) and CDI (148.13 mg, 913.57 μmol, 1.5 equiv) were added and stirred at 90 °C overnight. 2M methylamine in THF (609.04 μL, 1.22 mmol, 2 equiv) was added and stirring was continued at 90 °C overnight. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (0-50% DCM / MeOH 9:1 in DCM) to give the title compound intermediate A19 (45 mg, 29.1%) as a yellow solid. MS [M+H] + 254.04.

[0252] Intermediate A24 2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-6-chloro-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide [ka] Step 1: 6-Chloro-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide To a solution of 6-chloro-5-azaindole (9.0 g, 58.99 mmol, 1.0 equiv) in DCM (300 mL) was added tetrabutylammonium hydrogen sulfate (2.0 g, 5.9 mmol, 0.1 equiv), sodium hydroxide (5.9 g, 147.46 mmol, 2.5 equiv) and dimethylsulfamoyl chloride (12.7 g, 88.48 mmol, 1.5 equiv). The reaction mixture was stirred at 20° C. for 4 h. The mixture was concentrated under reduced pressure. The residue was poured into water (500 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine and sodium 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (9-25% EA in PE) to give the title compound 6-chloro-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide (13.4 g, 51.6 mmol, 80.2%) as a pale yellow solid. MS[M+H] + 260.0. Step 2: 6-Chloro-2-(2-hydroxyethyl)-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide A solution of 6-chloro-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide (13.6 g, 52.37 mmol, 1.0 equiv.) in THF (200 mL) was diluted with N 2 The mixture was stirred at −78° C. for 30 min under reduced pressure. Then LDA (34.04 mL, 68.08 mmol, 1.3 equiv) was added dropwise to the mixture and stirring at −78° C. was continued for 1 h. Then 1,3,2-dioxathiolane 2,2-dioxide (8.45 g, 68.08 mmol, 1.3 equiv) in THF (50 mL) was added at −78° C. and the mixture was stirred at 25° C. for 1 h. Finally HCl (40.0 mL, 480.0 mmol, 9.17 equiv) was added and stirring was continued at 25° C. for 16 h. EtOAc (200 mL) and NaHCO 3 Aqueous solution (300 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (300 mL) and Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by column chromatography (80% EA in PE) to give the title compound 6-chloro-2-(2-hydroxyethyl)-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide (1.1 g, 3.62 mmol, 6.8%) as a pale yellow solid. MS[M+H] + 304.0. Step 3: 2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-6-chloro-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide To a solution of 6-chloro-2-(2-hydroxyethyl)-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide (100.0 mg, 0.33 mmol, 1.0 equiv) and imidazole (24.65 mg, 0.36 mmol, 1.1 equiv) in DCM (5 mL) was added tert-butyldimethylchlorosilane (54.58 mg, 0.36 mmol, 1.1 equiv). The mixture was stirred at 25° C. for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (20% EA in PE) and concentrated to give the title compound intermediate A24 (108.0 mg, 0.26 mmol, 73.8%) as a white solid. MS [M+H] + 418.1.

[0253] The following intermediates were prepared similarly to intermediate A24. [Table 2]

[0254] Intermediate A28 5-Bromo-2-[(2S)-3-[tert-butyl(dimethyl)silyl]oxy-2-hydroxy-propyl]-N,N-dimethyl-pyrrolo[3,2-b]pyridine-1-sulfonamide [ka] Step 1: 5-Bromo-N,N-dimethyl-pyrrolo[3,2-b]pyridine-1-sulfonamide To a solution of 5-bromo-4-azaindole (CAS1000341-51-4; 1.0 g, 5.08 mmol, 1.0 equiv) in DCM (10 mL) was added tetrabutylammonium hydrogen sulfate (0.17 g, 0.51 mmol, 0.1 equiv), sodium hydroxide (0.51 g, 12.69 mmol, 2.5 equiv) and dimethylsulfamoyl chloride (1.09 g, 7.61 mmol, 1.5 equiv). The reaction mixture was stirred at 20° C. for 16 h. The reaction mixture was poured into water (50 mL) and extracted with EA (2×50 mL). The combined organic layers were washed with brine and diluted with Na 2 SO4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA 5:1) to give the title compound 5-bromo-N,N-dimethyl-pyrrolo[3,2-b]pyridine-1-sulfonamide (1.36 g, 4.47 mmol, 88.1%) as a white solid. MS[M+H] + 304.0. Step 2: 5-Bromo-2-[(2S)-3-[tert-butyl(dimethyl)silyl]oxy-2-hydroxy-propyl]-N,N-dimethyl-pyrrolo[3,2-b]pyridine-1-sulfonamide A solution of 5-bromo-N,N-dimethyl-pyrrolo[3,2-b]pyridine-1-sulfonamide (500.0 mg, 1.64 mmol, 1.0 equiv) in THF (10 mL) was cooled to -40°C and treated dropwise with LDA solution (1.64 mL, 3.29 mmol, 2.0 equiv). The mixture was stirred at -40°C for 0.5 h. Then tert-butyl-dimethyl-[[(2S)-oxiran-2-yl]methoxy]silane (464.41 mg, 2.47 mmol, 1.5 equiv) was added to the mixture and stirring was continued at 0°C for 1 h. The solution was diluted with NH 4 Pour into Cl solution (100 mL), extract with EtOAc (2×50 mL), wash the combined organic layers with brine (100 mL) and add Na 2 SO 4 The residue was dried at 40° C., filtered and concentrated, and purified by RPHPLC (95% ACN in 0.1% FA in water) to give the title compound intermediate A28 (220.0 mg, 0.45 mmol, 27.2%) as a yellow oil. MS [M+H] + 494.1.

[0255] Intermediate A20 6-Chloro-N-(2-hydroxyethyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxamide [ka] To a solution of 6-chloro-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid (500.0 mg, 2.54 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.89 mL, 5.09 mmol, 2.0 equiv) in DMF (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.26 g, 3.31 mmol, 1.3 equiv). The mixture was stirred at 25° C. for 15 min. 2-Hydroxyethylamine (0.31 mL, 5.09 mmol, 2.0 equiv) was added to the mixture. The mixture was stirred at 25° C. for 1 h. The mixture was quenched with water (0.5 mL) and then concentrated under reduced pressure. The residue was purified by RP column chromatography (0-60% ACN (FA) in water) to give the title compound intermediate A20 (600.0 mg, 2.5 mmol, 98.4%) as a pale yellow gum. MS [M+H] + 240.1.

[0256] The following examples were prepared similarly to intermediate A20. [Table 3]

[0257] Intermediate A27 6-Bromo-1H-pyrrolo[3,2-c]pyridine-3-carboxamide [ka] 6-Bromo-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde (65 mg, 288.84 μmol, 1 eq.) was dissolved in ultra-dry dimethyl sulfoxide (1 mL). Hydroxylamine hydrochloride (40.14 mg, 577.68 μmol, 2 eq.) was added and the mixture was stirred at 100 °C for 1 h. While still hot, 2 M sodium hydroxide (433.26 μL, 866.51 μmol, 3 eq.) was added dropwise and the mixture was stirred for 5 min. Then, 30% hydrogen peroxide (327.45 mg, 295 μL, 2.89 mmol, 10 eq.) was added dropwise and the mixture was stirred again for 5 min. Water (10 mL) was added and the mixture was extracted with DCM (3 × 10 mL). The organic layer was discarded, the aqueous layer was cooled to 0° C., and the precipitate formed was filtered and dried under reduced pressure to give the title compound intermediate A27 (46 mg, 62.4%) as a yellow solid. MS [M+H] + 240.01.

[0258] Intermediate A32 2-[(2-chloropyrrolo[3,2-d]pyrimidin-5-yl)methoxy]ethyl-trimethyl-silane [ka] To a stirred pale yellow solution of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (500.0 mg, 3.26 mmol, 1.0 equiv) in THF (10 mL) was added 60% sodium hydride in oil (182.31 mg, 4.56 mmol, 1.4 equiv) in three portions at 0° C. After stirring at 0° C. for 0.5 h, 2-(trimethylsilyl)ethoxymethyl chloride (0.69 mL, 3.91 mmol, 1.2 equiv) was added to the solution and stirred at 0° C. for 2 h. The solution was poured slowly into 0.5 N HCl solution (30 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (50 mL) and concentrated to 100° C. with 100% NaCl. 2 SO 4 The residue was purified by column chromatography (27% EA in PE) to give the title compound intermediate A32 (590.0 mg, 2.08 mmol, 58.1%) as a pale yellow oil. MS [M+H] + 284.0.

[0259] Intermediate A33 Benzyl N-[2-[2-(benzyloxycarbonylamino)ethyl-[2-[(6-bromo-3-pyridyl)amino]ethyl]amino]ethyl]carbamate [ka] Step 1: tert-Butyl N-[2-[(6-bromo-3-pyridyl)amino]ethyl]carbamate To a solution of 2-bromo-5-iodopyridine (5.0 g, 17.61 mmol, 1.0 equiv.), copper(I) iodide (0.72 mL, 21.13 mmol, 1.2 equiv.), 2-(2,6-dimethylanilino)-2-oxo-acetic acid (1360.17 mg, 7.04 mmol, 0.4 equiv.) and phosphoric acid, potassium salt (4.37 mL, 52.84 mmol, 3.0 equiv.) in DMSO (100 mL) was added N-BOC-ethylenediamine (3.1 g, 19.37 mmol, 1.1 equiv.). The mixture was degassed and then cooled to 5° C. with 5% CO.sub.2. 2 The mixture was stirred at 35° C. for 16 h under reduced pressure. The mixture was poured into water (80 mL) and EA (80 mL). The mixture was filtered through a pad of Celite (washing with EA, 3×20 mL). The organic layer was separated from the combined filtrate. The aqueous layer was extracted with EA (2×80 mL). The combined organic layers were washed with brine (3×50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (17-50% EA in PE) to give the title compound tert-butyl N-[2-[(6-bromo-3-pyridyl)amino]ethyl]carbamate (1.3 g, 4.11 mmol, 23.3%) as a pale yellow solid. MS[M+H] + 316.0. Step 2: N'-(6-bromo-3-pyridyl)ethane-1,2-diamine dihydrochloride To a solution of tert-butyl N-[2-[(6-bromo-3-pyridyl)amino]ethyl]carbamate (1.0 g, 3.16 mmol, 1.0 equiv.) in methanol (10 mL) was added hydrochloric acid in methanol (20.0 mL, 80.0 mmol, 25.3 equiv.). The mixture was stirred at 15° C. for 2 h and then concentrated under reduced pressure to give the title compound N′-(6-bromo-3-pyridyl)ethane-1,2-diamine dihydrochloride (1.0 g, 3.46 mmol, 98.5%) as a white solid. MS[M+H] + 218. Step 3: Benzyl N-(2,2-dimethoxyethyl)carbamate To a solution of aminoacetaldehyde dimethyl acetal (10.0 g, 95.11 mmol, 1.0 equiv) and sodium bicarbonate (10.39 g, 123.64 mmol, 1.3 equiv) in THF (100 mL) and water (50 mL) was added benzyl chloroformate (17.85 g, 104.62 mmol, 1.1 equiv) dropwise at 0° C. The mixture was stirred at 0° C. for 1 h and then at 15° C. for 16 h to give a white suspension. The mixture was diluted with water (50 mL) and extracted with EA (3×80 mL). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to give the title compound benzyl N-(2,2-dimethoxyethyl)carbamate (23.0 g, 96.13 mmol, 99.1%) as a pale yellow liquid. 1H NMR (CDCl3,400MHz): δ=7.39-7.35(m,5H),5.17(s,2H),4.95(br.s,1H),4.14(t,J=7.2Hz,1H),3.40(s,6H),3.35(t,J=5.6Hz,2H). Step 4: Benzyl N-(2-oxoethyl)carbamate To a solution of benzyl N-(2,2-dimethoxyethyl)carbamate (5.0 g, 20.9 mmol, 1.0 equiv) in THF (30 mL) was added hydrochloric acid (20.9 mL, 41.79 mmol, 2.0 equiv). The mixture was stirred at 15° C. for 4 h to give a colorless solution. The mixture was diluted with water (50 mL) and then extracted with EA (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to give the title compound benzyl N-(2-oxoethyl)carbamate (4.6 g, 23.81 mmol, 96.9%) as a pale yellow oil, which was used directly in the next step without further purification. Step 5: Benzyl N-[2-[2-(benzyloxycarbonylamino)ethyl-[2-[(6-bromo-3-pyridyl)amino]ethyl]amino]ethyl]carbamate To a mixture of N'-(6-bromo-3-pyridyl)ethane-1,2-diamine dihydrochloride (1.0 g, 3.11 mmol, 1.0 equiv), sodium acetate (0.94 mL, 12.46 mmol, 4.0 equiv) and 4 Å molecular sieves in methanol (20 mL) was added N-(2-oxoethyl)benzylcarbamate (3.15 g, 13.84 mmol, 4.44 equiv). The mixture was stirred at 15° C. for 0.5 h. Sodium cyanoborohydride (1.17 g, 18.69 mmol, 6.0 equiv) was then added in four portions. The mixture was stirred at 15° C. for an additional 16 h. Additional benzyl N-(2-oxoethyl)carbamate (2.03 g, 9.34 mmol, 3.0 equiv) was then added to the mixture, followed by sodium cyanoborohydride (0.59 g, 9.34 mmol, 3.0 equiv) in three portions. The mixture was stirred at 15° C. for an additional 16 h. The mixture was filtered and the solid was washed with MeOH (3×2 mL). The combined filtrate was concentrated under reduced pressure and the residue was diluted with EA (200 mL). The mixture was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by RP column chromatography (0-80% ACN in water (HCl)) to give the title compound (2.0 g, 3.51 mmol, 88.2%) as a colorless gum. MS[M+H] +572.1.

[0260] Intermediate A13 2-(5-Bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)ethanol [ka] Step 1: 4-(3-amino-6-bromo-2-pyridyl)but-3-yn-1-ol (6-Bromo-2-iodo-3-pyridyl)amine (Intermediate A7 Step 3; 683 mg, 2.28 mmol, 1 equiv.) was dissolved in ultra-dry acetonitrile (15 mL) and treated with copper(I) iodide (87.03 mg, 456.99 μmol, 0.2 equiv.), Pd(PPh 3 ) 2 Cl 2 (160.38 mg, 228.5 μmol, 0.1 equiv) and triethylamine (693.65 mg, 955.44 μL, 6.85 mmol, 3 equiv) were added to the mixture. Then, 3-butyn-1-ol (288.28 mg, 313.34 μL, 4.11 mmol, 1.8 equiv) was added dropwise and stirred at 50 °C overnight. The mixture was concentrated under reduced pressure and purified by column chromatography (0-50% DCM / MeOH 9:1 in DCM) to give the title compound 4-(3-amino-6-bromo-2-pyridyl)but-3-yn-1-ol (503 mg, 91.3%) as a brown viscous oil. MS [M+H] + 241.11. Step 2: 2-(5-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)ethanol 4-(3-amino-6-bromo-2-pyridyl)but-3-yn-1-ol (307 mg, 1.24 mmol, 1 equiv.) was dissolved in ultra-dry N-methyl-2-pyrrolidinone (6 mL) and treated with potassium tert-butoxide (304.93 mg, 2.72 mmol, 2.2 equiv.) and the mixture was stirred at ambient temperature for 4 days. Water (2 mL) was added and the mixture was directly purified by RP column chromatography (10-50% ACN in water) to give the title compound intermediate A13 (302 mg, 99.4%) as a yellow solid. MS[M+H] + 241.08.

[0261] Intermediate A34 tert-Butyl 5-bromo-2-(2-ethoxy-2-oxo-ethyl)pyrrolo[3,2-b]pyridine-1-carboxylate [ka] Step 1: Ethyl 2-(5-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)acetate To a solution of 5-bromo-4-azaindole (1100.0 mg, 5.58 mmol, 1.0 equiv) in DMF (5 mL) was added 2-norbornene (1051.31 mg, 11.17 mmol, 2.0 equiv), bis(benzonitrile)palladium(II) chloride (214.14 mg, 0.56 mmol, 0.1 equiv), ethyl bromoacetate (0.74 mL, 6.7 mmol, 1.2 equiv), sodium bicarbonate (1876.0 mg, 22.33 mmol, 4.0 equiv) and water (0.1 mL, 5.58 mmol, 1.0 equiv). The reaction was cooled to 5° C. for 2 hours and then cooled to 5° C. for 2 hours. 2 The mixture was stirred at 70° C. for 48 h under reduced pressure. The mixture was diluted with EtOAc (20 mL) and poured into water (20 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×50 mL) and brine (50 mL) and then extracted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under high vacuum. The residue was purified by column chromatography (30% EA in PE) and concentrated. The resulting material was purified again by RPHPLC (50-60% ACN in 0.1% FA in water) to give the title compound ethyl 2-(5-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)acetate (190.0 mg, 0.67 mmol, 11.8%) as a pink solid. MS[M+H] + 282.9. Step 2: tert-Butyl 5-bromo-2-(2-ethoxy-2-oxo-ethyl)pyrrolo[3,2-b]pyridine-1-carboxylate To a solution of ethyl 2-(5-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)acetate (190.0 mg, 0.67 mmol, 1.0 equiv.) in THF (5 mL) was added triethylamine (0.14 mL, 1.01 mmol, 1.5 equiv.), di-t-butyl dicarbonate (0.19 mL, 0.81 mmol, 1.2 equiv.) and 4-dimethylaminopyridine (16.4 mg, 0.13 mmol, 0.2 equiv.). The reaction mixture was stirred at 10° C. for 3 h. The mixture was concentrated under reduced pressure and the residue was purified using column chromatography (PE / EtOAc 10:1) to give the title compound intermediate A34 (280.0 mg, 0.73 mmol, quantitative) as a yellow solid. MS [M+H] + 385.1.

[0262] Intermediate A6 (1R)-1-[5-chloro-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethanol [ka] Step 1: 5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid A mixture of 2-bromo-6-chloro-pyridin-3-amine (23.0 g, 110.86 mmol, 1.0 equiv), pyruvic acid (26.39 g, 299.63 mmol, 2.7 equiv), palladium(II) acetate (2.49 g, 11.09 mmol, 0.1 equiv), triethylamine (48.51 g, 479.42 mmol, 4.32 equiv) and triphenylphosphine (25.93 g, 98.88 mmol, 0.89 equiv) in DMF (30 mL) was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature. EtOAc (500 mL) and water (400 mL) were added and the layers were separated. 1 M HCl (300 mL) was added and the mixture was extracted with EtOAc (4×300 mL). The combined extracts were concentrated under reduced pressure to give the title compound 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (14.0 g, 71.21 mmol, 64.2%) as a light brown solid, which was used in the next step without further purification. MS [M+H] +197.1. Step 2: 5-Chloro-N-methoxy-N-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide To a pale yellow stirred solution of 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (11.0 g, 55.95 mmol, 1.0 equiv), O,N-dimethylhydroxylamine hydrochloride (10.92 g, 111.91 mmol, 2.0 equiv), and N,N-diisopropylethylamine (38.98 mL, 223.82 mmol, 4.0 equiv) in DMF (100 mL) was added HATU (23.4 g, 61.55 mmol, 1.1 equiv) in portions at 10° C. After the addition, the solution was stirred at 10° C. for 1 h. The reaction mixture was diluted with saturated aqueous NaCl (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (500 mL), dried over MgSO4, filtered, and concentrated in vacuo to give a residue. The residue was diluted with EtOAc (50 mL), stirred for 10 min, filtered, and the filter cake was washed with MeOH (50 mL) and dried under reduced pressure to give the title compound 5-chloro-N-methoxy-N-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (10.0 g, 41.73 mmol, 74.6%) as a pale yellow solid. MS [M+H] + 240.1. Step 3: 1-(5-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)ethanone To a solution of 5-chloro-N-methoxy-N-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (10.0 g, 41.73 mmol, 1.0 equiv) in THF (120 mL) was added methyllithium solution (83.45 mL, 83.45 mmol, 2.0 equiv, 1 M) in N 2 After the addition, the mixture was stirred at -78°C for 2 hours. The reaction mixture was diluted with saturated NH 4Poured into Cl solution (100 mL) and extracted with EtOAc (4 x 100 mL). The combined organic layers were concentrated under reduced pressure and purified by column chromatography (50-75% EA in PE) to give the title compound 1-(5-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)ethanone (5.5 g, 28.26 mmol, 67.7%) as a yellow solid. MS [M+H] + 195.1. Step 4: 1-[5-chloro-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethanone To a solution of 1-(5-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)ethanone (5.5 g, 28.26 mmol, 1.0 equiv) in THF (30 mL) was added sodium hydride (1.02 g, 42.39 mmol, 1.5 equiv) at 0° C. and the mixture was stirred for 0.5 h. Then 2-(trimethylsilyl)ethoxymethyl chloride (6.0 mL, 33.91 mmol, 1.2 equiv) was added and the reaction mixture was stirred at 0° C. for an additional 4 h before being poured into water (20 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. Purification by RP column chromatography (70-90% ACN in water (0.1% FA)) afforded the title compound 1-[5-chloro-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethanone (4.0 g, 12.31 mmol, 43.6%) as a brown oil. MS[M+H] + 325.1. Step 5: (1R)-1-[5-chloro-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethanol To a solution of dichloro(p-cymene)ruthenium(II) dimer (188.5 mg, 0.31 mmol, 0.1 equiv.) in water (10 mL) was added (1R,2R)-(-)-Np-tosyl-1,2-diphenylethylenediamine (135.37 mg, 0.37 mmol, 0.12 equiv.) and the mixture was stirred at 70° C. for 1.5 h. 2The mixture was then degassed at 20° C. for 1 hour. The mixture was then cooled to room temperature (Solution A). To a solution of 1-[5-chloro-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethanone (1.0 g, 3.08 mmol, 1.0 equiv.) in THF (10 mL) was added sodium formate (1.05 g, 15.39 mmol, 5.0 equiv.) (Solution B). Solution B was diluted with N 2 Solution A was added under reduced pressure and the reaction mixture was stirred at 40° C. for an additional 2 h. The mixture was cooled to room temperature. EtOAc (20 mL) and water (20 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (30 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. Purification by RP column chromatography (70-90% ACN in water (0.1% FA)) afforded the title compound intermediate A6 (960.0 mg, 2.94 mmol, 95.4%) as a brown oil. MS [M+H] + 327.2.

[0263] Intermediate A48 (1S)-1-[5-chloro-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethanol [ka] To a solution of 1-[5-chloro-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethanone (Intermediate A6 step 4; 1 g, 3.1 mmol, 1 equiv.) in methanol (10 mL) was added sodium borohydride (58.23 mg, 1.54 mmol, 0.5 equiv.). The reaction mixture was stirred at -10 °C for 2 h and concentrated. The crude product was purified by RP column chromatography (70-90% ACN in water (0.1% FA)). The residue was then purified by SFC (column: DAI CEL CHIRA L CEL OD (250 mm * 30 mm, 10 μm); mobile phase: A1 = CO 2 -MeOH(0.05%DEA);B1=EtOH(0.1%NH 3 H 2O); Gradient elution: CO 2 -MeOH(0.1%NH 3 H 2 Further purification by HPLC (HPLC: 100° C.; flow rate: 150 mL / min; column temperature: 35° C.) afforded the title compound Intermediate A48 (490.0 mg, 1.5 mmol, 48.7%) (Peak 1: 1.065 min) as a pale yellow oil, which was confirmed by comparison with Intermediate A6 (Peak 2: 1.238 min).

[0264] Intermediate A16 Ethyl 2-(5-chloropyrrolo[3,2-b]pyridin-1-yl)-2-methyl-propanoate [ka] A solution of 5-chloro-1H-pyrrolo[3,2-b]pyridine (3.0 g, 19.66 mmol, 1.0 equiv) in THF (50 mL) was cooled to 0° C., then 60% sodium hydride in oil (1.18 g, 29.49 mmol, 1.5 equiv) was added in portions. The mixture was diluted with N 2 The mixture was stirred at 0° C. for 0.5 h under reduced pressure. Ethyl 2-bromoisobutyrate (3.84 g, 19.66 mmol, 1.0 equiv) was added in portions to the solution and the mixture was stirred at 0° C. for 2 h and warmed to 20° C. over 14 h. 1M HCl (10 mL) and water (20 mL) were added to the reaction mixture and the mixture was extracted with EtOAc (4×30 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA 2:1) to give the title compound intermediate A16 (1.9 g, 7.12 mmol, 36.2%) as a pale yellow oil. MS [M+H] + 267.1.

[0265] Intermediate A11 6-Bromo-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester [ka] Step 1: (2-Bromo-5-iodo-4-pyridyl)amine A mixture of (2-bromo-4-pyridyl)amine (9.75 g, 56.36 mmol, 1 equiv) in acetonitrile (200 mL) at 80° C. was treated with N-iodosuccinimide (13.95 g, 61.99 mmol, 1.1 equiv) and the mixture was stirred at 80° C. overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. 10% Na 2 S 2 O 3 (300 mL) was added and the mixture was extracted with ethyl acetate (3×250 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (10-35% ethyl acetate in heptane) to give (2-bromo-3-iodo-4-pyridyl)amine (6.52 g, 38.7%) as an off-white solid and the title compound (2-bromo-5-iodo-4-pyridyl)amine (5.12 g, 30.4%) as a yellow solid. MS[M+H] + 298.93. Step 2: 6-Bromo-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid A mixture of (2-bromo-5-iodo-4-pyridyl)amine (5100 mg, 17.06 mmol, 1.000 equiv) in ultra-dry N,N-dimethylformamide (35 mL) in a MW vial was treated with pyruvic acid (4.51 g, 3.58 mL, 51.19 mmol, 3 equiv), palladium diacetate (162.47 mg, 853.1 μmol, 0.05 equiv) and DABCO (5.74 g, 51.19 mmol, 3 equiv) and the mixture was stirred at 110° C. for 90 min under MW stirring. Methanol (100 mL) was added and the mixture was filtered through Celite. The solvent was removed under reduced pressure. The residue was purified by column chromatography (5-30% MeOH+2% AcOH in DCM) to give the title compound 6-bromo-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (5.55 g, 89.1%) as a brown solid. MS[M+H] + 241.02. Step 3: 6-Bromo-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester A mixture of 6-bromo-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (4.85 g, 13.28 mmol, 1 equiv.) in methanol (150 mL) was diluted with H 2 SO 4 (6.51 g, 3.54 mL, 66.4 mmol, 5 equiv.) and the mixture was stirred at 70° C. for 24 h. The mixture was concentrated under reduced pressure. 3 Aqueous solution (100 mL) was slowly added and the mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0-30% DCM / MeOH 9:1 in DCM) to give the title compound intermediate A11 (1.094 mg, 32.3%) as a pale yellow solid. MS[M+H] + 255.08.

[0266] Intermediate A39 (6-Bromo-1H-pyrrolo[3,2-c]pyridin-2-yl)methanol [ka] A mixture of 6-bromo-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (Intermediate A11 Step 2; 195 mg, 808.99 μmol, 1 equiv.) in ultra-dry tetrahydrofuran (5 mL) was treated dropwise with 2M borane dimethylsulfide complex (889.89 μL, 1.78 mmol, 2.200 equiv.) at 0° C. The reaction mixture was then allowed to warm to room temperature and stirred for 3 days. Water (10 mL) and saturated NaHCO 3 Aqueous solution (5 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic phase was dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the title compound Intermediate A39 (87 mg, 47.4%) as a yellow oil. MS[M+H] + 229.0.

[0267] Intermediate A18 tert-Butyl N-[2-[6-bromo-1-(dimethylsulfamoyl)pyrrolo[3,2-c]pyridin-2-yl]ethyl]carbamate [ka] Step 1: 2-Bromo-5-(3,3-diethoxyprop-1-ynyl)pyridin-4-amine A mixture of (2-bromo-5-iodo-4-pyridyl)amine (Intermediate A11 Step 1; 17.2 g, 57.54 mmol, 1.0 equiv.), propargylaldehyde diethyl acetal (7.74 g, 60.42 mmol, 1.05 equiv.), triethylamine (24.06 mL, 172.63 mmol, 3.0 equiv.), copper(I) iodide (0.19 mL, 5.75 mmol, 0.1 equiv.) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.21 g, 5.75 mmol, 0.1 equiv.) in THF (250 mL) was evacuated and purified with N. 2 (3x). The yellow mixture was then charged with N 2 The mixture was stirred at 60° C. for 16 h under reduced pressure. The reaction mixture was poured into water (300 mL) and extracted with EA (3×150 mL). The combined organic layers were washed with brine and 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by column chromatography (30% EA in PE) to give the title compound 2-bromo-5-(3,3-diethoxyprop-1-ynyl)pyridin-4-amine (10.0 g, 33.43 mmol, 50.3%) as a yellow solid. MS[M+H] + 299.0. Step 2: 6-Bromo-2-(diethoxymethyl)-1H-pyrrolo[3,2-c]pyridine To a yellow solution of 2-bromo-5-(3,3-diethoxyprop-1-ynyl)pyridin-4-amine (10.0 g, 33.43 mmol, 1.0 equiv) in 1-methyl-2-pyrrolidinone (200 mL) was added potassium tert-butoxide (9.38 g, 83.57 mmol, 2.5 equiv) in one portion at 20° C. The mixture was stirred at 50° C. for 2 h. The mixture was poured slowly into a cold 0.05 N HCl solution (50 mL, pH=6) and water (300 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (2×400 mL) and concentrated with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (30% EA in PE) to give the title compound 6-bromo-2-(diethoxymethyl)-1H-pyrrolo[3,2-c]pyridine (9.8 g, 32.76 mmol, 65.7%) as a yellow solid. MS[M+H] + 301.0. Step 3: 6-Bromo-2-(diethoxymethyl)-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide To a solution of 6-bromo-2-(diethoxymethyl)-1H-pyrrolo[3,2-c]pyridine (9.7 g, 32.42 mmol, 1.0 equiv) in DCM (150 mL) was added tetrabutylammonium hydrogen sulfate (1.1 g, 3.24 mmol, 0.1 equiv), sodium hydroxide (3.24 g, 81.06 mmol, 2.5 equiv) and dimethylsulfamoyl chloride (6.98 g, 48.64 mmol, 1.5 equiv). The reaction mixture was stirred at 20° C. for 16 h and concentrated in vacuo. The residue was poured into water (200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine and sodium 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. Purification by column chromatography (9-25% EA in PE) afforded the title compound 6-bromo-2-(diethoxymethyl)-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide (10.5 g, 25.84 mmol, 79.7%) as a yellow solid. MS[M+H] + 408.0. Step 4: 6-Bromo-2-formyl-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide To a solution of 6-bromo-2-(diethoxymethyl)-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide (10.5 g, 25.84 mmol, 1.0 equiv.) in THF (100 mL) / water (20 mL) was added p-toluenesulfonic acid monohydrate (7.37 g, 38.76 mmol, 1.5 equiv.) at 20° C. The mixture was stirred at 20° C. for 16 h. The solution was diluted with saturated NaHCO 3 The combined organic layers were washed with brine (200 mL) and extracted with Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated to give a yellow residue. The residue was purified by column chromatography (35% EA in PE) to give the title compound 6-bromo-2-formyl-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide (5.0 g, 15.05 mmol, 58.3%) as a yellow solid. MS[M+H] + 334.0. Step 5: 6-Bromo-2-[(E)-2-methoxyvinyl]-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide To a solution of (methoxymethyl)triphenylphosphonium chloride (9.29 g, 27.09 mmol, 2.0 equiv.) in THF (100 mL) was added sodium bis(trimethylsilyl)amide (27.09 mL, 27.09 mmol, 2.0 equiv.) at 0° C. and the mixture was stirred for 1 h. A solution of 6-bromo-2-formyl-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide (4.5 g, 13.55 mmol, 1.0 equiv.) in THF (10 mL) was added dropwise to the reaction mixture at 0° C. and the mixture was stirred at that temperature for 1 h and then at 20° C. for 16 h. The reaction mixture was cooled to room temperature. EtOAc (100 mL) and saturated NH 4 Aqueous Cl (150 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (300 mL) and Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by RPHPLC (50-80% ACN in 0.1% FA in water) to give the title compound 6-bromo-2-[(E)-2-methoxyvinyl]-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide (2.6 g, 7.22 mmol, 51.7%) as a yellow oil. MS[M+H] + 361.9. Step 6: 6-Bromo-N,N-dimethyl-2-(2-oxoethyl)pyrrolo[3,2-c]pyridine-1-sulfonamide To a solution of 6-bromo-2-[(E)-2-methoxyvinyl]-N,N-dimethyl-pyrrolo[3,2-c]pyridine-1-sulfonamide (2.6 g, 7.22 mmol, 1.0 equiv.) in THF (16 mL) was added 3M HCl (16.0 mL, 48.0 mmol, 6.65 equiv.) at 20° C. and the mixture was stirred at 20° C. for 16 h. The mixture was concentrated under reduced pressure and the crude material was purified by RPHPLC (50-80% ACN in water, 0.1% HCl) to give the title compound 6-bromo-N,N-dimethyl-2-(2-oxoethyl)pyrrolo[3,2-c]pyridine-1-sulfonamide (1.8 g, 5.2 mmol, 61.1%) as a yellow solid. MS[M+H] + 347.8. Step 7: tert-Butyl N-[2-[6-bromo-1-(dimethylsulfamoyl)pyrrolo[3,2-c]pyridin-2-yl]ethyl]carbamate A solution of 6-bromo-N,N-dimethyl-2-(2-oxoethyl)pyrrolo[3,2-c]pyridine-1-sulfonamide (0.7 g, 2.02 mmol, 1.0 equiv), ammonium chloride (0.54 g, 10.11 mmol, 5.0 equiv), 4 Å molecular sieves (817 mg) and di-t-butyl dicarbonate (882.57 mg, 4.04 mmol, 2.0 equiv) in methanol (10 mL) was stirred for 4 h at 20° C. The mixture was then treated with sodium cyanoborohydride (381.18 mg, 6.07 mmol, 3.0 equiv) and stirred at 20° C. for 12 h. The mixture was filtered, concentrated in vacuo, and purified by RPHPLC (50-80% ACN in 0.1% FA in water) to give the title compound Intermediate A18 (200.0 mg, 0.45 mmol, 20.9%) as a yellow solid. MS [M+H] + 449.1.

[0268] Intermediate A41 tert-Butyl 2-[[bis(tert-butoxycarbonyl)amino]methyl]-6-bromo-pyrrolo[3,2-c]pyridine-1-carboxylate [ka] Step 1: 6-Bromo-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde To a solution of 6-bromo-2-(diethoxymethyl)-1H-pyrrolo[3,2-c]pyridine (Intermediate A18 Step 2; 1.2 g, 4.01 mmol, 1.0 equiv) in THF (20 mL) / water (4 mL) was added p-toluenesulfonic acid monohydrate (1144.51 mg, 6.02 mmol, 1.5 equiv) at 10° C. The mixture was stirred at 10° C. for 1 h. The solution was diluted with saturated NaHCO 3 The combined extracts were washed with brine (50 mL) and diluted with Na 2 SO 4The mixture was dried at 70° C., filtered and concentrated. The residue was purified by column chromatography (35% EA in PE) to give the title compound 6-bromo-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (0.8 g, 3.55 mmol, 88.6%) as a pale yellow solid. MS [M+H] + 227.0. Step 2: tert-Butyl N-[(6-bromo-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl]carbamate To a mixture of 6-bromo-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (700.0 mg, 3.11 mmol, 1.0 equiv), tert-butyl carbamate (728.8 mg, 6.22 mmol, 2.0 equiv) and trifluoroacetic acid (0.72 mL, 9.33 mmol, 3.0 equiv) in ACN (30 mL) was added triethylsilane (3616.96 mg, 31.11 mmol, 10.0 equiv) at 10 °C. The mixture was stirred at 10 °C for 16 h. The solution was diluted with saturated NaHCO 3 The combined extracts were washed with brine (150 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by RPHPLC (50% ACN in 0.1% FA in water). The acetonitrile was removed under reduced pressure (<30° C.) and the remaining aqueous layer was extracted with EtAOC (100 mL), washed with brine (150 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the title compound tert-butyl N-[(6-bromo-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl]carbamate (590.0 mg, 1.81 mmol, 58.2%) as a pale yellow solid. MS[M+H] + 326.0. Step 3: tert-Butyl 2-[[bis(tert-butoxycarbonyl)amino]methyl]-6-bromo-pyrrolo[3,2-c]pyridine-1-carboxylate To a yellow solution of tert-butyl N-[(6-bromo-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl]carbamate (590.0 mg, 1.81 mmol, 1.0 equiv.), triethylamine (0.38 mL, 2.71 mmol, 1.5 equiv.) and 4-dimethylaminopyridine (44.19 mg, 0.36 mmol, 0.2 equiv.) in THF (10 mL) was added di-t-butyl dicarbonate (0.83 mL, 3.62 mmol, 2.0 equiv.) at 10° C. The mixture was stirred at 10° C. for 3 h. The reaction mixture was directly purified by column chromatography (20% EA in PE) to give the title compound intermediate A41 (700.0 mg, 1.33 mmol, 71.3%) as a pale yellow solid. MS [M+H] + 528.1.

[0269] Intermediate A36 2-(6-bromopyrrolo[3,2-c]pyridin-1-yl)ethoxy-tert-butyl-dimethyl-silane [ka] A mixture of 6-bromo-1H-pyrrolo[3,2-c]pyridine (83 mg, 421.26 μmol, 1 equiv.) in N,N-dimethylacetamide (500 mL) was treated with (2-bromoethoxy)-tert-butyldimethylsilane (503.88 mg, 453.95 μL, 2.11 mmol, 5 equiv.), PdCl 2 (MeCN) 2 (10.93 mg, 42.13 μmol, 0.1 equiv.), norbornene (79.33 mg, 842.51 μmol, 2 equiv.), water (18.98 mg, 18.98 μL, 1.05 mmol, 2.5 equiv.) and K 2 CO 3 (116.44 mg, 842.51 μmol, 2 equiv.). The mixture was stirred at 70° C. overnight, diluted with MTBE (20 mL), filtered through Celite, and concentrated under reduced pressure. The residue was purified by column chromatography (10-30% ethyl acetate in heptane) to give the title compound intermediate A36 (82 mg, 52%) as a yellow oil. MS[M+H] + 355.10.

[0270] Intermediate A26 6-Bromo-N-methyl-1H-pyrrolo[3,2-c]pyridine-3-carboxamide [ka] A solution of 6-bromo-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid (210 mg, 871.22 μmol, 1 equiv.) in ultra-dry acetonitrile (4 mL) was treated with 2M methylamine in THF (871.22 μL, 1.74 mmol, 2 equiv.), 1-methylimidazole (214.58 mg, 208.33 μL, 2.61 mmol, 3 equiv.) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (366.67 mg, 1.31 mmol, 1.5 equiv.) and the mixture was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure and purified by RP column chromatography (0-50% ACN in water) to give the title compound intermediate A26 (148 mg, 66.9%) as a colorless solid. MS [M+H] + 254.06.

[0271] Intermediate A45 6-Bromopyrrolo[3,2-c]pyridine-1,3-dicarboxylic acid O1-tert-butyl ester O3-methyl ester [ka] 6-Bromo-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid methyl ester (CAS 1427503-50-1; 721 mg, 2.83 mmol, 1 equiv.) was dissolved in ultra-dry dichloromethane (6 mL). Triethylamine (429.05 mg, 590.97 μL, 4.24 mmol, 1.5 equiv.) and (Boc) 2 O (740.31 mg, 787.56 μL, 3.39 mmol, 1.2 equiv) was added and the mixture was stirred for 90 min. 3 Aqueous solution (5 mL) and water (30 mL) were added and the mixture was extracted with DCM (3×30 mL). The combined organic layers were dried (Na 2 SO 4), filtered and concentrated under reduced pressure to give the title compound Intermediate A45 (1.026 g, quantitative) as an off-white solid. MS[M+H] + 355.15.

[0272] Intermediate A37 (6-Bromo-1H-pyrrolo[3,2-c]pyridin-3-yl)-morpholino-methanone [ka] Step 1: 6-Bromo-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid hydrochloride Intermediate A45 (108 mg, 0.304 mmol, 1 equiv) was dissolved in isopropanol (0.313 mL). After adding lithium hydroxide (36.41 mg, 1.52 mmol, 5 equiv), the mixture was stirred at 100° C. for 1 h. After removing iPrOH, 1M HCl (1 mL) was added to the aqueous mixture, forming a white precipitate. The mixture was extracted with EtOAc (3×) and the combined organics were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound 6-bromo-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid hydrochloride (80 mg, 94.8%) as a white solid. MS [M+HCOO] - 285.19. Step 2: (6-Bromo-1H-pyrrolo[3,2-c]pyridin-3-yl)-morpholino-methanone 6-Bromo-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid hydrochloride (100 mg, 360.36 μmol, 1 equiv.) was dissolved in N,N-dimethylformamide (1 mL) and DIPEA (232.88 mg, 314.71 μL, 1.8 mmol, 5 equiv.) was added. Morpholine (156.97 mg, 156.97 μL, 1.8 mmol, 5 equiv.) and HATU (164.42 mg, 432.43 μmol, 1.2 equiv.) were then added and the reaction mixture was stirred at room temperature for 7.5 h. Again, morpholine (156.97 mg, 156.97 μL, 1.8 mmol, 5 equiv.) was added and the reaction was stirred overnight. Again, DIPEA (93.15 mg, 125.88 μL, 720.72 μmol, 2 eq.) and morpholine (156.97 mg, 156.97 μL, 1.8 mmol, 5 eq.) were added and stirring was continued for 4 days. Water was added and extracted with ethyl acetate. The combined organic layers were washed twice with 5% LiCl solution and brine. The solvent was evaporated and the crude material was purified by column chromatography (DCM:MeOH in DCM 9:1) to give the title compound intermediate A37 (35.8 mg, 32%) as a white solid. MS [M+H] + 309.98.

[0273] Intermediate A38 (6-Bromo-1H-pyrrolo[3,2-c]pyridin-3-yl)-(4,4-difluoropiperidino)methanone [ka] 6-Bromo-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid (Intermediate A37 Step 1; 100 mg, 414.87 μmol, 1 equiv.) was dissolved in N,N-dimethylformamide (1 mL). DIPEA (268.11 mg, 362.31 μL, 2.07 mmol, 5 equiv.), 4,4-difluoropiperidine (100.51 mg, 829.74 μmol, 2 equiv.) and HATU (236.62 mg, 622.3 μmol, 1.5 equiv.) were added and the reaction mixture was stirred at room temperature for 3 days, 5% LiCl (10 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The organic layer was dried (Na 2 SO4 ), filtered and concentrated under reduced pressure to give the title compound Intermediate A38 (336 mg, quant.) as a yellow oil which was used without further purification. MS [M+H] + 346.0.

[0274] The following examples were prepared similarly to intermediate A38. [Table 4]

[0275] Intermediate A35 6-Bromopyrazolo[4,3-c]pyridine-1-carboxylic acid tert-butyl ester [ka] 6-Bromo-1H-pyrazolo[4,3-c]pyridine (191 mg, 0.965 mmol, 1 equiv.) was dissolved in ultra-dry dichloromethane (2 mL). Triethylamine (146.4 mg, 201.66 μL, 1.45 mmol, 1.5 equiv.) and (Boc) 2 O (252.62 mg, 1.16 mmol, 1.2 equiv) was added and the mixture was stirred for 45 min. 3 (5 mL) and water (30 mL) were added and the mixture was extracted with ethyl acetate (3×30 mL). The organic layer was dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0-20% DCM / MeOH 9:1 in DCM) to give the title compound intermediate A35 (206 mg, 71.6%) as a colorless solid. MS[M+H] + 298.00.

[0276] The following examples were prepared similarly to intermediate A35. [Table 5]

[0277] Intermediate A47 2-Bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester 4H-Thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester (CAS82782-85-2; 863 mg, 4.76 mmol, 1 equiv.) was dissolved in ethyl acetate (10.01 mL). At 0° C., NBS (873.09 mg, 4.91 mmol, 1.03 equiv.) in ethyl acetate (10.01 mL) was added dropwise. The yellow mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was filtered through a pad of silica and washed with chloroform (60 mL). 10% aqueous Na2S2O3 (30 mL) was added to the filtrate and the aqueous layer was extracted with DCM (3×30 mL). The combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the title compound Intermediate A47 (1.269 g, quantitative) as a yellow solid. MS[M+H] + 260.01.

[0278] Intermediate A49 1-[5-Bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethane-1,2-diol [ka] Step 1: 2-[(5-bromo-2-vinyl-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane To a mixture of 2-[5-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethanol (Intermediate A14 step 2; 550.0 mg, 1.48 mmol, 1.0 equiv) in DCM (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.33 mL, 8.89 mmol, 6.0 equiv) and methanesulfonic anhydride (1.21 g, 6.96 mmol, 4.7 equiv) at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The mixture was further treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 mL, 8.69 mmol, 5.87 equiv) and stirred at 40° C. for 2 h. The mixture was poured into water (20 mL). EtOAc (40 mL) and water (40 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (60 mL), dried over MgSO4, filtered and concentrated in vacuo to give a residue. The residue was purified by RP column chromatography (80-90% ACN in water (0.1% FA)) to give the title compound 2-[(5-bromo-2-vinyl-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (416.0 mg, 1.18 mmol, 79.5%) as a pale yellow solid. MS[M+H] + 353.0. Step 2: 1-[5-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]ethane-1,2-diol A solution of 2-[(5-bromo-2-vinyl-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (380.0 mg, 1.08 mmol, 1.0 equiv) in tert-butanol (2 mL) and water (2 mL) was treated with K 2 OsO 4 . 2H 2O (3.96 mg, 0.01 mmol, 0.01 equiv.) followed by AD-mix-β (1.52 g, 1.95 mmol, 1.81 equiv.) was added at 0° C. and the mixture was stirred for 1 h, followed by warming to 25° C. for 16 h. The mixture was directly purified by RP column chromatography (70-80% ACN in water (0.1% FA)) to give the title compound intermediate A49 (60.0 mg, 0.15 mmol, 14.4%) as a mixture of enantiomers (unknown ratio) as a light brown oil. MS [M+H] + 389.0.

[0279] Intermediate A40 tert-Butyl 5-bromo-2-[(tert-butoxycarbonylamino)methyl]pyrrolo[3,2-b]pyridine-1-carboxylate [ka] Step 1: 6-Bromo-2-(3,3-diethoxyprop-1-ynyl)pyridin-3-amine A mixture of triethylamine (20.98 mL, 150.55 mmol, 3.0 equiv.), copper(I) iodide (0.17 mL, 5.02 mmol, 0.1 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.67 g, 5.02 mmol, 0.1 equiv.), propargylaldehyde diethyl acetal (7.08 g, 55.2 mmol, 1.1 equiv.) and 6-bromo-2-iodo-pyridin-3-amine (Intermediate A7 step 3; 15.0 g, 50.18 mmol, 1.0 equiv.) in THF (300 mL) was evacuated and purified with N. 2 (3x). The yellow mixture was stirred at 50°C for 16 h and concentrated. The residue was purified by column chromatography (20% EA in PE) and concentrated to give the title compound 6-bromo-2-(3,3-diethoxyprop-1-ynyl)pyridin-3-amine (9.4 g, 31.42 mmol, 56.6%) as a yellow solid. MS[M+H] + 301.0. Step 2: 5-Bromo-2-(diethoxymethyl)-1H-pyrrolo[3,2-b]pyridine To a solution of 6-bromo-2-(3,3-diethoxyprop-1-ynyl)pyridin-3-amine (9.4 g, 31.42 mmol, 1.0 equiv) in NMP (120 mL) was added potassium tert-butoxide (7.05 g, 62.84 mmol, 2.0 equiv) at 10° C. The mixture was stirred at 50° C. for 12 h. The mixture was slowly poured into a cold 0.05 N HCl solution (80 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and extracted with Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated to give a yellow residue. The residue was purified by column chromatography (25% EA in PE) to give the title compound 5-bromo-2-(diethoxymethyl)-1H-pyrrolo[3,2-b]pyridine (7.0 g, 23.4 mmol, 74.5%) as a yellow solid. MS[M+H] + 299.3. Step 3: 5-Bromo-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde To a solution of 5-bromo-2-(diethoxymethyl)-1H-pyrrolo[3,2-b]pyridine (3.0 g, 10.03 mmol, 1.0 equiv.) in THF (50 mL) and water (10 mL) was added p-toluenesulfonic acid monohydrate (2.86 g, 15.04 mmol, 1.5 equiv.) at 10° C. The mixture was stirred at 10° C. for 2 h. EtOAc (60 mL) and saturated NaHCO 3 Aqueous solution (60 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined extracts were washed with brine (100 mL) and Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (30% EA in PE) to give the title compound 5-bromo-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde (1.5 g, 6.67 mmol, 47.1%) as a yellow solid. MS [M+H] + 225.0. Step 4: tert-Butyl N-[(5-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl]carbamate To a mixture of 5-bromo-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde (1.5 g, 6.67 mmol, 1.0 equiv), tert-butyl carbamate (1.56 g, 13.33 mmol, 2.0 equiv) and trifluoroacetic acid (1.54 mL, 20.0 mmol, 3.0 equiv) in ACN (30 mL) was added triethylsilane (7.75 g, 66.65 mmol, 10.0 equiv) at 10° C. The mixture was stirred at 10° C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by RPHPLC (50-80% ACN in 0.1% FA in water) to give the title compound tert-butyl N-[(5-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl]carbamate (400 mg, 1.23 mmol, 17.9%) as a yellow solid. MS[M+H] + 328.0. Step 5: tert-Butyl 5-bromo-2-[(tert-butoxycarbonylamino)methyl]pyrrolo[3,2-b]pyridine-1-carboxylate To a solution of tert-butyl N-[(5-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl]carbamate (400.0 mg, 1.23 mmol, 1.0 equiv.) in THF (10 mL) was added triethylamine (0.26 mL, 1.84 mmol, 1.5 equiv.) and di-t-butyl dicarbonate (0.56 mL, 2.45 mmol, 2.0 equiv.). The mixture was stirred at 10° C. for 3 h. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (20% EA in PE) to give the title compound intermediate A40 (180.0 mg, 0.58 mmol, 47.5%) as a yellow solid. MS [M+H] + 428.3.

[0280] Intermediate A43 2-(6-Bromo-1H-pyrrolo[3,2-c]pyridin-3-yl)ethanol [ka] Step 1: 2-(6-bromo-1H-pyrrolo[3,2-c]pyridin-3-yl)-2-ketoacetic acid A stirred suspension of 6-bromo-1H-pyrrolo[3,2-c]pyridine (600 mg, 3.05 mmol, 1 equiv) in dichloromethane (10 mL) at ambient temperature was treated with aluminum chloride (2.02 g, 15.15 mmol, 4.975 equiv). After stirring for 1 h, the mixture was treated with ethyl oxalyl chloride (2.07 g, 1.7 mL, 15.19 mmol, 4.988 equiv) and the resulting mixture was stirred overnight. The mixture was treated dropwise with MeOH (792 mg, 1 mL, 24.72 mmol, 8.117 equiv) and stirred at ambient temperature for 30 min. The mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (0-2% DCM / MeOH 9:1 in DCM) to give the title compound 2-(6-bromo-1H-pyrrolo[3,2-c]pyridin-3-yl)-2-ketoacetic acid (0.27 g, 32%) as a colorless oil. MS[M+H] + 268.9. Step 2: 2-(6-bromo-1H-pyrrolo[3,2-c]pyridin-3-yl)ethanol A stirred suspension of 2-(6-bromo-1H-pyrrolo[3,2-c]pyridin-3-yl)-2-ketoacetic acid (220 mg, 0.818 mmol, 1 equiv) in tetrahydrofuran (5 mL) at room temperature was treated with 2 M borane dimethylsulfide complex (1.7 mL, 3.4 mmol, 4.158 equiv) and the resulting mixture was heated at 65° C. for 2 h. The mixture was cooled to room temperature and partitioned three times between saturated aqueous sodium bicarbonate and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (0-80% DCM / MeOH 9:1 in DCM) to give the title compound intermediate A43 (197.13 mg, 93.8%) as a white solid. MS [M+H] + 242.98.

[0281] Intermediate AA1 4-[2-Methyl-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylic acid tert-butyl ester [ka] 4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-methyl-benzoyl]piperazine-1-carboxylic acid tert-butyl ester (CAS2673221-29-7; 6.12 g, 9.61 mmol, 1 equiv.), chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (642.42 mg, 0.961 mmol, 0.1 equiv.), Na 2 CO 3 A mixture of (2.04 g, 19.22 mmol, 2 equiv.) and [3-(trifluoromethyl)-1H-pyrazol-4-yl]boronic acid (2.59 g, 14.41 mmol, 1.5 equiv.) in 1,4-dioxane (50 mL) and water (5 mL) was evacuated and backfilled with argon (three times). The reaction mixture was then stirred at 100 °C overnight. After the mixture was cooled to room temperature, it was filtered through a Dicalite plug (washed with AcOEt). The combined organic layers were evaporated and the crude product was purified by column chromatography (0-30% DCM / MeOH 9:1 in DCM) to give the title compound intermediate AA1 (2.07 g, 38.4%) as a light brown solid. MS [M+H] + 562.69.

[0282] Intermediate AA2 4-[2-Fluoro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylic acid tert-butyl ester [ka] Step 1: 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-fluoro-benzoic acid ethyl ester 4-Amino-2-fluoro-benzoic acid methyl ester (500 mg, 2.96 mmol, 1 equiv) and 5-bromo-1-methyl-imidazole-2-carboxylic acid ethyl ester (826.7 mg, 3.55 mmol, 1.2 equiv) were dissolved in ultra-dry tetrahydrofuran (15 mL) and the mixture was cooled to -78°C. The reaction mixture was then treated dropwise with 1M LiHMDS in THF (4.43 mL, 4.43 mmol, 1.5 equiv). The reaction mixture was stirred at -78°C for a further 2 h before being allowed to warm to room temperature and stirred for a further 18 h. The reaction mixture was then concentrated under reduced pressure and the residue was redissolved in EtOAc (150 mL) which was washed with 10% citric acid (50 mL), water (50 mL) and brine (50 mL). The organic phase was dried (Na 2 SO 4 ), filtered and evaporated. The crude product was purified by column chromatography (0-35% EtOAc / EtOH 3:1 in heptane) to give 780 mg of a mixture of the title compound 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-fluoro-benzoic acid ethyl ester (780 mg) and the corresponding methyl ester (ratio ca. 2:1) as a pale yellow powder, which was used in the next step without further purification. MS[M+H] + 370.0. Step 2: 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-fluoro-benzoic acid 4-[(5-Bromo-1-methyl-imidazole-2-carbonyl)amino]-2-fluoro-benzoic acid ethyl ester (780 mg, 2.11 mmol, 1 equiv) was dissolved in tetrahydrofuran (6 mL), methanol (2 mL) and water (2 mL) and treated with LiOH (504.66 mg, 21.07 mmol, 10 equiv). The reaction mixture was stirred at room temperature for 16 h. Additional LiOH (252.33 mg, 10.54 mmol, 5 equiv) was added and the reaction mixture was stirred at room temperature for an additional 6 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with 0.5 M HCl (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4), filtered and evaporated to give the title compound 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-fluoro-benzoic acid (721 mg, quantitative) as a yellow solid, which was used in the subsequent step without further purification. MS[M+H] + 341.9. Step 3: 4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-fluoro-benzoyl]piperazine-1-carboxylic acid tert-butyl ester 4-[(5-Bromo-1-methyl-imidazole-2-carbonyl)amino]-2-fluoro-benzoic acid (720 mg, 2.1 mmol, 1 equiv.) was dissolved in ultra-dry N,N-dimethylformamide (30 mL) and treated with DIPEA (1.36 g, 1.84 mL, 10.52 mmol, 5 equiv.), followed by 1-Boc-piperazine (470.36 mg, 2.53 mmol, 1.2 equiv.) and HATU (960.24 mg, 2.53 mmol, 1.2 equiv.). The resulting mixture was stirred at room temperature for 2.5 days. Additional 1-Boc-piperazine (117.59 mg, 631.36 μmol, 0.3 equiv.) and HATU (240.06 mg, 631.36 μmol, 0.3 equiv.) were added. After stirring at room temperature for an additional 2 h, the reaction mixture was concentrated under reduced pressure and the residue was washed with half-saturated NaHCO 3 The mixture was suspended in aqueous solution (40 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were then washed with brine, dried (Na 2 SO 4 ), filtered and evaporated. The crude product was purified by column chromatography (0-55% EtOAc / EtOH 3:1 in heptane) to give the title compound 4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-fluoro-benzoyl]piperazine-1-carboxylic acid tert-butyl ester (425 mg, 39.6%) as a white solid. MS[MH] - 510.1. Step 4: 4-[2-fluoro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylic acid tert-butyl ester 4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-fluoro-benzoyl]piperazine-1-carboxylic acid tert-butyl ester (425 mg, 0.833 mmol, 1 equiv.), chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (55.68 mg, 83.27 μmol, 0.1 equiv.), Na 2 CO 3 (176.53 mg, 1.67 mmol, 2 equiv.) and [3-(trifluoromethyl)-1H-pyrazol-4-yl]boronic acid (224.7 mg, 1.25 mmol, 1.5 equiv.) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). The flask was then evacuated and filled with argon (3×). The reaction mixture was then heated to 100° C. and stirred under reflux for 2 days. The reaction mixture was cooled to room temperature and filtered through a Dicalite plug (washed with EtOAc (4×) and DCM / MeOH (1×)). The combined organic layers were evaporated and the crude product was purified by column chromatography (0-55% EtOAc / EtOH 3:1 in heptane) to give the title compound intermediate AA2 (269 mg, 56%) as a white solid. MS [MH] - 564.3.

[0283] Intermediate AAA1 N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[3-(difluoromethyl)-1H-pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide hydrochloride [ka] Step 1: 4-Iodo-1H-pyrazole-3-carbaldehyde To a solution of 1H-pyrazole-3-carbaldehyde (10.0 g, 104.07 mmol, 1.0 equiv) in water (100 mL) / sulfuric acid (10.0 mL, 104.07 mmol, 1.0 equiv) was added N-iodosuccinimide (24.58 g, 109.27 mmol, 1.05 equiv) at 0° C., and the solution was then stirred for 16 h at 30° C. The mixture was filtered and the residue was washed with water (500 mL) and MTBE / MeOH 10:1 (1 L) to give the title compound 4-iodo-1H-pyrazole-3-carbaldehyde (16.6 g, 74.78 mmol, 71.9%) as a white solid. 1H NMR (400MHz, CD3SOCD3, 298K): δ(ppm)=14.13(br s,1H),9.86(s,1H),8.11(br s,1H). Step 2: 4-Iodo-1-trityl-pyrazole-3-carbaldehyde To a solution of 4-iodo-1H-pyrazole-3-carbaldehyde (16.6 g, 74.78 mmol, 1.0 equiv) in THF (200 mL) was added 60% sodium hydride in oil (3.29 g, 82.26 mmol, 1.1 equiv) at 0° C. The mixture was stirred at 0° C. for 0.5 h, then triphenylmethyl chloride (22.93 g, 82.26 mmol, 1.1 equiv) was added portionwise to the solution, after which the mixture was stirred at 10° C. for 16 h. The mixture was diluted with saturated NH 4 The mixture was quenched with Cl (300 mL) and extracted with EtOAc (2×100 mL). The combined organics were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was washed with EtOAc / MTBE 10:1 to give the title compound 4-iodo-1-trityl-pyrazole-3-carbaldehyde (16.6 g, 35.75 mmol, 47.8%) as a white solid. MS [M+Na] + 487.1. Step 3: 3-(Difluoromethyl)-4-iodo-1-trityl-pyrazole To a solution of 4-iodo-1-trityl-pyrazole-3-carbaldehyde (16.6 g, 35.75 mmol, 1.0 equiv) in DCM (200 mL) cooled to -15 °C was added diethylaminosulfur trifluoride (14.06 mL, 107.26 mmol, 3.0 equiv). The resulting mixture was stirred at 30 °C for 16 h. The mixture was diluted with saturated NaHCO 3 The mixture was quenched with 50 ml of ethyl acetate, and the organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE / EA 100:1) to give the title compound 3-(difluoromethyl)-4-iodo-1-trityl-pyrazole (17.2 g, 35.37 mmol, 98.9%) as a white solid. MS[M+H] + 487.1. Step 4: [3-(difluoromethyl)-1-trityl-pyrazol-4-yl]boronic acid To a solution of 3-(difluoromethyl)-4-iodo-1-trityl-pyrazole (8.0 g, 16.45 mmol, 1.0 equiv.) and boron isopropoxide (4.56 mL, 19.74 mmol, 1.2 equiv.) in THF (100 mL) was added a solution of butyllithium (7.9 mL, 19.74 mmol, 1.2 equiv.) with N 2 The mixture was stirred at -70°C for 1 h. The mixture was diluted with 300 mL of saturated NH 4 Cl and stirred for 0.5 h. The mixture was extracted with EtOAc (2×300 mL), washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (PE / EA 4:1) to afford the title compound [3-(difluoromethyl)-1-trityl-pyrazol-4-yl]boronic acid (1.1 g, 2.72 mmol, 16.5%) as a colorless oil, which was used directly in the next step without further characterization. Step 5: tert-Butyl 4-[2-chloro-4-[[5-[3-(difluoromethyl)-1-trityl-pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate A mixture of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (152.78 mg, 0.21 mmol, 0.1 equiv.), tert-butyl 4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carboxylate (CAS 2489205-91-4; 1.1 g, 2.09 mmol, 1.0 equiv.), sodium carbonate (442.61 mg, 4.18 mmol, 2.0 equiv.) and [3-(difluoromethyl)-1-trityl-pyrazol-4-yl]boronic acid (1.01 g, 2.51 mmol, 1.2 equiv.) in 1,4-dioxane (15 mL) / water (1 mL) was dissolved in N 2 The mixture was stirred at 85° C. for 16 h under reduced pressure. The mixture was filtered, concentrated and purified by column chromatography (35% EA in PE) and RPHPLC (100% ACN in 0.1% FA in water) to give the title compound tert-butyl 4-[2-chloro-4-[[5-[3-(difluoromethyl)-1-trityl-pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate (330.0 mg, 0.41 mmol, 19.6%) as a white solid. MS[M+H] + 806.3. Step 6: N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[3-(difluoromethyl)-1H-pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide hydrochloride A solution of tert-butyl 4-[2-chloro-4-[[5-[3-(difluoromethyl)-1-trityl-pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate (330.0 mg, 0.41 mmol, 1.0 equiv.) in hydrochloric acid in MeOH (10.0 mL, 40.0 mmol, 97.73 equiv.) was stirred at 30° C. for 16 h. The mixture was concentrated and the residue was diluted with MTBE / MeOH 10:1 (100 mL). The mixture was filtered and the solid was dried to give the title compound intermediate AAA1 (160.0 mg, 0.32 mmol, 84.3%) as a white solid. MS[M+H] + 464.2.

[0284] Intermediate AAA2 N-[3-Fluoro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; dihydrochloride [ka] Step 1: tert-Butyl 4-[2-fluoro-4-[[1-methyl-5-[3-(trifluoromethyl)-1-trityl-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate A mixture of intermediate BB1 ​​(1.46 g, 4.52 mmol, 1.2 equiv) and ethyl 1-methyl-5-[3-(trifluoromethyl)-1-trityl-pyrazol-4-yl]imidazole-2-carboxylate (CAS2489206-32-6; 2.0 g, 3.77 mmol, 1.0 equiv) in THF (40 mL) was cooled to -40 °C and treated dropwise with sodium bis(trimethylsilyl)amide (4.9 mL, 4.9 mmol, 1.3 equiv) at -40 °C. The mixture was stirred at -40 °C for 1 h. The mixture was diluted with saturated NH 4 The mixture was quenched with Cl (100 mL) and then extracted with EA (3×80 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by RP column chromatography (13-75% ACN (FA) in water) to give the title compound tert-butyl 4-[2-fluoro-4-[[1-methyl-5-[3-(trifluoromethyl)-1-trityl-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate (2.1 g, 2.6 mmol, 67.2%) as a pale yellow solid. MS[M+H] + 808.2. Step 2: N-[3-fluoro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; dihydrochloride salt A mixture of tert-butyl 4-[2-fluoro-4-[[1-methyl-5-[3-(trifluoromethyl)-1-trityl-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate (1.0 g, 1.24 mmol, 1.0 equiv.) in 4M HCl in dioxane (20.0 mL, 80.0 mmol, 64.63 equiv.) was stirred at 30° C. for 16 h to give a white suspension. The mixture was concentrated under reduced pressure and the residue was triturated with EA / MTBE 1:3 (30 mL) to give the title compound intermediate AAA2 (690.0 mg, 1.28 mmol, 89.6%) as a white solid. MS [M+H] + 466.2.

[0285] Intermediate BB1 tert-Butyl 4-(4-amino-2-fluoro-benzoyl)piperazine-1-carboxylate [ka] To a solution of 1-BOC-piperazine (12.01 g, 64.46 mmol, 1.0 equiv), 4-amino-2-fluorobenzoic acid (10.0 g, 64.46 mmol, 1.0 equiv) and N,N-diisopropylethylamine (13.47 mL, 77.35 mmol, 1.2 equiv) in DMF (120 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (26.96 g, 70.91 mmol, 1.1 equiv) at 0° C. The mixture was stirred at 0° C. for 0.5 h to give a brown solution. The mixture was poured into water (300 mL) and then extracted with EA (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0-100% EA in PE) to give the title compound intermediate BB1 ​​(20.0 g, 61.85 mmol, 92.2%) as a light brown gum. MS [M-tBu+H] + 268.1.

[0286] Intermediate CC1 Ethyl 5-[1-(2-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxylate [ka] To a solution of 2-fluoro-4-methoxyphenylboronic acid (2.359 g, 13.88 mmol, 2.0 equiv.), ethyl 1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxylate (CAS2489206-33-7; 2.0 g, 6.94 mmol, 1.0 equiv.), pyridine (1.68 mL, 20.82 mmol, 3.0 equiv.) and 4 Å molecular sieves (2.0 g) in DMF (40 mL) was added copper(II) acetate (2.521 g, 13.88 mmol, 2.0 equiv.). The mixture was stirred under air at 20° C. for 16 h. Again, 2-fluoro-4-methoxyphenylboronic acid (1.179 g, 6.94 mmol, 1.0 equiv) and copper(II) acetate (1.260 g, 6.94 mmol, 1.0 equiv) were added to the mixture. The mixture was stirred under air at 20° C. for another 20 h. Then, additional 2-fluoro-4-methoxyphenylboronic acid (1.179 g, 6.94 mmol, 1.0 equiv), diacetoxycopper (1.260 mg, 6.94 mmol, 1.0 equiv) and pyridine (1.12 mL, 13.88 mmol, 2.0 equiv) were added to the mixture. The mixture was stirred under air at 20° C. for another 20 h. The mixture was poured into water (200 mL) and stirred for 24 h. The mixture was filtered through a Celite pad (washing with EA, 4×30 mL). The combined filtrates were extracted with EA (2×80 mL). The combined organic layers were washed with brine (3×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (30-100% EA in PE) to give the title compound intermediate CC1 (280.0 mg, 0.68 mmol, 9.8%) as a pale yellow oil. MS [M+H] + 413.1.

[0287] Intermediate I1 3-[[1-(2-tert-butoxy-2-keto-ethyl)-4-(piperazine-1-carbonyl)piperidin-1-ium-1-yl]methyl]azetidine-1-carboxylic acid tert-butyl ester.1:1 2,2,2-trifluoroacetate [ka] Step 1: 4-[1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-keto-ethyl)piperidin-1-ium-4-carbonyl]piperazine-1-carboxylic acid benzyl ester.1:1 2,2,2-trifluoroacetate A mixture of intermediate H2 (155 mg, 0.338 mmol, 1 equiv) in N,N-dimethylformamide (1.5 mL) was treated with DIPEA (218.44 mg, 295.19 μL, 1.69 mmol, 5 equiv), benzyl 1-piperazinecarboxylate (111.68 mg, 97.97 μL, 0.507 mmol, 1.5 equiv), followed by HATU (192.79 mg, 0.507 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature O / N. Water was added to the reaction mixture and it was extracted with EtOAc. After removal of the solvent, the crude residue was purified by RPHPLC to give 4-[1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-keto-ethyl)piperidin-1-ium-4-carbonyl]piperazine-1-carboxylic acid benzyl ester.1:1 2,2,2-trifluoroacetate (146.3 mg, 57%) as an off-white lyophilized solid. MS[M]+ 615.4. Step 2: 3-[[1-(2-tert-butoxy-2-keto-ethyl)-4-(piperazine-1-carbonyl)piperidin-1-ium-1-yl]methyl]azetidine-1-carboxylic acid tert-butyl ester. 1:1 2,2,2-trifluoroacetate 4-[1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-keto-ethyl)piperidin-1-ium-4-carbonyl]piperazine-1-carboxylic acid benzyl ester. A mixture of 1:1 2,2,2-trifluoroacetate (146.3 mg, 0.193 mmol, 1 equiv.) in methanol (5 mL) was treated with palladium hydroxide on carbon (1.35 mg, 0.010 mmol, 0.05 equiv.) and the reaction mixture was diluted with H 2 Stirred under atmosphere. After 3.5 h, the reaction mixture was filtered under Ar and the solvent was evaporated to dryness to give the title compound Intermediate I1 as a white solid. MS[M]+481.3.

[0288] The following examples were prepared similarly to intermediate I1. [Table 6]

[0289] Intermediate I3 3-[[1-(2-tert-butoxy-2-keto-ethyl)-4-(piperazine-1-carbonyl)piperazin-1-ium-1-yl]methyl]azetidine-1-carboxylic acid tert-butyl ester.1:1 2,2,2-trifluoroacetate [ka] Step 1: 4-[4-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-4-(2-tert-butoxy-2-keto-ethyl)piperazin-4-ium-1-carbonyl]piperazine-1-carboxylic acid benzyl ester 2,2,2-trifluoroacetate To a light brown suspension of intermediate J2 (500 mg, 1.11 mmol, 1 equiv) in dichloromethane (12.34 mL) was added DIPEA (717.39 mg, 0.969 mL, 5.55 mmol, 5 equiv) followed by triphosgene (131.77 mg, 444.04 μmol, 0.4 equiv) (careful addition, slightly exothermic). After stirring at room temperature for 30 min, benzyl 1-piperazinecarboxylate (733.56 mg, 643.48 μL, 3.33 mmol, 3 equiv) was added and stirring was continued for 1 h. The reaction mixture was concentrated and directly purified by RP column chromatography (acetonitrile in water (TFA)) to give the title compound 4-[4-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-4-(2-tert-butoxy-2-keto-ethyl)piperazin-4-ium-1-carbonyl]piperazine-1-carboxylic acid benzyl ester 2,2,2-trifluoroacetate (449.5 mg, 43.83%) as a light brown lyophilized solid. MS[M]+617.48. Step 2: 3-[[1-(2-tert-butoxy-2-keto-ethyl)-4-(piperazine-1-carbonyl)piperazin-1-ium-1-yl]methyl]azetidine-1-carboxylic acid tert-butyl ester 2,2,2-trifluoroacetate 4-[4-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-4-(2-tert-butoxy-2-keto-ethyl)piperazin-4-ium-1-carbonyl]piperazine-1-carboxylic acid benzyl ester 2,2,2-trifluoroacetate (449.5 mg, 0.487 mmol, 1 equiv.) was dissolved in methanol to give a light brown solution. Palladium on carbon 10% (2.59 mg, 24.33 μmol, 0.05 equiv.) was added and the reaction mixture was diluted with H 2 The mixture was stirred overnight under atmospheric pressure. The reaction mixture was filtered. Palladium hydroxide on carbon (3.42 mg, 24.33 μmol, 0.05 equiv.) was added to the resulting solution (filtrate) and the reaction mixture was diluted with H 2Stirred under atmosphere for 3 hours. The suspension was filtered and concentrated under reduced pressure to give the title compound intermediate I3 (234.9 mg, 79.18%) as a light brown foam which was used in the next step without further purification. MS[M]+482.18.

[0290] The following examples were prepared similarly to intermediate I3. [Table 7]

[0291] Intermediate H3 Bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-keto-ethyl)-(3-carboxypropyl)ammonium bromide [ka] 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., and then the mixture was stirred at 70° C. for 16 h. The solution was concentrated and the residue was purified by RPHPLC to give 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)propyl]-(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., and then the mixture was stirred at 80° C. for 16 h. The solution was concentrated and the residue was purified by RPHPLC to give (4-benzyloxy-4-oxo-butyl)-bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)ammonium; bromide (1 g) as a colorless oil. MS[M] + 622.5. Step 3: Bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)-(3-carboxypropyl)ammonium; bromide A solution of palladium on activated carbon (151.44 mg, 0.140 mmol) in methanol (10 mL) was diluted with (4-benzyloxy-4-oxo-butyl)-bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)ammonium bromide (1.0 g, 1.42 mmol) in N 2 and then the mixture was cooled to 50° C. 2 The mixture was stirred at 10° C. for 16 hours under reduced pressure. The mixture was filtered and concentrated to give the title compound intermediate H3 (700 mg). MS[M] + 532.4.

[0292] The following examples were prepared similarly to intermediate H3. [Table 8]

[0293] Intermediate H2 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-oxo-ethyl)piperidin-1-ium-4-carboxylic acid; 2,2,2-trifluoroacetate [ka] Step 1: Benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]piperidine-4-carboxylate To a solution of benzyl piperidine-4-carboxylate hydrochloride (16.0 g, 62.56 mmol, 1 equiv.) and potassium carbonate (25.94 g, 187.69 mmol, 3 equiv.) in DMF (150 mL) was added 1-BOC-3-(bromomethyl)azetidine (18.78 g, 75.08 mmol, 1.2 equiv.). The mixture was stirred at 50° C. for 16 h, diluted with EA (800 mL), and then washed with brine (3×300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (33-100% EtOAc in PE) to give benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]piperidine-4-carboxylate as a pale yellow oil. MS[M+H] + 389.1. Step 2: Benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-oxo-ethyl)piperidin-1-ium-4-carboxylate; 2,2,2-trifluoroacetate To a solution of benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]piperidine-4-carboxylate (25.0 g, 64.35 mmol, 1 eq.) and sodium iodide (964.57 mg, 6.44 mmol, 0.100 eq.) in DMF (250 mL) was added tert-butyl bromoacetate (25.1 g, 128.7 mmol, 2 eq.) and N,N-diisopropylethylamine (33.63 mL, 193.05 mmol, 3 eq.). The mixture was stirred at 60° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified twice by RPHPLC to give benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-oxo-ethyl)piperidin-1-ium-4-carboxylate; 2,2,2-trifluoroacetate (20.2 g, 47.8%) as a yellow solid. MS[M] + 503.2. Step 3: 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-oxo-ethyl)piperidin-1-ium-4-carboxylic acid; 2,2,2-trifluoroacetate Benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-oxo-ethyl)piperidin-1-ium-4-carboxylate; 2,2,2-trifluoroacetate (19.0 g, 30.81 mmol, 1 equiv.) in methanol (300 mL) was treated with palladium on charcoal (1.4 mL, 1.35 mmol, 0.040 equiv.) and palladium hydroxide on charcoal (1438.71 mg, 1.02 mmol, 0.030 equiv.) in N 2 The mixture was degassed and then diluted with H 2 The mixture was stirred at 15° C. for 4 h under reduced pressure. The mixture was filtered through a pad of Celite and the residue was washed with MeOH (4×20 mL). The combined filtrate was concentrated under reduced pressure. The residue was dissolved in water (100 mL) and then lyophilized to give the title compound intermediate H2 (15.07 g, 92.9%) as a pale yellow solid. MS[M] + 413.2.

[0294] The following examples were prepared similarly to intermediate H2. [Table 9]

[0295] Preparation of cis- and trans-isomers of intermediate H2: Intermediate H10 trans-1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-keto-ethyl)piperidin-1-ium-4-carboxylic acid.1:1 2,2,2-trifluoroacetate And

[0296] Intermediate H4 cis-1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-1-(2-tert-butoxy-2-keto-ethyl)piperidin-1-ium-4-carboxylic acid.1:1 2,2,2-trifluoroacetate Pure cis- and trans-isomers of intermediate H2 were prepared similarly to the preparation of the cis / trans mixture intermediate H2. Separation of the diastereoisomers was carried out after step 2 by SFC using the following conditions: column Achiral 100PEI, 5 μm, 250×30 mm, 15% MeOH+0.2% TFA with the following retention times: trans isomer Rt=4.580 min (MS 503.3), cis isomer Rt=4.986 min (MS 503.4). [Table 10]

[0297] Intermediate H5 1-[3-(tert-butoxycarbonylamino)propyl]-1-(2-tert-butoxy-2-keto-ethyl)piperidin-1-ium-4-carboxylic acid.1:1 formate [ka] Step 1: 1-[3-(tert-butoxycarbonylamino)propyl]isonipecotic acid benzyl ester A 1:1 mixture of isonipecotic acid benzyl ester, hydrogen chloride (1 g, 3.79 mmol, 1 equiv.) in ultra-dry N,N-dimethylformamide (18 mL) was dissolved in water and cooled to 50° C. A 1:1 mixture of isonipecotic acid benzyl ester, hydrogen chloride (1 g, 3.79 mmol, 1 equiv.) in ultra-dry N,N-dimethylformamide (18 mL) was dissolved in water and cooled to 50° C. 2 CO 3(1.05 g, 7.59 mmol, 2 equiv.) and the suspension was stirred at 50° C. O / N. The reaction mixture (suspension) was filtered and extracted with DCM (3×15 mL). The combined organics were washed with 5% LiCl solution, brine, dried (sodium sulfate), filtered and evaporated to give crude 1-[3-(tert-butoxycarbonylamino)propyl]isonipecotic acid benzyl ester (3 g, quant.) as a pale yellow oil, which was used directly in the next step. MS[M+H] + 377. Step 2: 1-[3-(tert-butoxycarbonylamino)propyl]-1-(2-tert-butoxy-2-keto-ethyl)piperidine-1-ium-4-carboxylic acid benzyl ester. 1:1 formate salt A mixture of 1-[3-(tert-butoxycarbonylamino)propyl]isonipecotic acid benzyl ester (1.4 g, 3.72 mmol, 1 equiv.) and tert-butyl bromoacetate (1.09 g, 824.21 μL, 5.58 mmol, 1.5 equiv.) in N,N-dimethylformamide was treated with DIPEA (1.92 g, 2.59 mL, 14.87 mmol, 4 equiv.) and stirred at 80° C. for 3 days. The reaction mixture was extracted with DCM (3×20 mL). The combined organic layers were washed with 5% LiCl solution (20 mL), brine, dried (Na 2 SO 4 ), filtered and evaporated. The crude product was purified by RPHPLC to give 1-[3-(tert-butoxycarbonylamino)propyl]-1-(2-tert-butoxy-2-keto-ethyl)piperidin-1-ium-4-carboxylic acid benzyl ester. 1:1 formate salt as an orange oil. MS[M] + 491. Step 3: 1-[3-(tert-butoxycarbonylamino)propyl]-1-(2-tert-butoxy-2-keto-ethyl)piperidine-1-ium-4-carboxylic acid. 1:1 formate salt To a solution of 1-[3-(tert-butoxycarbonylamino)propyl]-1-(2-tert-butoxy-2-keto-ethyl)piperidin-1-ium-4-carboxylic acid benzyl ester; formate salt (500 mg, 0.932 mmol, 1 equiv.) in methanol under argon was added palladium hydroxide on charcoal (39.25 mg, 0.028 mmol, 0.030 equiv.). The reaction mixture was degassed and then diluted with H 2 The mixture was stirred under ambient atmosphere for 2 h. The reaction mixture was filtered through Celite and the residue was washed with MeOH (3×5 mL). The solvent was evaporated to give the title compound Intermediate H5 (410 mg, 96.6%) as an orange waxy solid which was lyophilized to give an orange lyophilized solid. MS[M] + 401.

[0298] Preparation of cis- and trans-isomers of intermediate H5: Intermediate H6 trans-1-[3-(tert-butoxycarbonylamino)propyl]-1-(2-tert-butoxy-2-keto-ethyl)piperidin-1-ium-4-carboxylate And Intermediate H7 Cis-1-[3-(tert-butoxycarbonylamino)propyl]-1-(2-tert-butoxy-2-keto-ethyl)piperidin-1-ium-4-carboxylate Pure cis and trans isomers of intermediate H5 were prepared similarly to the preparation of the cis / trans mixture intermediate H5. Separation of the diastereoisomers was achieved by SFC using the following conditions after step 3: column Chiral 4-cellulose, 5 μm, 250×20 mm, 30% MeOH+0.2% DEA with the following retention times: trans isomer Rt=1.252 min (MS 401.5), cis isomer Rt=1.291 min (MS 401.5). [Table 11]

[0299] Intermediate H11 rac-3-(tert-butoxycarbonylamino)propyl-(2-tert-butoxy-2-keto-ethyl)-(3-carboxypropyl)-methyl-ammonium; bromide [ka] Step 1: Benzyl 4-[3-(tert-butoxycarbonylamino)propylamino]butanoate To a stirred solution of 3-(BOC-amino)propyl bromide (5.18 g, 21.77 mmol, 1 equiv.) and triethylamine (6.37 mL, 45.71 mmol, 2.1 equiv.) in ACN (50 mL) was added benzyl 4-aminobutanoate; hydrochloride (5.0 g, 21.77 mmol, 1 equiv.) at 10° C., and the mixture was then stirred at 30° C. for 16 h. The solution was filtered, concentrated, and the residue was purified by RPHPLC to give benzyl 4-[3-(tert-butoxycarbonylamino)propylamino]butanoate (1.8 g, 23.6%) as a pale yellow oil. MS[M+H] + 351.2. Step 2: Benzyl 4-[3-(tert-butoxycarbonylamino)propyl-methyl-amino]butanoate To a stirred solution of benzyl 4-[3-(tert-butoxycarbonylamino)propylamino]butanoate (1.8 g, 5.14 mmol, 1 equiv.) and formaldehyde in water (0.83 g, 10.27 mmol, 2 equiv.) in methanol (20 mL) was added sodium cyanoborohydride (645.52 mg, 10.27 mmol, 2 equiv.) at 10° C. and stirred for 16 h. The solution was purified by RPHPLC to give benzyl 4-[3-(tert-butoxycarbonylamino)propyl-methyl-amino]butanoate (1.4 g, 74.8%) as a colorless oil. MS[M+H] + 365.2. Step 3: rac-(4-benzyloxy-4-oxo-butyl)-[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)-methyl-ammonium; bromide To a solution of tert-butyl bromoacetate (1.24 mL, 7.68 mmol, 2 equiv.) in ACN (20 mL) was added benzyl 4-[3-(tert-butoxycarbonylamino)propyl-methyl-amino]butanoate (1.4 g, 3.84 mmol, 1 equiv.) at 10° C., and the mixture was then stirred at 50° C. for 16 h. The solution was concentrated and the residue was purified by RPHPLC to give rac-(4-benzyloxy-4-oxo-butyl)-[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)-methyl-ammonium; bromide (1.1 g, 59.7%) as a colorless oil. MS[M]+479.3. Step 4: rac-3-(tert-butoxycarbonylamino)propyl-(2-tert-butoxy-2-oxo-ethyl)-(3-carboxypropyl)-methyl-ammonium; bromide rac-(4-benzyloxy-4-oxo-butyl)-[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)-methyl-ammonium; A solution of the bromide (0.63 g, 1.12 mmol, 1 equiv.) in methanol (20 mL) was treated with palladium on activated carbon (0.12 g, 0.110 mmol, 0.1 equiv.) in N 2 The mixture was then cooled to 10° C. and then cooled to 37° C. 2 (1460mmHg) at 35°C for 16 hours. The solution was filtered and concentrated to give the title compound Intermediate H11 (415mg, 74.7%) as a pale yellow solid. MS[M]+389.1.

[0300] The following examples were prepared analogously to intermediate H11. [Table 12]

[0301] Intermediate K1 tert-Butyl N-[3-[4-(3-aminopropyl)-2-pyridyl]propyl]carbamate; hydrochloride [ka] Step 1: Benzyl N-prop-2-ynyl carbamate To a mixture of propargylamine (5.0 g, 90.78 mmol, 1 equiv) and sodium bicarbonate (38.13 g, 453.89 mmol, 5 equiv) in EtOAc (100 mL) / water (100 mL) was added benzyl chloroformate (14.25 mL, 99.85 mmol, 1.1 equiv) dropwise at 0° C., and the mixture was then stirred at 0° C. for 1 h. The solution was poured into water (50 mL), extracted with EtOAc (2×30 mL), washed with brine, and diluted with Na 2 SO 4 The mixture was dried at 40° C., concentrated under reduced pressure and purified by column chromatography (50% EtOAc in PE) to give benzyl N-prop-2-ynylcarbamate (15.4 g, 89.7%) as a pale 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 equiv.), copper(I) iodide (0.32 mL, 9.51 mmol, 0.3 equiv.) and tetrakis(triphenylphosphine)palladium(0) (1.83 g, 1.59 mmol, 0.05 equiv.) in toluene (20 mL) was diluted with N 2 The reaction mixture was treated with 2-bromo-4-iodopyridine (9.0 g, 31.7 mmol, 1 equiv.), tetrabutylammonium fluoride (31.7 mL, 31.7 mmol, 1 equiv.) in THF and triethylamine (13.26 mL, 95.11 mmol, 3 equiv.) and then the mixture was stirred at 25° C. for 16 h. The reaction was directly purified by column chromatography (20-33% EtOAc in PE) to give benzyl N-[3-(2-bromo-4-pyridyl)prop-2-ynyl]carbamate (9.1 g, 83.2%) as a brown oil. MS[M+H] + 345.0. Step 3: tert-Butyl N-[3-[4-[3-(benzyloxycarbonylamino)prop-1-ynyl]-2-pyridyl]prop-2-ynyl]carbamate A mixture of N-BOC-propargylamine (4.09 g, 26.36 mmol, 1 equiv.), copper(I) iodide (0.16 mL, 4.78 mmol, 0.18 equiv.) and bis(triphenylphosphine)palladium(II) chloride (0.93 g, 1.32 mmol, 0.050 equiv.) in DMF (10 mL) was dissolved in N 2 The mixture was treated with benzyl N-[3-(2-bromo-4-pyridyl)prop-2-ynyl]carbamate (9.1 g, 26.36 mmol, 1 equiv.) and triethylamine (91.0 mL, 652.89 mmol, 24.77 equiv.) under reduced pressure, then the mixture was stirred at 50° C. for 16 h. The reaction was directly purified by column chromatography (17-50% EtOAc in PE) to give tert-butyl N-[3-[4-[3-(benzyloxycarbonylamino)prop-1-ynyl]-2-pyridyl]prop-2-ynyl]carbamate (9.4 g, 85%) as a brown oil. [M+H] + 420.3. Step 4: tert-Butyl N-[3-[4-(3-aminopropyl)-2-pyridyl]propyl]carbamate; hydrochloride To a mixture of tert-butyl N-[3-[4-[3-(benzyloxycarbonylamino)prop-1-ynyl]-2-pyridyl]prop-2-ynyl]carbamate (4.0 g, 9.54 mmol, 1 equiv.) and ammonium hydroxide (1 mL, 9.54 mmol, 1 equiv.) in methanol (50 mL) was added 10% wet palladium on activated carbon (400 mg, 9.54 mmol, 1.0 equiv.) at 25° C. The mixture was degassed and purified with H 2 The mixture was then purged with hexanes (3x). The mixture was then stirred under hydrogen (50 psi) at 25°C for 48 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by RPHPLC, and the purified residue was dissolved in 5% aqueous HCl (100 mL) and lyophilized to give the title compound intermediate K1 (2.091 g, 64.5%) as a pale yellow oil. [M+H] + 293.9.

[0302] Intermediate J1 tert-Butyl 2-[1-[3-(tert-butoxycarbonylamino)propyl]piperazin-1-ium-1-yl]acetate;formate [ka] Step 1: Benzyl 4-[3-(tert-butoxycarbonylamino)propyl]piperazine-1-carboxylate 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 under reduced pressure and purified by column chromatography (1-67% EtOAc in PE) to give benzyl 4-[3-(tert-butoxycarbonylamino)propyl]piperazine-1-carboxylate (5.2 g, 60.7%) as a light brown solid. MS [M+H] + 378.3. Step 2: Benzyl 4-[3-(tert-butoxycarbonylamino)propyl]-4-(2-tert-butoxy-2-oxo-ethyl)piperazin-4-ium-1-carboxylate; formate To a solution of benzyl 4-[3-(tert-butoxycarbonylamino)propyl]piperazine-1-carboxylate (5.2 g, 13.78 mmol) in MeCN (100 mL) was added triethylamine (1.92 mL, 13.78 mmol) and tert-butyl bromoacetate (5.37 g, 27.55 mmol), then the mixture was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure and purified by RPHPLC to give benzyl 4-[3-(tert-butoxycarbonylamino)propyl]-4-(2-tert-butoxy-2-oxo-ethyl)piperazin-4-ium-1-carboxylate; formate salt (4 g, 59%) as a pale yellow solid. MS[M+H] + 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-oxo-ethyl)piperazin-4-ium-1-carboxylate;formate (4.0 g, 8.12 mmol) in THF (40 mL) was added 10% palladium on charcoal (400 mg) and the reaction was stirred under hydrogen atmosphere at 25° C. for 16 hours. The mixture was concentrated under reduced pressure and purified by RPHPLC to give the title compound Intermediate J1 (1.5 g, 51.5%) as a white solid. MS[M]+358.3.

[0303] The following intermediates were prepared similarly to intermediate J1. [Table 13]

[0304] Intermediate L1 Bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)-(2-hydroxyethyl)ammonium formate [ka] Step 1: tert-Butyl N-[3-[3-(tert-butoxycarbonylamino)propylamino]propyl]carbamate A solution of dipropylenetriamine (23.0 g, 175.28 mmol, 1.0 equiv) and triethylamine (73.29 mL, 525.83 mmol, 3.0 equiv) in THF (400 mL) was stirred at 0° C. To the mixture was added tert-butyl [(E)-[cyano(phenyl)methylene]amino]carbonate (86.33 g, 350.56 mmol, 2.0 equiv) in THF (300 mL) and stirred at 0° C. for 2 h. The reaction mixture was then stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP column chromatography (40-60% ACN in water (0.1% FA)) to give the title compound tert-butyl N-[3-[3-(tert-butoxycarbonylamino)propylamino]propyl]carbamate (58.0 g, 174.99 mmol, 99.8%) as a light brown solid. MS[M]+332.2. Step 2: tert-Butyl N-[3-[2-benzyloxyethyl-[3-(tert-butoxycarbonylamino)propyl]amino]propyl]carbamate A mixture of tert-butyl N-[3-[3-(tert-butoxycarbonylamino)propylamino]propyl]carbamate (20.0 g, 60.34 mmol, 1.0 equiv.), benzyl 2-bromoethyl ether (14.28 g, 66.38 mmol, 1.1 equiv.) and triethylamine (10.93 mL, 78.44 mmol, 1.3 equiv.) in ACN (200 mL) was heated and stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RPHPLC (50-80% ACN in 0.1% FA in water) to give the title compound tert-butyl N-[3-[2-benzyloxyethyl-[3-(tert-butoxycarbonylamino)propyl]amino]propyl]carbamate (5.0 g, 10.74 mmol, 16.9%) as a yellow oil. MS[M]+466.4. Step 3: 2-Benzyloxyethyl-bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)ammonium formate To a solution of tert-butyl N-[3-[2-benzyloxyethyl-[3-(tert-butoxycarbonylamino)propyl]amino]propyl]carbamate (900.0 mg, 1.93 mmol, 1.0 equiv) in MeCN (20 mL) was added tert-butyl bromoacetate (2.26 g, 11.6 mmol, 6.0 equiv) and N,N-diisopropylethylamine (1.01 mL, 5.8 mmol, 3.0 equiv), then the solution was stirred at 55° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RPHPLC (28-48% ACN in water (0.225% FA)) to give the title compound 2-benzyloxyethyl-bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)ammonium formate (900.0 mg, 1.44 mmol, 74.4%) as a brown solid. MS[M]+580.6. Step 4: Bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)-(2-hydroxyethyl)ammonium formate To a solution of 2-benzyloxyethyl-bis[3-(tert-butoxycarbonylamino)propyl]-(2-tert-butoxy-2-oxo-ethyl)ammonium formate (900.0 mg, 1.44 mmol, 1.0 equiv.) in methanol (20 mL) was added Pd(OH)2 / C (180.0 mg, 2.88 mmol, 2.0 equiv.) and 10% wet palladium on activated carbon (90.0 mg, 2.88 mmol, 2.0 equiv.). The mixture was degassed and diluted with H 2 The mixture was then purged with 50 psi hydrogen for 48 h at 25° C. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound intermediate L1 (750.0 mg, 1.4 mmol, 97.4%) as a light brown oil, which was used in the next step without further purification. MS[M]+490.3.

[0305] Intermediate H15 trans-1-(2-tert-butoxy-2-oxo-ethyl)-1-[2-(dimethylamino)ethyl]piperidin-1-ium-4-carboxylic acid 2,2,2-trifluoroacetate [ka] Step 1: Benzyl 1-[2-(tert-butoxycarbonylamino)ethyl]piperidine-4-carboxylate To a solution of benzyl piperidine-4-carboxylate hydrochloride (500.0 mg, 1.96 mmol, 1.0 equiv) and potassium carbonate (540.42 mg, 3.91 mmol, 2.0 equiv) in DMF (10 mL) was added tert-butyl N-(2-bromoethyl)carbamate (525.77 mg, 2.35 mmol, 1.2 equiv). The mixture was stirred at 20° C. for 16 h. The mixture was diluted with EA (60 mL) and then washed with brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound benzyl 1-[2-(tert-butoxycarbonylamino)ethyl]piperidine-4-carboxylate (900.0 mg, 2.48 mmol, 99.1%) as a pale yellow oil, which was used without further purification. MS[M]+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-carboxylate (9.23 g, 25.46 mmol, 1.0 equiv), sodium iodide (381.7 mg, 2.55 mmol, 0.1 equiv) and N,N-diisopropylethylamine (6.65 mL, 38.2 mmol, 1.5 equiv) in DMF (90 mL) was added tert-butyl bromoacetate (5.96 g, 30.56 mmol, 1.2 equiv). The mixture was stirred at 20° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified twice by RPHPLC (TFA conditions) to give the title compound 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, 46.9%) as a pale yellow gum. MS[M]+477.2. Step 3: cis-benzyl 1-(2-tert-butoxy-2-oxo-ethyl)-1-[2-(dimethylamino)ethyl]piperidine-1-ium-4-carboxylate 2,2,2-trifluoroacetate and trans-benzyl 1-(2-tert-butoxy-2-oxo-ethyl)-1-[2-(dimethylamino)ethyl]piperidine-1-ium-4-carboxylate 2,2,2-trifluoroacetate To a stirred solution of benzyl 1-[2-(tert-butoxycarbonylamino)ethyl]-1-(2-tert-butoxy-2-oxo-ethyl)piperidin-1-ium-4-carboxylate 2,2,2-trifluoroacetate (2.0 g, 3.39 mmol, 1.0 equiv.) and 37% aqueous formaldehyde (1.65 g, 20.32 mmol, 6.0 equiv.) in ACN (10 mL) in DCM (20 mL) was added sodium cyanoborohydride (1276.78 mg, 20.32 mmol, 6.0 equiv.) in one portion at 10° C. After stirring at 10° C. for 2 h, trifluoroacetic acid (10.0 mL, 129.8 mmol, 38.33 equiv.) was added to the solution at 10° C. and stirring was continued for 14 h. The solution was diluted with ACN (100 mL), concentrated (at 10° C.) and purified by RP column chromatography (40% ACN in 0.1% FA in water) to give a colorless oil. The obtained material was further purified by RPHPLC (water-ACN, 2% ACN, Phenomenex Luna C18 150*40 mm*15 μm) to give the title compound: trans-benzyl 1-(2-tert-butoxy-2-oxo-ethyl)-1-[2-(dimethylamino)ethyl]piperidin-1-ium-4-carboxylate 2,2,2-trifluoroacetate (360.0 mg, 0.69 mmol, 20.5%): MS[M] + 405.3; Rt = 1.259 min as a pale yellow oil. and cis-benzyl 1-(2-tert-butoxy-2-oxo-ethyl)-1-[2-(dimethylamino)ethyl]piperidin-1-ium-4-carboxylate 2,2,2-trifluoroacetate (320.0 mg, 0.62 mmol, 18.2%); MS[M] + 405.3; Rt = 1.196 min; was obtained as a pale yellow oil. Step 4: trans-1-(2-tert-butoxy-2-oxo-ethyl)-1-[2-(dimethylamino)ethyl]piperidin-1-ium-4-carboxylic acid 2,2,2-trifluoroacetate A stirred solution of trans-benzyl 1-(2-tert-butoxy-2-oxo-ethyl)-1-[2-(dimethylamino)ethyl]piperidin-1-ium-4-carboxylate 2,2,2-trifluoroacetate (0.36 g, 0.69 mmol, 1.0 equiv.) in methanol (20 mL) was evacuated and purified with N 2 Palladium on activated carbon (0.15 g, 0.14 mmol, 0.2 equiv) was added to the solution in one portion, then the black mixture was evacuated and charged with H 2 (3x). The mixture was charged with H 2 (760 mmHg) at 10° C. for 16 h. The mixture was filtered through diacetate and concentrated to give the title compound Intermediate H15 (245.0 mg, 0.57 mmol, 82.4%) as a white oil which was used without further purification. MS[M]+ 315.1.

[0306] Intermediate H16 cis-1-(2-tert-butoxy-2-oxo-ethyl)-1-[2-(dimethylamino)ethyl]piperidin-1-ium-4-carboxylic acid; 2,2,2-trifluoroacetate [ka] The title compound was prepared similarly to Intermediate H15 using the cis isomer isolated in step 3 to give Intermediate H16 (220.0 mg, 0.51 mmol, 83.2%) as a colorless oil. MS[M]+ 315.1.

[0307] Intermediate B1 2-Chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoic acid methyl ester A mixture of 2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoic acid methyl ester (600 mg, 1.4 mmol, 1 equiv.) in acetonitrile (12 mL) was treated with 2-fluoro-5-nitro-pyridine (298.95 mg, 2.1 mmol, 1.5 equiv.) and potassium carbonate (581.55 mg, 4.21 mmol, 3 equiv.) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM, filtered and evaporated to give the crude title compound intermediate B1 (850 mg, 85%) as an orange solid, which was used directly in the next step. MS [M+H] + 550.1.

[0308] The following intermediates were prepared similarly to intermediate B1. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4]

[0309] Intermediate B2 4-[[5-[1-[5-[2-(tert-butoxycarbonylamino)ethyl]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoic acid methyl ester In a microwave vial, 2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoic acid methyl ester (62 mg, 0.145 mmol, 1 equiv.), N-[2-(6-bromo-3-pyridyl)ethyl]carbamic acid tert-butyl ester (85 mg, 0.282 mmol, 1.95 equiv.), cuprous iodide (8.28 mg, 0.043 mmol, 0.3 equiv.) and K 2 CO 3 (42.07 mg, 0.304 mmol, 2.1 equiv). The vial was evacuated and backfilled with Ar (3x). Ultra-dry DMF (0.827 mL) and trans-N,N-dimethylcyclohexane-1,2-diamine (12.37 mg, 13.71 μL, 0.087 mmol, 0.6 equiv) were added, the vial was sealed and stirred in a microwave at 135 °C for 30 min. The mixture was cooled to room temperature and diluted with 5% EDTA (1 mL) and half-saturated NaHCO 3 The mixture was diluted with aqueous ethyl acetate (30 mL) and extracted with EtOAc (3×12 mL). The combined organic layers were washed with brine (10 mL) and diluted with Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated. Purification by column chromatography (0-40% EtOAc / EtOH 3:1 in heptane) afforded the title compound intermediate B2 (48 mg, 41.9%) as a white solid. MS [M+H] + 648.4.

[0310] The following intermediates were prepared similarly to intermediate B2. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] [Table 15-6] [Table 15-7] [Table 15-8] [Table 15-9] [Table 15-10] [Table 15-11] [Table 15-12] [Table 15-13] [Table 15-14] [Table 15-15] [Table 15-16]

[0311] Intermediate A23 4-[4-[[5-[1-[2-(2-amino-2-keto-ethyl)pyrazolo[4,3-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carboxylic acid tert-butyl ester 6-Bromo-1H-pyrazolo[4,3-c]pyridine (161 mg, 0.813 mmol, 1.25 equiv) was dissolved in ultra-dry tetrahydrofuran (2 mL). NaH (48.78 mg, 1.22 mmol, 1.875 equiv) was added at 0° C. After stirring for 30 min, 2-bromoacetamide (242.28 mg, 1.76 mmol, 2.7 equiv) and KI (53.99 mg, 325.22 μmol, 0.5 equiv) were added and the mixture was stirred at 50° C. overnight. NaHCO 3 (5 mL) and water (30 mL) were added. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by RP column chromatography (0-40% ACN in water) to give 2-(6-bromopyrazolo[4,3-c]pyridin-2-yl)acetamide (188 mg) and its regioisomers as a mixture. Similar to intermediate B2, the resulting mixture of isomers was subjected to Ullmann coupling with 4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylic acid tert-butyl ester in t-amyl alcohol to give the title compound intermediate A23 (55 mg, 9.7%) as an off-white solid. MS[M+H] + 756.24.

[0312] Intermediate B5 4-[[5-[1-[6-(tert-butoxycarbonylamino)-3-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoic acid methyl ester A mixture of 2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoic acid methyl ester (75 mg, 0.168 mmol, 1 equiv.) and [6-(tert-butoxycarbonylamino)-3-pyridyl]boronic acid (72.12 mg, 0.303 mmol, 1.8 equiv.) in ultra-dry N,N-dimethylformamide (1 mL) was treated with cupric acetate (64.2 mg, 0.353 mmol, 2.1 equiv.) and pyridine (26.6 mg, 27.2 μL, 0.337 mmol, 2 equiv.) and the mixture was stirred under air at 50° C. for 24 h. Additional 6-(tert-butoxycarbonylamino)pyridin-3-ylboronic acid (40.07 mg, 0.168 mmol, 1 equiv.) was added and stirring was continued for 24 h at 50° C. The reaction mixture was cooled to room temperature and treated with NaHCO 3 The combined organic layers were washed with 5% aqueous LiCl, brine, dried (Na 2 SO 4 ), filtered and evaporated. Purification by column chromatography (0-100% EtOAc in heptane) afforded the title compound Intermediate B5 (13.5 mg, 10.5%) as a pale yellow solid. MS[M+H] + 620.2.

[0313] The following intermediates were prepared similarly to Intermediate B5. [Table 16]

[0314] Intermediate D21 tert-Butyl 4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1-[1-(2-trimethylsilylethoxymethyl)indazol-3-yl]pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate A mixture of 4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylic acid tert-butyl ester (800.0 mg, 1.37 mmol, 1 equiv), Intermediate A2 (514.51 mg, 1.37 mmol, 1 equiv), copper(II) oxide (10.93 mg, 0.140 mmol, 0.1 equiv) and iron(III)-acetylacetonate (145.65 mg, 0.410 mmol, 0.300 equiv) in DMF (20 mL) was treated with cesium carbonate (0.9 g, 2.75 mmol, 2 equiv) and stirred at 115° C. for 48 h. The mixture was poured into water (30 mL) and extracted with EtOAc (2×20 mL). The combined organics were washed with brine (50 mL) and concentrated. Purification by RPHPLC afforded the title compound intermediate D21 (200 mg, 0.240 mmol, 18%) as a yellow solid. MS[M+H] + 828.4.

[0315] Intermediate B7 4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoic acid methyl ester A suspension of Intermediate B1 (850 mg, 1.19 mmol, 1 equiv) in ethanol (25.5 mL) / water (8.5 mL) was treated with ammonium chloride (3.18 g, 59.52 mmol, 50 equiv) and zinc (1.56 g, 23.81 mmol, 20 equiv) and the mixture was stirred at room temperature O / N. The reaction mixture was filtered through Celite and concentrated. The residue was purified by column chromatography (0-100% DCM / MeOH in DCM 9:1) to give the title compound Intermediate B7 (294 mg, 36%) as an orange solid. MS [M+H] + 520.1.

[0316] The following intermediates were prepared similarly to intermediate B7. [Table 17]

[0317] Intermediate D107 tert-Butyl 4-[2-fluoro-4-[[5-[1-(2-fluoro-4-methoxy-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate A mixture of intermediate BB1 ​​(188.21 mg, 0.58 mmol, 1.2 equiv) and intermediate CC1 (200.0 mg, 0.49 mmol, 1.0 equiv) in THF (4 mL) was cooled to −40° C. Sodium bis(trimethylsilyl)amide (0.63 mL, 0.63 mmol, 1.3 equiv) was added dropwise at −40° C. and the mixture was stirred at that temperature for 1 h. The mixture was diluted with saturated NH 4 The mixture was quenched with Cl (30 mL) and then extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by RP column chromatography (13-75% acetonitrile in water, formic acid) to give the title compound intermediate D107 (320 mg, 0.46 mmol, 96%) as a pale yellow solid. MS [M+H] + 690.4.

[0318] Intermediate D108 tert-Butyl 4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carboxylate To a solution of intermediate D58 (640.0 mg, 0.91 mmol, 1.0 equiv) in MeOH (15 mL) was added palladium on charcoal (320 mg, 3.01 mmol, 3.29 equiv). The reaction mixture was stirred for 3 h. 2 The mixture was stirred at 25° C. for 0.5 h under ambient conditions and filtered through a celite pad (MeOH wash, 3×8 mL). The combined filtrate was concentrated under reduced pressure and the residue was purified by RPHPLC (water (TFA) / ACN 0-100%) to give the title compound intermediate D108 (500 mg, 82%) as a white solid. MS [M+H]+ 671.3.

[0319] The following intermediates were prepared similarly to intermediate D108. [Table 18]

[0320] Intermediate B8 4-[[5-[1-[6-[2-(tert-butoxycarbonylamino)ethylamino]-3-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoic acid methyl ester A mixture of intermediate B6 (66 mg, 0.120 mmol, 1 equiv) in N,N-dimethylformamide (1 mL) was treated with potassium carbonate (24.86 mg, 0.180 mmol, 1.5 equiv) and N-(2-aminoethyl)carbamic acid tert-butyl ester (28.82 mg, 0.180 mmol, 1.5 equiv) and the reaction mixture was stirred at room temperature for 1 h and subsequently at 100° C. O / N. Additional N-(2-aminoethyl)carbamic acid tert-butyl ester (38.43 mg, 0.240 mmol, 2 equiv) was added and stirring was continued at 100° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered. The filtrate was washed with 5% LiCl solution, brine, dried (Na 2 SO 4 ), filtered and evaporated. Purification by column chromatography (0-80% EtOAc in heptane) afforded the title compound Intermediate B8 (41 mg, 43%) as an off-white solid. MS [M+H] + 663.2.

[0321] The following intermediates were prepared similarly to Intermediate B8. [Table 19]

[0322] Intermediate D32 4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester A mixture of intermediate E1 (1 g, 1.56 mmol, 1 equiv) in dichloromethane (12 mL) was treated with 9H-fluoren-9-ylmethyl chloroformate (422.75 mg, 1.63 mmol, 1.05 equiv), stirred at room temperature for 5 min, and subsequently treated with a solution of DIPEA (804.59 mg, 1.09 mL, 6.23 mmol, 4 equiv) in dichloromethane (3 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with half-saturated NaHCO 3 The combined organic layers were dried (Na 2 SO 4 ), filtered and evaporated. Purification by column chromatography (0-80% EtOAc in DCM) afforded the title compound intermediate D32 (0.63 g, 51%) as a pale yellow foam. MS[M+H] + 796.2.

[0323] Intermediate B9 4-[[5-[1-[5-[2-[tert-butoxycarbonyl(methyl)amino]ethylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoic acid methyl ester A mixture of intermediate B7 (30.15 mg, 0.058 mmol, 1 equiv) in dichloromethane (0.6 mL) was treated with N-(2-ketoethyl)-N-methyl-carbamic acid tert-butyl ester (0.064 mmol, 1.1 equiv) and acetic acid (3.48 mg, 3.32 μL) followed by the addition of sodium triacetoxyborohydride (24.59 mg). The reaction mixture was stirred at room temperature, O / N. Additional aldehyde (1 equiv), acetic acid (1 equiv) and molecular sieves were added to the reaction mixture and stirring was continued at room temperature-40° C. for an additional 72 h. The reaction mixture was diluted with dichloromethane. The organic layer was washed with water, brine and dried (Na2 SO 4 ), filtered and evaporated to give the crude title compound Intermediate B9 (57 mg, quantitative) as a brown viscous oil, which was used directly in the next step without further purification. MS [M+H] + 677.4.

[0324] The following intermediates were prepared similarly to intermediate B9. [Table 20-1] [Table 20-2] [Table 20-3]

[0325] Intermediate C1 4-[[5-[1-[5-[2-(tert-butoxycarbonylamino)ethyl]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoic acid A mixture of Intermediate B2 (48 mg, 0.061 mmol, 1 equiv) in tetrahydrofuran (1.5 mL) / methanol (0.500 mL) / water (0.500 mL) was treated with LiOH (14.55 mg, 0.607 mmol, 10 equiv) and the mixture was stirred at room temperature for 7 h. All volatiles were evaporated. The residue was suspended in 0.5 M HCl (30 mL) and extracted with EtOAc (3×12 mL). The combined organic layers were washed with brine (12 mL), dried (Na 2 SO 4 ), filtered and evaporated to give the crude title compound Intermediate C1 (48 mg, quantitative) as a white solid, which was used directly in the next step without further purification. MS[MH] - 632.5.

[0326] The following intermediates were prepared similarly to intermediate C1. [Table 21-1] [Table 21-2] [Table 21-3]

[0327] Intermediate D38 4-[4-[[5-[1-[5-(benzyloxycarbonylaminomethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carboxylic acid tert-butyl ester A vial was charged with intermediate D5 (50 mg, 0.068 mmol, 1 equiv.), 2-(benzyloxycarbonylamino)acetic acid (21.26 mg, 0.102 mmol, 1.5 equiv.), Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (3.8mg, 0.003mmol, 0.05eq), NiCl 2 -glyme (4.47 mg, 0.020 mmol, 0.3 equiv.), 4,4'-di-tert-butyl-2,2'-bipyridyl (8.18 mg, 0.030 mmol, 0.45 equiv.) and Cs 2 CO 3 (33.1 mg, 0.102 mmol, 1.5 equiv). The vial was evacuated and backfilled with Ar (3x) and ultra-dry N,N-dimethylformamide (3.3 mL) was added. The vial was sealed and then stirred at room temperature under blue LED (420 nm) illumination for 24 h. The mixture was diluted with half-saturated NaHCO 3 The mixture was diluted with aqueous ethyl acetate (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. Purification by column chromatography (0-40% DCM / MeOH 9:1 in DCM) afforded the title compound intermediate D38 (23 mg, 38%) as a colorless amorphous. MS [M+HCOO] - 866.3.

[0328] Intermediate D41 4-[2-Chloro-4-[[1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylic acid tert-butyl ester A vial was charged with sodium tert-butoxide (31.23 mg, 0.325 mmol, 2.5 equiv), racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (32.38 mg, 0.052 mmol, 0.400 equiv), tris(dibenzylideneacetone)dipalladium (23.81 mg, 0.026 mmol, 0.200 equiv) and saturated with Ar. A solution of intermediate D5 (95.9 mg, 0.130 mmol, 1 equiv) in ultra-dry toluene (1.8 mL) was added, followed by a 2 M solution of methylamine in THF (0.650 mmol, 5 equiv). The vial was sealed and placed in a heat block shaker at 110 °C for 24 h. The vial was cooled to room temperature, diluted with half-saturated brine (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were evaporated and the residue was purified by RPHPLC to give the title compound intermediate D41 (33 mg, 37%) as an off-white lyophilized solid.

[0329] The following intermediates were prepared similarly to intermediate D41. [Table 22-1] [Table 22-2]

[0330] Intermediate D118 4-[4-[[5-[1-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carboxylic acid tert-butyl ester A mixture of intermediate D7 (217 mg, 0.292 mmol, 1 equiv) in DCM (3 mL) was treated with imidazole (29.83 mg, 0.438 mmol, 1.5 equiv) and TBDMSCl (52.82 mg, 0.350 mmol, 1.2 equiv) and the reaction mixture was stirred at room temperature for 3.5 h. Water was added and the mixture was extracted. 2 SO 4 After drying at 40° C., filtering and evaporating to dryness, the crude title compound intermediate D118 (217.3 mg, 79.5%) was obtained as an off-white solid, which was used in the next step without further purification. MS [M+H] + 842.46.

[0331] Intermediate D44 4-[2-Chloro-4-[[1-methyl-5-[1-(1-methylpyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylic acid tert-butyl ester A mixture of NaH (3.96 mg, 0.099 mmol, 1.2 equiv) in N,N-dimethylformamide was cooled to 0° C. and treated dropwise with a mixture of intermediate D2 (60 mg, 0.083 mmol, 1 equiv) dissolved in DMF (0.1 mL) and the reaction mixture was stirred until hydrogen evolution was complete. Iodomethane (11.7 mg, 5.2 μL, 0.083 mmol, 1 equiv) was then added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 3 h. Water was added and the mixture was extracted with DCM. The combined organic layers were washed with 5% LiCl solution, sodium chloride, dried (Na 2 SO 4), filtered and evaporated. Purification by column chromatography (0-80% DCM / MeOH 9:1 in DCM) afforded the title compound intermediate D44 (58.5 mg, 98%) from a pale yellow amorphous. MS [M+H] + 712.5.

[0332] The following intermediates were prepared similarly to intermediate D44. [Table 23]

[0333] Intermediate D48 4-[2-Chloro-4-[[5-[1-[6-(dimethylamino)-3-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylic acid tert-butyl ester A mixture of intermediate D14 (50 mg, 0.052 mmol, 1 equiv) and 2M dimethylamine in THF (1.29 mL, 2.58 mmol, 50 equiv) was heated in a microwave at 100 °C for 45 min. All volatiles were evaporated and the residue was purified by column chromatography (0-80% DCM / MeOH 9:1 in DCM) to give the title compound intermediate D48 (31 mg, 72%) as a white solid. MS [M+H] + 702.4.

[0334] Intermediate D52 4-[2-Chloro-4-[[5-[1-(1H-imidazo[4,5-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylic acid tert-butyl ester A mixture of intermediate D51 (130 mg, 0.172 mmol, 1 equiv) in ultra-dry toluene (2 mL) was treated with trimethyl orthoformate (182.18 mg, 188 μL, 1.72 mmol, 10 equiv) and p-toluenesulfonic acid monohydrate (3.3 mg, 0.017 mmol, 0.1 equiv) and the mixture was stirred for 4 h at 80° C. All volatiles were evaporated to give the crude title compound intermediate D52 (120 mg, 93%) as a yellow solid, which was used directly in the next step without further purification.

[0335] Intermediate D123 tert-Butyl 4-[4-[[5-[1-[2-(3-amino-3-oxo-propyl)-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carboxylate Step 1: A mixture of intermediate D63 (450.0 mg, 0.49 mmol, 1.0 equiv) and lithium hydroxide monohydrate (206.49 mg, 4.92 mmol, 10.0 equiv) in water (1.5 mL) / THF (1.5 mL) was stirred at 25° C. for 2 h. EtOAc (10 mL) and water (30 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2×10 mL) and the combined extracts were washed with brine (30 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (PE / EA 4:1) to give 3-[5-[4-[2-[[4-(4-tert-butoxycarbonylpiperazine-1-carbonyl)-3-chloro-phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]propanoic acid (400.0 mg, 0.44 mmol, 58%) as a yellow oil. MS[M+H] + 900.5. Step 2: A mixture of 3-[5-[4-[2-[[4-(4-tert-butoxycarbonylpiperazine-1-carbonyl)-3-chloro-phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]propanoic acid (400 mg, 0.4 mmol, 1 equiv.) in DMF (2 mL) was treated with DIPEA (0.09 mL, 0.49 mmol, 1.1 equiv.), HATU (405.39 mg, 1.07 mmol, 2.4 equiv.) and NH 4 Cl (47.52 mg, 0.89 mmol, 2.0 equiv). The reaction mixture was stirred at 25° C. for 2 h and diluted with EtOAc (10 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined extracts were washed with brine (20 mL), dried (MgSO4), filtered and evaporated. Purification by column chromatography (PE / EA 1:1) afforded the title compound intermediate D123 (300 mg, 75%) as a yellow oil. MS [M+H] + 899.7.

[0336] Intermediate E53 5-[1-(2-fluoro-4-hydroxyphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-fluoro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-imidazole-2-carboxamide; hydrochloride To a solution of intermediate D107 (290.0 mg, 0.42 mmol, 1.0 equiv) in DCM (5 mL) was added boron tribromide (2.11 g, 8.41 mmol, 20.0 equiv) and the mixture was stirred at 25° C. for 16 h to give a pale yellow suspension. The mixture was concentrated under reduced pressure. MeOH (20 mL) was added dropwise to the residue and the resulting mixture was stirred for 10 min and then concentrated under reduced pressure. The residue was dissolved in DMSO (4 mL) and purified by RP column chromatography (0-80% acetonitrile in water, HCl) to give the title compound intermediate E53 (150 mg, 0.25 mmol, 58%) as a white solid. MS[M+H] + 576.2.

[0337] Intermediate E1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-imidazole-2-carboxamide.1:1 Hydrogen chloride A mixture of intermediate D31 (1.09 g, 1.6 mmol, 1 equiv) in dichloromethane (5 mL) was treated with 4M HCl in dioxane (4.8 g, 4 mL, 16.01 mmol, 10 equiv) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness and dried under HV to give the title compound intermediate E1 (1.21 g, quant.) as an off-white solid, which was used in the next step without further purification. MS [M+H] + 574.2.

[0338] The following intermediates were prepared similarly to intermediate E1. [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] [Table 24-5] [Table 24-6] [Table 24-7] [Table 24-8] [Table 24-9] [Table 24-10]

[0339] Intermediate E3 N-[2-[[6-[4-[2-[[3-chloro-4-(piperazine-1-carbonyl)phenyl]carbamoyl]-3-methyl-imidazol-4-yl]-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]amino]ethyl]carbamic acid tert-butyl ester A mixture of intermediate D33 (44 mg, 0.044 mmol, 1 equiv) in acetonitrile (2.5 mL) was treated with 2M dimethylamine in THF (110 μL, 0.220 mmol, 5 equiv) and stirred at room temperature for 3 h. The mixture was evaporated to give the crude title compound intermediate E3 (32 mg, quant.) as an off-white solid, which was used directly in the next step without further purification. MS [M+HCOO] - 761.6.

[0340] The following intermediates were prepared similarly to intermediate E3. [Table 25-1] [Table 25-2]

[0341] Intermediate E84 N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-[2-[(2S)-2,3-dihydroxypropyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carboxamide; hydrochloride Step 1: A mixture of intermediate D88 (290.0 mg, 0.29 mmol, 1.0 equiv) in HCl solution in MeOH (6.0 mL, 24.0 mmol, 82.23 equiv) was stirred at 20° C. for 1 h. The mixture was treated with MeOH (3×10 mL) and concentrated under reduced pressure to give N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-[2-[(2S)-2,3-dihydroxypropyl]-1-(dimethylsulfamoyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide (240.0 mg, 0.31 mmol, quantitative) as a yellow solid. MS[M+H] + 779.2. Step 2: A mixture of N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-[2-[(2S)-2,3-dihydroxypropyl]-1-(dimethylsulfamoyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide (220.0 mg, 0.28 mmol, 1.0 equiv) in TFA (10 mL, 129.8 mmol, 460 equiv) and trifluoromethanesulfonic acid (42.4 mg, 0.28 mmol, 1.0 equiv) was stirred at 20° C. for 16 h. The reaction mixture was treated with MeOH (3 x 5 mL) and concentrated under reduced pressure to give N-[3-chloro-4-[4-(2,2,2-trifluoroacetyl)piperazine-1-carbonyl]phenyl]-5-[1-[2-[(2S)-2,3-dihydroxypropyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide (210.0 mg, 0.27 mmol, 17.6%) as a brown liquid. MS [M+H] + 767.9. Step 3: A mixture of N-[3-chloro-4-[4-(2,2,2-trifluoroacetyl)piperazine-1-carbonyl]phenyl]-5-[1-[2-[(2S)-2,3-dihydroxypropyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide (210.0 mg, 0.27 mmol, 1.0 equiv.) in methanol (5 mL) was treated with potassium carbonate (188.94 mg, 1.37 mmol, 5.0 equiv.) and stirred at 20° C. for 3 h. The mixture was concentrated under reduced pressure and purified by RPHPLC to give the title compound intermediate E84 (45.0 mg, 0.07 mmol, 24.5%) as a yellow solid. MS[M+H] + 672.4.

[0342] The following intermediates were prepared similarly to intermediate E84. [Table 26]

[0343] Intermediate E32 N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-(1H-indazol-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide A mixture of intermediate D21 (200.0 mg, 0.240 mmol, 1 equiv) in DCM (5 mL) was treated with trifluoroacetic acid (1.0 mL, 12.98 mmol, 54 equiv) and the mixture was stirred at 25° C. for 1 h. The mixture was concentrated and the residue was dissolved in 7M NH 3 (5.0 mL, 35 mmol, 145 equiv). The mixture was stirred at 25° C. for 1 h and concentrated. Purification by RPHPLC afforded the title compound Intermediate E32 (40 mg, 28%) as a white solid. MS[M+H] + 598.2.

[0344] Intermediate E40 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[(3S)-3-methylpiperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide, 1:1 formic acid A mixture of intermediate C10 (37.47 mg, 0.060 mmol, 1 equiv.) in DMF (1 mL) was reacted with HATU (31.94 mg, 0.084 mmol, 1.4 equiv.) and Et 3 N (30.36 mg, 41.81 μL, 0.3 mmol, 5 equiv). The mixture was stirred at RT for 10 min and then treated with tert-butyl (2S)-2-methylpiperazine-1-carboxylate (18.03 mg, 0.090 mmol, 1.5 equiv). The mixture was stirred at RT O / N and evaporated to dryness. The residue was dissolved in DCM (1 mL) and treated with excess 4M HCl (189 mg, 180 μL, 0.720 mmol, 40 equiv) and stirred at RT O / N. The mixture was evaporated and purified by RPHPLC to give the title product intermediate E40 (19.9 mg, 52%). MS[M+H] + 588.2.

[0345] The following intermediates were prepared similarly to intermediate E40. [Table 27-1] [Table 27-2]

[0346] Intermediate F1 1-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]isonipecotic acid Step 1: A mixture of intermediate C10 (200 mg, 0.395 mmol, 1 equiv.) and isonipecotic acid methyl ester; hydrochloride (85.23 mg, 0.474 mmol, 1.2 equiv.) in N,N-dimethylformamide (2.5 mL) was treated with DIPEA (153.3 mg, 207.16 μL, 1.19 mmol, 3 equiv.) followed by HATU (225.5 mg, 0.593 mmol, 1.5 equiv.). The...

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, X and Y are each independently selected from N and CH; n is selected from 0 to 6; A is a 5- to 14-membered heteroaryl and C ６ -C １４ -aryl, B is a 3- to 14-membered heterocyclyl, a 5- to 14-membered heteroaryl, and C ３ -C １０ -cycloalkyl, L is a covalent bond, carbonyl, NHC(O), C(O)NH, CH ２ NH, NHCH ２ and NH; L １ is —O— or a covalent bond, R １ teeth, (i) C substituted with one amino and one carboxy substituent １ -C ６ - alkyl, (ii) one amino and one carboxy-C １ -C ６ -C substituted with alkyl-NH- substituents １ -C ６ - alkyl, (iii) C １ -C ６ -alkyl-N(R １ａ R １ｂ ), (iv)-L １ -C １ -C ６ -Alkyl-N ＋ (R １ｃ R １ｄ R １ｅ ), (v) group 【Chemistry 2】 and (vi) group 【Transformation 3】 is selected from R １ａ is amino-C １ -C ６ - alkyl, R １ｂ is carboxy-C １ -C ６ - alkyl; R １ｃ is amino-C １ -C ６ -alkyl and (3- to 14-membered heterocyclyl)-C １ -C ６ - alkyl, R １ｄ is carboxy-C １ -C ６ - alkyl, R １ｅ is C １ -C ６ -Alkyl, amino-C １ -C ６ -alkyl and (3- to 14-membered heterocyclyl)-C １ -C ６ -alkyl-, R １ｆ is C １ -C ６ -Alkyl, hydroxy-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, and (3- to 14-membered heterocyclyl)-C １ -C ６ - alkyl, R １ｇ is carboxy-C １ -C ６ - alkyl, R １ｈ is carboxy-C １ -C ６ - alkyl, R １ｉ is amino-C １ -C ６ - alkyl, R ２ is hydrogen, C １ -C ６ -Alkyl and C １ -C ６ -alkoxy, R ３ and R ７ are both hydrogen, or R ２ and R ７ together with the atoms to which they are attached form a 4- to 14-membered heterocycle or C ４ -C １０ - forms a cycloalkyl, R ３ is hydrogen, or R ２ and R ３ together with the carbon atoms to which they are attached, form C ３ -C １０ - forms a cycloalkyl, R ７ is hydrogen, R ４ is hydrogen and C １ -C ６ - alkyl, R ５ and R ６ are both hydrogen, or R ４ and R ６ together with the atoms to which they are attached form a 4- to 14-membered heterocyclic ring, and R ５ is hydrogen, or R ４ and R ５ together with the carbon atoms to which they are attached, form C ３ -C １０ - forms a cycloalkyl, R ６ is hydrogen, R ８ is hydrogen, cyano, hydroxy, amino, C １ -C ６ -alkyl-NH-, (C １ -C ６ -alkyl) ２ N-, (C １ -C ６ -alkyl) ２ N-SO ２ -, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -Alkyl-, amino-C １ -C ６ -Alkyl, amino-C １ -C ６ -alkoxy, amino-C １ -C ６ -alkyl-NH-, (amino-C １ -C ６ -alkyl) ２ N-, (amino-C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-NH-, C １ -C ６ -Alkyl-NH-C １ -C ６ -alkyl-NH-, C １ -C ６ -alkoxy-C １ -C ６ -Alkyl-NH-, halo-C １ -C ６ -alkoxy-C １ -C ６ -alkyl-NH-, C ３ -C １０ -cycloalkyl-NH-, C １ -C ６ -alkoxy, C １ -C ６ -Alkyl, cyano-C １ -C ６ -Alkyl-, hydroxy-C １ -C ６ -Alkyl-, hydroxy-C １ -C ６ -Alkyl-NH-, hydroxy-C １ -C ６ -Alkyl-NHC(O)-, halo-hydroxy-C １ -C ６ -Alkyl-NHC(O)-, carbamoyl, hydroxycarbamoyl, C １ -C ６ -alkyl-NHC(O)-, (C １ -C ６ -alkyl) ２ NC(O)-, carbamoyl-C １ -C ６ -alkyl-, and groups 【Chemistry 4】 is selected from R ９ is hydrogen, halogen, amino, C １ -C ６ -Alkyl and hydroxy-C １ -C ６ -alkyl-, R １０ is hydrogen, C １ -C ６ - selected from alkyl, halogen, hydroxy, oxo, imino and amino, R １１ is selected from hydrogen and halogen; R １２ is a halogen and C １ -C ６ - alkyl, R １３ Halo-C １ -C ６ -alkyl) or a pharmaceutically acceptable salt thereof.

2. L is a covalent bond, carbonyl, NHC(O), CH ２ 2. The compound of formula (I) according to claim 1, wherein R is selected from NH and NH, or a pharmaceutically acceptable salt thereof.

3. R １ｆ But C １ -C ６ -Alkyl, hydroxy-C １ -C ６ -Alkyl, amino-C １ -C ６ - alkyl, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl and (3- to 14-membered heterocyclyl)-C １ -C ６ 3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: -alkyl- is selected from:

4. R １ teeth, (i) C １ -C ６ -Alkyl-N ＋ (R １ｃ R １ｄ R １ｅ ), and (ii) group 【Transformation 5】 is selected from Y is CH; R １ｃ and R １ｅ All of these are amino-C １ -C ６ - alkyl, R １ｄ and R １ｇ All of these are carboxy-C １ -C ６ - alkyl, R １ｆ However, amino-C １ -C ６ -alkyl and (3- to 14-membered heterocyclyl)-C １ -C ６ 3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: -alkyl- is selected from:

5. R １ teeth, (i) -(CH ２ ) ３ -N ＋ (R １ｃ R １ｄ R １ｅ ), and (ii) group 【Transformation 6】 is selected from Y is CH; R １ｃ and R １ｅ are all 4-aminobutyl, R １ｄ and R １ｇ are all carboxymethyl, R １ｆ 4. The compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, wherein is selected from 3-aminopropyl and azetidin-3-ylmethyl.

6. R ２ , R ３ , R ４ , R ５ , R ６ and R ７ 3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein all are hydrogen.

7. 3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is selected from thiazolyl, isothiazolyl, pyridyl, 1H-pyrrolo[3,2-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1,3-benzothiazole, benzothiophene, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 2H-pyrazolo[4,3-c]pyridine, 1H-pyrrolo[3,2-d]pyrimidine, 1H-indazolyl, furo[3,2-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine, and phenyl.

8. 3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein B is selected from morpholine, thiomorpholine, piperazine, pyrrolidinyl, piperidyl, pyridyl, cyclopropyl, cyclopentyl, 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrole, 9-oxa-3,7-diazabicyclo[3.3.1]nonane, 7-oxa-2-azaspiro[3.5]nonane, and 2,6-dioxa-9-azaspiro[4.5]decane.

9. A is a 5- to 14-membered heteroaryl and C ６ -C １４ -aryl, B is 3- to 14-membered heterocyclyl; L is a covalent bond; R ８ is hydrogen, amino, hydroxy, C １ -C ６ -Alkyl-NH-, amino-C １ -C ６ -Alkyl-NH-, hydroxy-C １ -C ６ -Alkyl-, hydroxy-C １ -C ６ -alkyl-NH-, C １ -C ６ -alkoxy-C １ -C ６ -Alkyl-NH-, Carbamoyl-C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ NC(O)-, and groups 【Transformation 7】 is selected from R ９ is selected from hydrogen and halogen; R １０ is an amino: R １１ is hydrogen, 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

10. A is selected from pyridyl, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrrolo[3,2-c]pyridine, 2H-pyrazolo[4,3-c]pyridine, and phenyl; B is pyrrolidine; L is a covalent bond; R ８ is hydrogen, hydroxy, amino, CH ３ -NH-, amino-(CH ２ ) ３ -NH-, hydroxymethyl, 2-hydroxyethyl, hydroxy-(CH ２ ) ２ -NH-, methoxy-(CH ２ ) ２ -NH-, H ２ N—C(O)—CH ２ -, (CH ３ ) ２ N—C(O)—, and groups 【Transformation 8】 is selected from R ９ is selected from hydrogen and fluoro; R １０ is an amino: R １１ 10. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

11. 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is N.

12. R １２ is selected from chloro and methyl; R １３ But CHF ２ and C.F. ３ 3. The compound of formula (I) according to claim 1 or 2, selected from: or a pharmaceutically acceptable salt thereof.

13. R １２ is selected from chloro and methyl; R １３ is CF ３ 13. The compound of formula (I) according to claim 12, wherein:

14. X and Y are each independently selected from N and CH; n is selected from 0 to 6; A is a 5- to 14-membered heteroaryl and C ６ -C １４ -aryl, B is 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, and C ３ -C １０ -cycloalkyl, L is a covalent bond, carbonyl, NHC(O), CH ２ NH and NH; L １ is —O— or a covalent bond, R １ teeth, (i) C substituted with one amino and one carboxy substituent １ -C ６ - alkyl, (ii) one amino and one carboxy-C １ -C ６ -C substituted with alkyl-NH- substituents １ -C ６ - alkyl, (iii) C １ -C ６ -alkyl-N(R １ａ R １ｂ ), (iv)-L １ -C １ -C ６ -Alkyl-N ＋ (R １ｃ R １ｄ R １ｅ ), (v) group 【Chemistry 9】 and (vi) group 【Chemistry 10】 is selected from R １ａ is amino-C １ -C ６ - alkyl, R １ｂ is carboxy-C １ -C ６ - alkyl; R １ｃ However, amino-C １ -C ６ -alkyl and (3- to 14-membered heterocyclyl)-C １ -C ６ - alkyl, R １ｄ is carboxy-C １ -C ６ - alkyl, R １ｅ But C １ -C ６ -Alkyl, amino-C １ -C ６ -alkyl and (3- to 14-membered heterocyclyl)-C １ -C ６ -alkyl-, R １ｆ But C １ -C ６ -Alkyl, hydroxy-C １ -C ６ -Alkyl, amino-C １ -C ６ - alkyl, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl and (3- to 14-membered heterocyclyl)-C １ -C ６ -alkyl-, R １ｇ is carboxy-C １ -C ６ - alkyl, R １ｈ is carboxy-C １ -C ６ - alkyl, R １ｉ is amino-C １ -C ６ - alkyl, R ２ But hydrogen, C １ -C ６ -Alkyl and C １ -C ６ -alkoxy, R ３ and R ７ are both hydrogen, or R ２ and R ７ together with the atoms to which they are attached form a 4- to 14-membered heterocycle or C ４ -C １０ - forms a cycloalkyl, R ３ is hydrogen, or R ２ and R ３ together with the carbon atoms to which they are attached, ３ -C １０ - forms a cycloalkyl, R ７ is hydrogen, R ４ is hydrogen and C １ -C ６ - alkyl, R ５ and R ６ are both hydrogen, or R ４ and R ６ together with the atoms to which they are attached form a 4- to 14-membered heterocyclic ring, and R ５ is hydrogen, or R ４ and R ５ together with the carbon atoms to which they are attached, form C ３ -C １０ - forms a cycloalkyl, R ６ is hydrogen, R ８ is hydrogen, cyano, amino, hydroxy, C １ -C ６ -alkyl-NH-, (C １ -C ６ -alkyl) ２ N-, (C １ -C ６ -alkyl) ２ N-SO ２ -, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -Alkyl-, amino-C １ -C ６ -Alkyl, amino-C １ -C ６ -alkoxy, amino-C １ -C ６ -alkyl-NH-, (amino-C １ -C ６ -alkyl) ２ N-, (amino-C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-NH-, C １ -C ６ -Alkyl-NH-C １ -C ６ -alkyl-NH-, C １ -C ６ -alkoxy-C １ -C ６ -Alkyl-NH-, halo-C １ -C ６ -alkoxy-C １ -C ６ -alkyl-NH-, C ３ -C １０ -cycloalkyl-NH-, C １ -C ６ -alkoxy, C １ -C ６ -Alkyl, cyano-C １ -C ６ -Alkyl-, hydroxy-C １ -C ６ -Alkyl-, hydroxy-C １ -C ６ -Alkyl-NH-, hydroxy-C １ -C ６ -Alkyl-NHC(O)-, halo-hydroxy-C １ -C ６ -Alkyl-NHC(O)-, carbamoyl, hydroxycarbamoyl, C １ -C ６ -alkyl-NHC(O)-, (C １ -C ６ -alkyl) ２ NC(O)-, carbamoyl-C １ -C ６ -alkyl-, and groups 【Chemistry 11】 is selected from R ９ But hydrogen, halogen, amino, C １ -C ６ -Alkyl and hydroxy-C １ -C ６ -alkyl-, R １０ But hydrogen, C １ -C ６ - selected from alkyl, halogen, hydroxy, oxo, imino and amino, R １１ is selected from hydrogen and halogen; R １２ but halogen and C １ -C ６ - alkyl, R １３ Halo-C １ -C ６ 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is - alkyl.

15. A is a 5- to 14-membered heteroaryl and C ６ -C １４ -aryl, B is 3- to 14-membered heterocyclyl; L is a covalent bond; X is N; Y is CH; R １ teeth, (i) C １ -C ６ -Alkyl-N ＋ (R １ｃ R １ｄ R １ｅ ), and (ii) group 【Chemistry 12】 is selected from R １ｃ and R １ｅ All of these are amino-C １ -C ６ - alkyl, R １ｄ and R １ｇ All of these are carboxy-C １ -C ６ - alkyl, R １ｆ However, amino-C １ -C ６ -alkyl and (3- to 14-membered heterocyclyl)-C １ -C ６ -alkyl-, R ２ , R ３ , R ４ , R ５ , R ６ and R ７ are all hydrogen, R ８ is hydrogen, amino, hydroxy, C １ -C ６ -Alkyl-NH-, amino-C １ -C ６ -Alkyl-NH-, hydroxy-C １ -C ６ -Alkyl-, hydroxy-C １ -C ６ -alkyl-NH-, C １ -C ６ -alkoxy-C １ -C ６ -Alkyl-NH-, Carbamoyl-C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ NC(O)-, and groups 【Chemistry 13】 is selected from R ９ is selected from hydrogen and halogen; R １０ is amino, R １１ is hydrogen, R １２ but halogen and C １ -C ６ - alkyl, R １３ Halo-C １ -C ６ 15. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, wherein: - is alkyl.

16. A is selected from pyridyl, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrrolo[3,2-c]pyridine, 2H-pyrazolo[4,3-c]pyridine, and phenyl; B is pyrrolidine; L is a covalent bond; R １ teeth, (i) -(CH ２ ) ３ -N ＋ (R １ｃ R １ｄ R １ｅ ), and (ii) group 【Chemistry 14】 is selected from R １ｃ and R １ｅ are all 4-aminobutyl, R １ｄ and R １ｇ are all carboxymethyl, R １ｆ is selected from 3-aminopropyl and azetidin-3-ylmethyl; R ８ is hydrogen, hydroxy, amino, CH ３ -NH-, amino-(CH ２ ) ３ -NH-, hydroxymethyl, 2-hydroxyethyl, hydroxy-(CH ２ ) ２ -NH-, methoxy-(CH ２ ) ２ -NH-, H ２ N—C(O)—CH ２ -, (CH ３ ) ２ N—C(O)—, and groups 【Chemistry 15】 is selected from R ９ is selected from hydrogen and fluoro; R １０ is amino, R １１ is hydrogen, R １２ is selected from chloro and methyl; R １３ is CF ３ 11. The compound of formula (I) according to claim 10, wherein:

17. The compound of formula (I) bis(4-aminobutyl)-(carboxymethyl)-[4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazino]-4-keto-butyl]ammonium, cis-2-[4-[4-[4-[[5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, bis(4-aminobutyl)-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)ammonium, 2-[4-[4-[4-[[5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, bis(3-aminopropyl)-(carboxymethyl)-[4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazino]-4-keto-butyl]ammonium, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-c]pyridin-6-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[5-(3-aminopropylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-[5-[[(2S)-2-aminopropyl]amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, bis(4-aminobutyl)-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)ammonium, 2-[4-[4-[4-[[5-[1-[5-(aminomethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-[5-(2-aminoethyl)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-[5-(2-aminoethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[5-(2-pyridylmethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-[5-[(1-aminocyclopentyl)methylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-(5-morpholino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-[5-[[(2S)-pyrrolidin-2-yl]methylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[5-(2-methoxyethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, trans-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-(5-piperazino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-[5-[2-(methylamino)ethylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, bis(3-aminopropyl)-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)ammonium, bis(4-aminobutyl)-[4-[4-[4-[[5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)ammonium, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(4-methoxyphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[5-(2-hydroxyethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1-methylpyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]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-[1-[5-(isopropylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-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-[[1-methyl-5-[1-[5-(2-pyridylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrazolo[4,3-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-thiazol-2-yl-3-(trifluoromethyl)pyrazol-4-yl]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-[1-[5-(cyclopropylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-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-[1-[5-(dimethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-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-[1-[4-(dimethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-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-[[1-methyl-5-[1-[5-[[(3S)-morpholin-3-yl]methylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[6-(dimethylamino)-3-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, [4-[4-[4-[[5-[1-(5-aminopyridin-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chlorobenzoyl]piperazin-1-yl]-4-oxobutyl]-bis(azetidin-3-ylmethyl)-(carboxymethyl)azanium, 2-[4-[4-[4-[[5-[1-[5-(6-aminohexylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[4-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-[5-(4-methylpiperazino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]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-[1-(5-hydroxy-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(1H-imidazo[4,5-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-(6-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[5-(4-piperidylmethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]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-[1-[5-[[(2S,4S)-4-fluoropyrrolidin-2-yl]methylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-(5-amino-3-fluoro-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 4-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]butyric acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]-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-[1-(1H-indazol-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]-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-[1-furo[3,2-b]pyridin-5-yl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, trans-2-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[5-[(2,2-difluorocyclopropyl)methylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 3-aminopropyl-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)-methyl-ammonium, bis(3-aminopropyl)-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)ammonium, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(5,6-diamino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-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-[[1-methyl-5-[1-[6-(methylamino)-3-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]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-[1-[5-(cyclobutylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[2-(3-aminopropyl)-4-[3-[[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]amino]propyl]pyridin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-(4-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[3-aminopropyl-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]amino]acetic acid, cis-2-[4-[4-[4-[[5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-(2-amino-4-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[1-(3-aminopropyl)-4-[1-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperidine-4-carbonyl]piperazin-1-ium-1-yl]acetic acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(5-cyano-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[4-[(2S)-4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-2-methyl-piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[4-[(3R)-4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-3-ethyl-piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[4-[(3S)-4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-3-methyl-piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-(1,3-benzothiazol-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[[(5S)-5-amino-6-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-6-keto-hexyl]amino]acetic acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(6-methoxy-3-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, (2S) 2-amino-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyric acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[5-[(dimethylamino)methyl]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, (3R)-3-amino-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyric acid, 2-[4-[7-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-4,7-diazaspiro[2.5]octane-4-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[4-[1-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperidine-4-carbonyl]-1-(azetidin-3-ylmethyl)piperazin-1-ium-1-yl]acetic acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-(methylamino)-4-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-(6-amino-3-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[4-[8-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-3,8-diazabicyclo[3.2.1]octane-3-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, (2S)-2-amino-5-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-5-keto-valeric acid, (3S)-3-amino-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyric acid, 2-[4-[4-[4-[[5-[1-[6-(2-aminoethylamino)-3-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[4-[3-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-3,9-diazabicyclo[3.3.1]nonane-9-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-4,7-diazaspiro[2.5]octane-7-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-(4-aminoisothiazol-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-(benzothiophen-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[2-(3-aminopropyl)-4-[3-[[1-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperidine-4-carbonyl]amino]propyl]pyridin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-2-(methoxymethyl)piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[5-[1-[2-(3-hydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[2-(3-amino-3-oxo-propyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(3-aminopropyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[5-[1-(2-fluoro-4-morpholino-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-[2-[(1S)-1-hydroxyethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[5-[1-[2-[2-hydroxy-1-(hydroxymethyl)ethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[1-methyl-2-(morpholine-4-carbonyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[5-[1-[2-(2-hydroxyethylcarbamoyl)-1-methyl-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-[(1S)-1,2-dihydroxyethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-[(1R)-1,2-dihydroxyethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-[2-fluoro-4-(methylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-fluoro-4-[[5-[1-[2-fluoro-4-(methylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-[4-(dimethylamino)-2-fluorophenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-fluoro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(2-fluoro-4-hydroxyphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-[2-fluoro-4-(2-methoxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[2-[(3aS,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-(7-oxa-2-azaspiro[3.5]nonane-2-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(1-imino-1-keto-1,4-thiazinan-4-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(2-hydroxyethylcarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-(9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-[(3,3,3 trifluoro-2-hydroxy-propyl)carbamoyl]-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-(piperazine-1-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(2,2-difluoromorpholine-4-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-[(2-ketopyrrolidin-3-yl)carbamoyl]-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-[(5R)-2,6-dioxa-9-azaspiro[4.5]decane-9-carbonyl]-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-(thiomorpholine-4-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(dimethylcarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-fluoro-4-[[5-[1-[2-fluoro-4-(2-methoxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(hydroxycarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[4-[2-(difluoromethoxy)ethylamino]-2-fluorophenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-[2-(2-hydroxyethyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(difluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[2-(2-aminoethyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]oxyethyl-bis(3-aminopropyl)-(carboxymethyl)ammonium, cis-2-[1-(3-aminopropyl)-4-[4-[2-fluoro-4-[[5-[1-(2-fluoro-4-hydroxy-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-methyl-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-fluoro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[1-(3-aminopropyl)-4-[1-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]isonipecotoyl]piperazin-1-ium-1-yl]acetic acid, 2-[4-[1-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]isonipecotoyl]-1-(3-aminopropyl)piperazin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-fluoro-4-[[5-[1-(2-fluoro-4-hydroxyphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[4-[[(2S)-2,3-dihydroxypropyl]amino]-2-fluoro-phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[1-(2-amino-1,1-dimethyl-2-oxo-ethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[2-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperazin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(3-aminopropyl)piperazin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[2-(2-aminoethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[1-(methylcarbamoyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]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-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperazin-1-ium-1-yl]acetic acid, 2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperazin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[3-(2-hydroxyethylcarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[3-(piperazine-1-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[3-(4-methylpiperazine-1-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[2-(2-amino-2-keto-ethyl)pyrazolo[4,3-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-[(1R)-1-hydroxyethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-fluoro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-methyl-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(2-hydroxyethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[3-[(3S)-3-hydroxypyrrolidine-1-carbonyl]-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[3-(methylcarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-(3-carbamoyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(dimethylsulfamoyl)-2-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(3-hydroxypropyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-[(2S)-2,3-dihydroxypropyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-[1-(3-amino-2-methyl-3-oxo-propyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(2-hydroxyethyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-(2-fluoro-4-hydroxy-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-[(2-hydroxy-2-methyl-propyl)amino]phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(5H-pyrrolo[3,2-d]pyrimidin-2-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-[5-[2-[bis(2-aminoethyl)amino]ethylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[2-(2-amino-2-oxo-ethyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[1-(2-amino-2-keto-ethyl)pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(cyanomethyl)-2-methylol-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(3-aminopropyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(3-aminopropyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[3-(dimethylcarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(2-hydroxyethyl)-2-methylol-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-(methylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[3-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-(2-hydroxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[3-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 4-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]butanoic acid, [4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazin-1-yl]-4-oxo-butyl]-bis(3-aminopropyl)-(3-carboxypropyl)ammonium, [4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazin-1-yl]-4-oxo-butyl]-bis(3-aminopropyl)-(carboxymethyl)ammonium, cis-2-[4-[4-[4-[[5-[1-[2-(aminomethyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-(2-methoxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[4-(3-aminopropylamino)-2-fluorophenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, trans-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-[2-(dimethylamino)ethyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-[2-(dimethylamino)ethyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[2-(aminomethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[1-(2-aminoethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-(6-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-methyl-piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[3-(2-hydroxyethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazin-1-yl]-4-oxo-butyl]-(azetidin-3-ylmethyl)-methyl-ammonio]acetate, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[4-[[5-[1-[5-[bis(2-aminoethyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(cyanomethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(2-hydroxyethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[1-(2-amino-2-keto-ethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[2,3-c]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, 2-[4-[4-[4-[[5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-methyl-piperidin-1-ium-1-yl]acetate, and 2. The compound of formula (I) of claim 1, or a pharmaceutically acceptable salt thereof, selected from cis-2-[4-[4-[4-[[5-[1-[5-[(3S)-3-aminopyrrolidin-1-yl]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid.

18. The compound of formula (I) bis(4-aminobutyl)-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazino]-4-keto-butyl]-(carboxymethyl)ammonium, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-c]pyridin-6-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[5-(3-aminopropylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, trans-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[5-(2-hydroxyethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(3-aminopropyl)-4-[4-[4-[[5-[1-(2-fluoro-4-hydroxyphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-methyl-4-[[1-methyl-5-[1-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[2-(2-amino-2-keto-ethyl)pyrazolo[4,3-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-(4-amino-2-fluoro-phenyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-methyl-4-[[1-methyl-5-[1-(2-methylol-1H-pyrrolo[3,2-b]pyridin-5-yl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-(2-hydroxyethyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[3-(dimethylcarbamoyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[1-(2-hydroxyethyl)pyrrolo[3,2-c]pyridin-6-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-(2-hydroxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[1-(azetidin-3-ylmethyl)-4-[4-[2-chloro-4-[[5-[1-[2-fluoro-4-(2-methoxyethylamino)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidin-1-ium-1-yl]acetic acid, cis-2-[4-[4-[4-[[5-[1-[1-(2-amino-2-keto-ethyl)pyrrolo[3,2-b]pyridin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid, and 18. The compound of formula (I) of claim 17 or a pharmaceutically acceptable salt thereof, selected from cis-2-[4-[4-[4-[[5-[1-[5-[(3S)-3-aminopyrrolidin-1-yl]-2-pyridyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-1-(azetidin-3-ylmethyl)piperidin-1-ium-1-yl]acetic acid.

19. 10. A method for preparing a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, said method being as set forth in Scheme 4 disclosed herein.

20. A compound of formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, when prepared according to the process as set forth in Scheme 4 disclosed herein.

21. 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 for use as a therapeutically active substance.

22. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier.

23. 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 for use as an antibiotic.

24. 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 or 2 for use in the treatment or prevention of nosocomial infections and resulting diseases.

25. 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections caused by Gram-negative bacteria and the resulting diseases.

26. 26. The compound for use according to claim 25, wherein the Gram-negative bacteria is selected from Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species and E. coli.

27. 27. The compound for use according to claim 26, wherein the Gram-negative bacterium is Acinetobacter baumannii.

28. 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or combinations thereof.

29. 10. A method for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, comprising administering to a mammal a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

30. 10. Use of a compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an antibiotic.

31. 3. Use of a compound of formula (I) according to claim 1 or 2, 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 thereof.

32. 3. Use of a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

33. 10. An invention as hereinbefore described.

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