HK40078454B - Novel heterocyclic compounds - Google Patents

Description

Novel heterocyclic compounds

Technical Field

This invention relates to novel heterocyclic compounds exhibiting antibacterial properties. The invention also relates to methods of using said compounds to treat or prevent bacterial infections and diseases caused therefrom, particularly methods of treating or preventing Acinetobacter baumannii infection and diseases caused therefrom.

Background Technology

Acinetobacter baumannii is a Gram-negative, aerobic, non-fermenting bacterium that has been considered an emerging pathogen with very limited treatment options for the past few decades.

Acinetobacter baumannii is considered a serious threat by the U.S. Centers for Disease Control and Prevention and belongs to the so-called "ESKAPE" pathogens (Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species and Escherichia coli), which currently cause most hospital infections and effectively "escape" the activity of antimicrobial agents.

Acinetobacter baumannii is most commonly encountered in intensive care units and surgical wards, where the widespread use of antibiotics has enabled it to develop resistance to all known antimicrobial agents. In these wards, Acinetobacter baumannii causes infections including bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

Acinetobacter baumannii has an excellent ability to upregulate and acquire resistance determinants and exhibits environmental persistence that allows it to survive and spread in hospital settings, making the organism a common cause of infection outbreaks and endemic pathogens associated with healthcare.

Due to increasing resistance to most (if not all) available treatments of antibiotics, multidrug-resistant (MDR) Acinetobacter baumannii infections, especially those caused by carbapenem-resistant Acinetobacter baumannii, are difficult or even untreatable, have high mortality rates, and increase morbidity and prolong hospital stays in intensive care units.

According to the Antimicrobial Benefit Assessment Group (AATF) of the Infectious Diseases Society of America (IDSA), Acinetobacter baumannii remains "the best example of the mismatch between unmet medical needs and current antimicrobial agent development pathways." Therefore, there is an urgent need and demand to identify compounds suitable for treating diseases and infections caused by Acinetobacter baumannii.

This invention provides novel compounds that exhibit activity against both drug-sensitive and drug-resistant strains of Acinetobacter baumannii.

Summary of the Invention

In a first aspect, the present invention provides a compound of formula (I).

Or its medicinal salts, wherein ^R1 to ^R4 , m, n and p are as described herein.

In one aspect, the present invention provides a method for preparing compounds of formula (I) as described herein, wherein the method is as described in any of embodiments 1 to 5 herein.

In another aspect, the present invention provides compounds of formula (I) as described herein, prepared according to the methods described herein.

In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, which is used as a therapeutically active substance.

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

In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, which is used as an antibiotic.

In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, for the treatment or prevention of hospital-acquired infections and the resulting diseases.

In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, for the treatment or prevention of infections and diseases caused by Gram-negative bacteria.

In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, for the treatment or prevention of infections and diseases caused by Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof.

In another aspect, the present invention provides a method for treating or preventing infections and diseases caused by Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof, the method comprising administering to a mammal a compound of formula (I) as described herein or a pharmaceutical salt thereof.

In another aspect, the present invention provides the use of compounds of formula (I) as described herein, or pharmaceutical salts thereof, as antibiotics.

On the other hand, the present invention provides the use of compounds of formula (I) as described herein or pharmaceutical salts thereof for the treatment or prevention of infections and diseases caused by Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof.

In another aspect, the present invention provides the use of compounds of formula (I) as described herein or pharmaceutical salts thereof for the preparation of medicaments for the treatment or prevention of infections and diseases caused by Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof.

Detailed Implementation

definition

Features, integers, properties, compounds, chemical parts, or groups described in connection with a particular aspect, embodiment, or example of the invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless incompatible therewith. All features disclosed in this specification (including any appended claims, abstract, and drawings) and/or all steps of any method or process disclosed thereby may be combined in any combination, except for at least some mutually exclusive combinations of these features and/or steps. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any appended claims, abstract, and drawings), or to any novel step or any novel combination of steps of any method or process disclosed thereby.

The term "alkyl" refers to a monovalent or polyvalent (e.g., monovalent or divalent) straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms (" _C1 - _C6 -alkyl") (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). In some embodiments, the alkyl group contains 1 to 3 carbon atoms, such as 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred but non-limiting example of an alkyl group is methyl.

The term "alkynyl" refers to a monovalent straight-chain or branched hydrocarbon group (" _C2 - _C6 -alkynyl") having 2 to 6 carbon atoms and at least one carbon-carbon triple bond. In certain embodiments, the alkynyl group has 2 to 4 carbon atoms and at least one triple bond. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, or isobutynyl. A preferred alkynyl group is propynyl.

The term "alkoxy group" refers to an alkyl group as defined above, attached to a parent molecule via an oxygen atom. Unless otherwise stated, an alkoxy group contains 1 to 6 carbon atoms (" _C1 - _C6 -alkoxy"). In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred, but non-limiting, example of an alkoxy group is methoxy.

The term "halogen" or "halogenated" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Preferably, the term "halogen" or "halogenated" refers to fluorine (F), chlorine (Cl), or bromine (Br). Particularly preferred, but not limiting, examples of "halogen" or "halogenated" are fluorine (F) and chlorine (Cl).

As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic hydrocarbon group having 3 to 10 ring carbon atoms (" _C3 - _C10 -cycloalkyl"). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbon rings having two common carbon atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) and a spirocyclic moiety (i.e., the two rings are connected via a common ring atom). Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 6 ring carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms). Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and spiro[2.3]hexane-5-yl.

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

The term "aminoalkoxyalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by an aminoalkoxy group. Preferably, "aminoalkoxyalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group have been replaced by an aminoalkoxy group. Most preferably, "aminoalkoxyalkoxy" refers to an alkoxy group in which one hydrogen atom of the alkoxy group has been replaced by an aminoalkoxy group.

The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic system, having 3 to 10 ring atoms, preferably 3 to 8 ring atoms, wherein 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 heterocyclic group" refers to a heterocyclic portion consisting of two rings sharing two common ring atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) and a spirocyclic portion (i.e., the two rings are connected via a common ring atom). Some non-limiting examples of heterocyclic groups include azacyclobutane-3-yl, azacyclobutane-2-yl, oxacyclobutane-3-yl, oxacyclobutane-2-yl, piperidinyl, piperazinyl, pyrrolylyl, 2-oxopyrrolin-1-yl, 2-oxopyrrolin-3-yl, 5-oxopyrrolin-2-yl, 5-oxopyrrolin-3-yl, 2-oxo-1-piperidinyl, 2-oxo-3-piperidinyl, 2-oxo-4-piperidinyl, 6-oxo-2-piperidinyl, 6-oxo-3-piperidinyl, 1- Piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, morpholino, morpholin-2-yl, morpholin-3-yl, pyrrolylyl (e.g., pyrrolidine-3-yl), 3-azabicyclo[3.1.0]hexane-6-yl, 2,5-diazabicyclo[2.2.1]heptane-2-yl, 2-azaspiro[3.3]heptane-2-yl, 2,6-diazaspiro[3.3]heptane-2-yl and 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrolo-5-yl.

The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system (" _C6 - _C10 -aryl") having a total of 6 to 10 ring members, wherein at least one ring in the ring system is aromatic. A particularly preferred, but non-limiting, example of an aryl group is the phenyl group.

The term "heteroaryl" refers to a monovalent or multivalent monocyclic or bicyclic, preferably bicyclic, ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, and more preferably 5 to 10 ring members, wherein at least one ring in the ring system is aromatic and contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5-10 membered heteroaryl containing 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl groups include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, indole-1-yl, 1H-indole-2-yl, 1H-indole-3-yl, 1H-indole-4-yl, 1H-indole-5-yl, 1H-indole-6-yl, 1H-indole-7-yl, 1,2-benzoxazole-3-yl, 1,2-benzoxazole-4-yl, 1,2-benzoxazole-5-yl, 1,2-benzoxazole-6-yl, 1,2-Benzoxazol-7-yl, 1H-indazole-3-yl, 1H-indazole-4-yl, 1H-indazole-5-yl, 1H-indazole-6-yl, 1H-indazole-7-yl, pyrazole-1-yl, 1H-pyrazole-3-yl, 1H-pyrazole-4-yl, 1H-pyrazole-5-yl, imidazole-1-yl, 1H-imidazole-2-yl, 1H-imidazole-4-yl, 1H-imidazole-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazolyl-4-yl, and 1,2,4-oxadiazol-3-yl. Most preferably, "heteroaryl" refers to pyridinyl and pyrimidinyl.

The term "heteroaryl group" refers to a heteroaryl group, as defined above, that is attached to a part of the parent molecule via an oxygen atom.

The term "hydroxyl group" refers to the –OH group.

The term "amino" refers to the –NH ₂ group.

The term "cyano" refers to the –CN (nitrile) group.

The term "oxo" refers to double-bonded oxygen (=O).

The term "carbamoyl" refers to the –C(O) _NH2 group.

The term "formamidinyl" refers to a group or

The term "carboxyl group" refers to the -C(O)OH group (i.e., the carboxylic acid moiety).

The term "carbonyl" refers to a carbon radical (C=O) that shares two of its four covalent bonds with an oxygen atom.

The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a halogen atom, preferably fluorine. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluorine. Non-limiting examples of haloalkyl groups are fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, 2-fluoroethyl, and 2,2-difluoroethyl. A particularly preferred but non-limiting example of a haloalkyl group is trifluoromethyl.

The term "cyanoalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a cyano group. Preferably, "cyanoalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group have been replaced by a cyano group. Most preferably, "cyanoalkyl" refers to an alkyl group in which one hydrogen atom of the alkyl group has been replaced by a cyano group.

The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by a halogen atom, preferably fluorine. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluorine. Particularly preferred, but non-limiting, examples of haloalkoxy groups are fluoromethoxy ( _FCH₂O- ), difluoromethoxy ( _F₂CHO- ), and trifluoromethoxy ( _F₃CO- ).

The term "cyanoalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by a cyano group. Preferably, "cyanoalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group have been replaced by a cyano group. Most preferably, "cyanoalkoxy" refers to an alkoxy group in which one hydrogen atom of the alkoxy group has been replaced by a cyano group.

The term "carbamoylalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by a carbamoyl group. Preferably, "carbamoylalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group have been replaced by a carbamoyl group. Most preferably, "carbamoylalkoxy" refers to an alkoxy group in which one hydrogen atom of the alkoxy group has been replaced by a carbamoyl group.

The term "alkoxyalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by an alkoxy group (preferably methoxy). Preferably, "alkoxyalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group have been replaced by an alkoxy group (preferably methoxy). A preferred but non-limiting example of alkoxyalkoxy is 2-methoxyethoxy.

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

The term "aminoalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by an amino group. Preferably, "aminoalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms (most preferably one hydrogen atom) of the alkyl group have been replaced by an amino group. Preferred, but non-limiting, examples of aminoalkyl are aminomethyl, aminoethyl (e.g., 2-aminoethyl), and 3-amino-3-methyl-butyl.

The term "carboxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a carboxyl group. Preferably, "carboxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms (most preferably one hydrogen atom) of the alkyl group have been replaced by a carboxyl group. Preferred, but non-limiting, examples of carboxyalkyl are carboxymethyl, carboxyethyl (e.g., 2-carboxyethyl), and 3-carboxy-3-methyl-butyl.

The term "medicinal salt" refers to salts that retain the biological effects and properties of free bases or free acids, and which are not undesirable in biological or other applications. These salts are formed using inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., 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.). Alternatively, these salts can be prepared by adding inorganic or organic bases to free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of the following: 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, polyimide resins, etc.). Specific pharmaceutical salts of compounds of formula (I) are hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid), and trifluoroacetate.

Compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers (e.g., racemates), optically pure diastereomers, mixtures of diastereomers, diastereomers racemates, or mixtures of diastereomers racemates.

According to the Cahn-Ingold-Prelog convention, an asymmetric carbon atom can be either "R" or "S" configuration.

As used herein, the term "treatment" includes: (1) a state, symptom, or condition that suppresses at least one clinical or subclinical symptom of a disease (e.g.,, in the case of maintenance therapy, preventing, alleviating, or delaying the progression of the disease or its recurrence); and/or (2) a condition that alleviates the symptoms (i.e., the state, symptom, or condition of the disease or at least one clinical or subclinical symptom). The benefit of treatment to a patient is statistically significant or at least perceptible to the patient or physician. However, it should be understood that when a patient is given medication to treat a disease, the outcome may not always be an effective treatment.

As used herein, the term “prevention” includes: prevention or delay of the development of clinical symptoms of a state, condition or illness in mammals, particularly in humans, that may have or be susceptible to the state, condition or illness but have not yet experienced or displayed clinical or subclinical symptoms of the state, condition or illness.

As used herein, the term "mammal" includes both humans and non-humans, and includes, but is not limited to, humans, non-human primates, dogs, cats, rats, cattle, horses, and pigs. In a particularly preferred embodiment, the term "mammal" refers to humans.

The term "hospital-acquired infection" refers to a hospital-acquired infection (HAI), which is an infection acquired in a hospital or other healthcare facility. To emphasize the hospital and non-hospital settings, it is sometimes also referred to as a healthcare-associated infection (HAI or HCAI). This type of infection can be acquired in hospitals, nursing homes, rehabilitation facilities, outpatient clinics, or other clinical settings.

The compounds of the present invention

In a first aspect, the present invention provides a compound of formula (I).

Or its medicinal salt, wherein:

^R1, each time it appears, is independently selected from hydroxyl, halogen, cyano, amino, _C1 - _C6 -alkoxy, halo- _C1 - _C6 -alkoxy, amino- _C1 - _C6 -alkoxy-, group, and group _C1 - _C6 -alkyl- ^L2- ; wherein the _C1 - _C6 -alkyl is optionally substituted by 1-3 substituents selected from: hydroxyl, amino, halogen, cyano, _C1 - _C6 -alkyl-NH-, ( _C1 - _C6 -alkyl) _2N- , amino- _C1 - _C6 -alkoxy- _C1 - _C6 -alkoxy-, carbamoyl, carbamoyl _{- C1} - _C6 -alkoxy-, formamidinyl, ( _C1 - _{C6-alkyl)2NC1-C6 - alkoxy-} , ( _C1 - _C6 -alkyl) _{2NC1 - C6} -alkyl-C(O)-NH- _C1 - _C6 -alkoxy-, _C2 - _C6 -alkynyl-NH-, carboxyl and _C1 - _C6 -alkoxy;

^R2 is independently selected from halogen, cyano, _C1 - _C6 -alkyl, _C1 - _C6 -alkoxy, halo- _C1 - _C6 -alkyl, and halo- _C1 - _C6 -alkoxy each time it appears;

^R3 is selected from hydrogen, _C1 - _C6 -alkyl, and halo- _C1 - _C6 -alkyl;

^R4, in each occurrence, is independently selected from halogens, _C1 - _C6 -alkyl, _C1 - _C6 -alkoxy, cyano, halo- _C1 - _C6 -alkyl, cyano- _C1 - _C6 -alkyl, ( _C1 - _C6 -alkyl) _2N- , halo- _C1 - _C6 -alkoxy, cyano- _C1 - _C6 -alkoxy, _C1 - _C6 -alkoxy- _C1 - _C6 -alkoxy-, ( _C1 - _C6 -alkyl) _2NC (O)-, and 5- to 14-membered heteroaryloxy groups; and

R ⁵ , each time appearing independently, is selected from amino, hydroxy, _C1 - _C6 -alkyl, amino- _C1 - _C6 -alkyl-, hydroxy- _C1 - _C6 -alkyl-, halo- _C1 - _C6 -alkyl-, _C1 - _C6 -alkoxy, halo- _C1 - _C6 -alkoxy, ( _C1 - _C6 -alkyl) _2N- , ( _C1 - _C6 -alkyl) _{2NC1 -C6 -} alkyl-, ( _C1 - _C6 -alkyl) _2NC1 - _{C6 -} alkyl-C(O)-, oxo, carbamoyl, carbamoyl- _C1 - _C6 -alkyl, carboxyl, carboxyl- _C1 - _C6 -alkyl, halogen (fluorine), cyano, _C1 - _C6 -aminoalkyl-S(O) _2- , and groups.

^R6, each time it appears, is independently selected from amino, hydroxy, _C1 - _C6 -alkyl, amino- _C1 - _C6 -alkyl-, hydroxy- _C1 - _C6 -alkyl-, halo- _C1 - _C6 -alkyl-, _C1 - _C6 -alkoxy, halo- _C1 - _C6 -alkoxy, ( _C1 - _C6 -alkyl) _2N- , ( _C1 - _C6 -alkyl) _{2NC1 -C6 -} alkyl-, ( _C1 - _C6 -alkyl) _{2NC1 -C6 -} alkyl-C(O)-, oxo, carbamoyl, carbamoyl- _C1 - _C6 -alkyl, carboxyl, carboxyl- _C1 - _C6 -alkyl, halogen, cyano, and _C1 - _C6 -aminoalkyl-S(O) _2- ;

A is a 3- to 14-membered heterocyclic group;

B and C are independently selected from 3- to 14-membered heterocyclic groups, _C3 - _C10 -cycloalkyl groups, 5- to 14-membered heteroaryl groups, and _C6 - _C10 -aryl groups;

^L1 and ^L3 are independently selected from covalent bonds, -O-, -NH-, -N( _C1 - _C6 -alkyl)-, _-CH2O- , -OCH2-, -(CH2) _sC (O)-, _-CH2NHC (O)-, _-CH2C ( _O )NH-, -CH2- _, -NHC(O)-, -S(O) _2- , -S(O) _2NH- , -C(O)NH( _CH2 ) _{2- and} -NH-NHC(O)-;

^L2 is selected from covalent bonds, carbonyl groups, -S(O) _2- , -NHC(O)-, -C(O)NH-, and -S(O) _2NH- ;

m can be 1, 2, 3, or 4;

n can be 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3, 4 or 5;

q is 0, 1, or 2;

r is 0 or 1; and

s can be 0, 1, 2, 3 or 4.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein m is 1.

In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein ^R1 is selected from amino, amino- _C1 - _C6 -alkoxy, group, and group _C1 - _C6 -alkyl- ^L2- ; wherein:

The _C1 - _C6 -alkyl group is substituted with one or two substituents selected from the following: hydroxyl, amino, cyano, _C1 - _C6 -alkyl-NH-, ( _C1 - _C6 -alkyl) _2N- , amino- _C1 - _C6 -alkoxy- _C1 - _C6 -alkoxy-, carbamoyl, carbamoyl- _C1 - _C6 -alkoxy-, formamidinyl, ( _C1 - _C6 -alkyl) _{2NC1 - C6} -alkoxy-, ( _C1 - _C6 -alkyl) _2NC1 - _C6 - _alkyl -C(O)-NH- _C1 - _C6 -alkoxy-, _C2 - _C6 -alkynyl-NH-, carboxyl, and _C1 - _C6 -alkoxy; and

^R5 , q, B, ^L1 , and ^L2 are as defined in this paper.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein ^R1 is a group and ^R5 , q, B, ^L1 and ^L2 are as defined herein.

In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein ^L1 is selected from _-CH2O- , -( _CH2 ) _sC (O)-, _-CH2NHC (O)-, _-CH2C (O)NH-, _-CH2- , -NHC(O)-, -S(O) _2- , -S(O) _2NH- , -C(O)NH( _CH2 ) _2- and -NH-NHC(O)-.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein ^L1 is selected from carbonyl, _-CH2C (O)-, _-CH2NHC (O)- and -NHC(O)-.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein ^L2 is selected from covalent bonds, carbonyl groups, -S(O) _2- , -NHC(O)-, -C(O)NH- and -S(O) _2NH- .

In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein q is 0, 1 or 2.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein q is 0 or 1.

In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein s is 0, 1 or 4.

In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein B is selected from 3- to 14-membered heterocyclic groups, _C3 - _C10 -cycloalkyl groups, and 5- to 14-membered heteroaryl groups.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein B is a 3- to 14-membered heterocyclic group.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein B is selected from aziridine, pyrrolidinyl, 3-azirbicyclo[3.1.0]hexyl and piperidinyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein ^R5, each time appearing, is independently selected from amino, hydroxy, _C1 - _C6 -alkyl, amino- _C1 - _C6 -alkyl-, hydroxy- _C1 - _C6 -alkyl-, ( _C1 - _C6 -alkyl) _2N- , ( _C1 - _C6 -alkyl) _{2NC1 - C6} -alkyl-, ( _C1 - _C6 -alkyl) _2NC1 - _{C6 -} alkyl-C(O)-, oxo, carbamoyl, carbamoyl- _C1 - _C6 -alkyl, carboxyl, carboxyl- _C1 - _C6 -alkyl, halogen, aminoalkyl-S(O) _2- and groups wherein ^R6 , r, C and ^L3 are as defined herein.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein ^R5 is independently selected from amino, hydroxyl and hydroxy- _C1 - _C6 -alkyl- each time it appears.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein ^R5 is independently selected from amino, hydroxy and hydroxymethyl each time it appears.

In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein ^L3 is a covalent bond or a carbonyl group.

In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein r is 0 or 1.

In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein C is a _C3 - _C10 cycloalkyl or a 3- to 14-membered heterocyclic group.

In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein ^R6 is a hydroxyl group.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, wherein:

m is 1; and

^R1 is selected from amino, amino- _C1 - _C6 -alkoxy-, group, and group _C1 - _C6 -alkyl- ^L2- ; wherein:

The _C1 - _C6 -alkyl group is substituted with one or two substituents selected from the following: hydroxyl, amino, cyano, _C1 - _C6 -alkyl-NH-, ( _C1 - _C6 -alkyl) _2N- , amino- _C1 - _C6 -alkoxy- _C1 - _C6 -alkoxy-, carbamoyl, carbamoyl- _C1 - _C6 -alkoxy-, formamidinyl, ( _C1 - _C6 -alkyl) _{2NC1 - C6} -alkoxy-, ( _C1 - _C6 -alkyl) _2NC1 - _C6 - _alkyl -C(O)-NH- _C1 - _C6 -alkoxy-, _C2 - _C6 -alkynyl-NH-, carboxyl, and _C1 - _C6 -alkoxy.

L ¹ is selected from -CH ₂ O-, -(CH ₂ ) _s C(O)-, -CH ₂ NHC(O)-, -CH ₂ C(O)NH-, -CH ₂ -, -NHC(O)-, -S(O) ₂ -, -S(O) ₂ NH-, -C(O)NH(CH ₂ ) ₂ - and -NH-NHC(O)-;

^L2 is selected from covalent bonds, carbonyl groups, -S(O) _2- , -NHC(O)-, -C(O)NH-, and -S(O) _2NH- ;

q is 0, 1, or 2;

s is 0, 1, or 4;

B is selected from 3- to 14-membered heterocyclic groups, _C3 - _C10 -cycloalkyl groups, and 5- to 14-membered heteroaryl groups; and

R ^5, in each occurrence, is independently selected from amino, hydroxyl, _C1 - _C6 -alkyl, amino- _C1 - _C6 -alkyl-, hydroxy- _C1 - _C6 -alkyl-, ( _C1 - _C6 -alkyl) _2N- , ( _C1 - _C6 -alkyl) _2NC1 - _{C6 -} alkyl-, ( _C1 - _{C6 -} alkyl) _2NC1 - _C6 -alkyl-C(O)-, oxo, carbamoyl, carbamoyl- _C1 - _C6 -alkyl, carboxyl, carboxyl- _C1 - _C6 -alkyl, halogen, aminoalkyl-S(O) _2- , and groups wherein:

^L3 is a covalent bond or a carbonyl group;

r is 0 or 1;

C is a _C3 - _C10 cycloalkyl or a 3- to 14-membered heterocyclic group; and

^R6 is a hydroxyl group.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, wherein:

m is 1; and

^R1 is a group where:

^L1 is selected from carbonyl, _-CH2C (O)-, _-CH2NHC (O)- and -NHC(O)-;

q is 0 or 1;

B is a 3- to 14-membered heterocyclic group; and

^R5 is selected from amino, hydroxyl, and hydroxy- _C1 - _C6 -alkyl-.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, wherein:

m is 1; and

^R1 is a group where:

^L1 is selected from carbonyl, _-CH2C (O)-, _-CH2NHC (O)- and -NHC(O)-;

q is 0 or 1;

B is selected from aziridine, pyrrolidinyl, 3-azirbicyclo[3.1.0]hexyl, and piperidinyl; and

^R5 is selected from amino, hydroxy, and hydroxymethyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein n is 1 and ^R2 is selected from halogens and _C1 - _C6 -alkyl groups.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein n is 1 and ^R2 is selected from chlorine and methyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, wherein the compound of formula (I) is a compound of formula (II):

^R1 , ^R2 , ^R3 and ^R4 , m and p are as defined in this paper.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein ^R3 is a _C1 - _C6 -alkyl group.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein ^R3 is methyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein p is 1, 2, 3 or 4, and ^R4 is independently selected each time it appears from halogen, _C1 - _C6 -alkyl, _C1 - _C6 -alkoxy, cyano, halo- _{C1 - C6} -alkyl, cyano- _C1 - _C6 -alkyl, ( _C1 -C6-alkyl) _2N- , halo- _C1 - _C6 -alkoxy, _{cyano - C1} - _C6 -alkoxy, C1-C6-alkoxy- _C1 - _C6 -alkoxy-, ( _C1 - _C6 -alkyl) _2NC (O)- and heteroaryloxy.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein p is 2 or 3 and ^R4 is independently selected from _C1 - _C6 -alkoxy, halo- _C1 - _C6 -alkoxy and cyano- _C1 - _C6 -alkoxy each time it appears.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein p is 2 or 3 and ^R4 is independently selected from fluorine, chlorine, methoxy, _FCH₂O– , _F₂CHO– and _CNCH₂O– each time it appears.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, wherein the compound of formula (I) is a compound of formula (III):

in:

R ^4a is selected from hydrogen, halogen, _C1 - _C6 -alkyl, cyano, and halo- _C1 - _C6 -alkyl;

R ^4b is selected from hydrogen, halogen, cyano, and _C1 - _C6 -alkoxy groups;

R ^4c is selected from halogens, _C1 - _C6 -alkoxy groups, cyano- _C1 - _C6 -alkyl groups, cyano- _C1 - _C6 -alkoxy groups, ( _C1 - _C6 -alkyl) _2N- groups, halo- _C1 - _C6 -alkoxy groups, _C1 - _C6 -alkoxy- _C1 - _C6 -alkoxy groups, ( _C1 - _C6 -alkyl) _2NC (O)- groups, and heteroaryloxy groups;

R ^4d is selected from hydrogen and halogens; and

^R1 , ^R2 , ^R3 , m, and n are as defined in this paper.

In a preferred embodiment, the present invention provides a compound of formula (III) as described herein, or a pharmaceutical salt thereof, wherein:

R ^4a is a halogen;

R ^4b is selected from hydrogen and halogens;

^R4c is selected from _C1 - _C6 -alkoxy, cyano- _C1 - _C6 -alkoxy, and halo- _C1 - _C6 -alkoxy; and

R ^4d is hydrogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (III) as described herein, or a pharmaceutical salt thereof, wherein:

R ^4a is selected from fluorine and chlorine;

R ^4b is selected from hydrogen, fluorine, and chlorine;

R ^4c is selected from methoxy, FCH ₂ O-, F ₂ CHO-, and CNCH ₂ O-; and

R ^4d is hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, wherein:

m is 1; and

^R1 is selected from amino, amino- _C1 - _C6 -alkoxy-, group, and group _C1 - _C6 -alkyl- ^L2- ; wherein:

The _C1 - _C6 -alkyl group is substituted with one or two substituents selected from the following: hydroxyl, amino, cyano, _C1 - _C6 -alkyl-NH-, ( _C1 - _C6 -alkyl) _2N- , amino- _C1 - _C6 -alkoxy- _C1 - _C6 -alkoxy-, carbamoyl, carbamoyl- _C1 - _C6 -alkoxy-, formamidinyl, ( _C1 - _C6 -alkyl) _{2NC1 - C6} -alkoxy-, ( _C1 - _C6 -alkyl) _2NC1 - _C6 - _alkyl -C(O)-NH- _C1 - _C6 -alkoxy-, _C2 - _C6 -alkynyl-NH-, carboxyl, and _C1 - _C6 -alkoxy.

L ¹ is selected from -CH ₂ O-, -(CH ₂ ) _s C(O)-, -CH ₂ NHC(O)-, -CH ₂ C(O)NH-, -CH ₂ -, -NHC(O)-, -S(O) ₂ -, -S(O) ₂ NH-, -C(O)NH(CH ₂ ) ₂ - and -NH-NHC(O)-;

^L2 is selected from covalent bonds, carbonyl groups, -S(O) _2- , -NHC(O)-, -C(O)NH-, and -S(O) _2NH- ;

q is 0, 1, or 2;

s is 0, 1, or 4;

B is selected from 3- to 14-membered heterocyclic groups, _C3 - _C10 -cycloalkyl groups, and 5- to 14-membered heteroaryl groups; and

R ^5, in each occurrence, is independently selected from amino, hydroxyl, _C1 - _C6 -alkyl, amino- _C1 - _C6 -alkyl-, hydroxy- _C1 - _C6 -alkyl-, ( _C1 - _C6 -alkyl) _2N- , ( _C1 - _C6 -alkyl) _2NC1 - _{C6 -} alkyl-, ( _C1 - _{C6 -} alkyl) _2NC1 - _C6 -alkyl-C(O)-, oxo, carbamoyl, carbamoyl- _C1 - _C6 -alkyl, carboxyl, carboxyl- _C1 - _C6 -alkyl, halogen, aminoalkyl-S(O) _2- , and groups wherein:

^L3 is a covalent bond or a carbonyl group;

r is 0 or 1;

C is a _C3 - _C10 cycloalkyl or a 3- to 14-membered heterocyclic group;

^R6 is a hydroxyl group;

n is 1;

^R2 is selected from halogens and _C1 - _C6 -alkyl groups;

^R3 is a _C1 - _C6 -alkyl group;

p is 1, 2, 3, or 4; and

^R4 is independently selected each time it appears from halogen, _C1 - _C6 -alkyl, _C1 - _C6 -alkoxy, cyano, halo- _C1 - _C6 -alkyl, cyano- _C1 - _C6 -alkyl, ( _C1 - _C6 -alkyl) _2N- , halo- _C1 - _C6 -alkoxy, cyano- _C1 - _C6 -alkoxy, _C1 - _C6 -alkoxy- _C1 - _C6 -alkoxy-, ( _C1 - _C6 -alkyl) _2NC (O)- and heteroaryloxy.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, wherein:

m is 1; and

^R1 is a group where:

^L1 is selected from carbonyl, _-CH2C (O)-, _-CH2NHC (O)- and -NHC(O)-;

q is 0 or 1;

B is a 3- to 14-membered heterocyclic group; and

R ⁵ is selected from amino, hydroxyl, and hydroxy- _C1 - _C6 -alkyl-

n is 1;

^R2 is selected from halogens and _C1 - _C6 -alkyl groups;

^R3 is a _C1 - _C6 -alkyl group;

p is 2 or 3; and

^R4 is independently selected from halogen, _C1 - _C6 -alkoxy, halogenated- _C1 - _C6 -alkoxy, and cyano- _C1 - _C6 -alkoxy each time it appears.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, wherein:

m is 1; and

^R1 is a group where:

^L1 is selected from carbonyl, _-CH2C (O)-, _-CH2NHC (O)- and -NHC(O)-;

q is 0 or 1;

B is selected from aziridine, pyrrolidinyl, 3-azirbicyclo[3.1.0]hexyl, and piperidinyl; and

R ⁵ is selected from amino, hydroxy, and hydroxymethyl groups;

n is 1;

^R2 is selected from chlorine and methyl;

^R3 is a methyl group;

p is 2 or 3; and

^R4 is independently selected from fluorine, chlorine, methoxy, _FCH2O- , _F2CHO- and _CNCH2O- each time it appears.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, wherein the compound of formula (I) is selected from:

N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[3-(dimethylamino)propyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;

N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[2-(aminomethyl)morpholine-4-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[(2S,4S)-4-aminopyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2S)-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2S)-piperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(3S)-piperidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(2-aminoethyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(methylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2R)-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-(3-amino-2-hydroxy-propyl)-1-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide;

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-N-[3-methyl-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(3S)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(1,1-dioxo-1,4-thiazinyl-4-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-N-[3-methyl-4-[4-[2-(methylamino)acetyl]piperazine-1-carbonyl]phenyl]imidazol-2-carboxamide;

N-[3-chloro-4-[4-(morpholin-4-carbonyl)piperidin-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-N-[3-methyl-4-[4-(morpholin-4-carbonyl)piperidine-1-carbonyl]phenyl]imidazol-2-carboxamide;

N-[3-chloro-4-[4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazolium-2-carboxamide;

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[4-(1,1-dioxo-1,4-thiazin-4-carbonyl)piperidine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[(2R)-2-(aminomethyl)morpholine-4-carbonyl]piperidine-1-carbonyl]-3-methyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(thiomorpholine-4-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(3-aminoazacyclobutane-1-carbonyl)piperidine-1-carbonyl]-3-methyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(aminomethyl)piperidin-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(5-hydroxypiperidin-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-(2-Aminoethyl)-4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide;

N-[3-chloro-4-(4-piperazin-1-ylsulfonylpiperidin-1-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-[[(2S)-pyrrolidine-2-carbonyl]amino]ethyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[(2S)-2-(aminomethyl)morpholine-4-carbonyl]piperidine-1-carbonyl]-3-methyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(4-piperidinylsulfonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[2-[(2-amino-2-oxo-ethyl)amino]ethyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

(3R)-1-[2-[4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]pyrrolidine-3-carboxylic acid;

1-[2-[4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]azacyclobutane-3-carboxylic acid;

5-[3-chloro-4-(cyanomethoxy)-2-fluoro-phenyl]-N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[racemic-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazolium-2-carboxamide;

N-[4-[4-(2-aminoethyl)piperidin-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(3-hydroxypyrrolidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-3-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[2-(azacyclobutane-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-N-[3-chloro-4-[4-[2-[(3S)-pyrrolidine-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide;

5-[2-chloro-4-(difluoromethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[2-[(3S)-pyrrolidine-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(4-hydroxypyrrolidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidine-3-yl]methyl]piperidine-4-carboxamide;

N-[4-[4-(2-aminoacetyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[(2S)-azacyclobutane-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(2-pyrrolidone-1-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(2-pyrrolidone-3-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-[(2R)-pyrrolid-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-[(3R)-pyrrolidone-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-[(2S)-pyrrolid-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidine-3-yl]methyl]piperidine-4-carboxamide;

1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[[(3S)-pyrrolidine-3-yl]methyl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidin-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3-hydroxyazacyclobutane-3-yl)methyl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-[2-[(2S)-pyrrolid-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-[(3S)-pyrrolidone-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-[(2S)-pyrrolid-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(3-hydroxyazacyclobutane-3-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[1-(2-aminoethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(azacyclobutane-3-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(pyrrolidone-3-ylmethyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidine-3-yl]piperidine-4-carboxamide;

1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[racemic-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-yl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(dimethylamino)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide;

5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[2-[(3S)-pyrrolidine-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-(2,3,5-trifluoro-4-methoxy-phenyl)imidazol-2-carboxamide;

1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[racemic-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-yl]piperidine-4-carboxamide;

N-[4-[3-(2-aminoethoxy)azacyclobutane-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidine-3-yl]methyl]piperidine-4-carboxamide;

5-[2-chloro-4-(difluoromethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(4-ethoxy-2,3-difluoro-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(5-hydroxypiperidin-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

5-[2-chloro-4-(difluoromethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[1-(azacyclobutane-3-carbonyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-3-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-(azacyclobutane-2-ylmethyl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-[2-(3-hydroxyazacyclobutane-3-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[2-(azacyclobutane-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[1-(4-hydroxypiperidin-4-carbonyl)piperidin-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-[(2S)-pyrrolid-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-3-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R)-pyrrolidine-3-yl]piperidine-4-carboxamide;

1-[2-chloro-4-[[5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidine-3-yl]piperidine-4-carboxamide;

5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-5-(4-ethoxy-2,3-difluoro-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[3-[3-(aminomethyl)azacyclobutane-1-carbonyl]azacyclobutane-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

3-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]propionic acid;

4-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]butyric acid;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazin-1-carbonyl]phenyl]-5-[4-(dimethylcarbamoyl)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[racemic-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide;

N-[4-[4-[3-(aminomethyl)cyclobutanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(2-amino-2-oxo-ethyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[racemic-(3aR,6aS)-5-(piperidin-4-carbonyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolo-2-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(3-hydroxyazacyclobutane-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]azacyclobutane-3-yl]piperidine-4-carboxamide;

N-[3-chloro-4-[3-(piperazin-1-carbonyl)azacyclobutane-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[racemic-(3aR,6aS)-5-[racemic-(3R)-pyrrolidine-3-carbonyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolo-2-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide;

N-[3-chloro-4-[3-[[2-(dimethylamino)acetyl]amino]azacyclobutane-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[3-[racemic-(3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrolo-5-carbonyl]azacyclobutane-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide;

N-[3-chloro-4-[racemic-(3aS,6aR)-2-[2-(dimethylamino)acetyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-(2,3,4-trifluorophenyl)imidazol-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(3-cyano-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[3-[racemic-(3aR,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrolo-5-carbonyl]pyrrolidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(3-cyano-2,4-difluoro-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-[(3S)-pyrrolidone-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-[[2-(dimethylamino)acetyl]amino]piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

1-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]-2-ethyl-benzoyl]-N-[3-(prop-2-ynylamino)propyl]piperidine-4-carboxamide;

5-(2,3-Difluoro-4-methoxy-phenyl)-N-[4-[4-[4-[4-[3-(dimethylamino)propyl]piperazine-1-carbonyl]piperidine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazol-2-carboxamide;

N-(2-aminoethyl)-1-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]-2-ethyl-benzoyl]piperidine-4-carboxamide;

1-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]-2-ethyl-benzoyl]-N-[2-[2-(dimethylamino)ethoxy]ethyl]piperidine-4-carboxamide;

5-[4-(difluoromethoxy)phenyl]-N-[4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazol-2-carboxamide;

5-(2-chloro-4-methoxy-phenyl)-N-[4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-5-(3-fluoro-4-isopropoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[(3-cyclobutyl-1,2,4-oxadiazol-5-yl)methyl]piperidin-1-carbonyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide;

4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide;

4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide;

N-[3-chloro-4-[4-[(3S,4S)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2S,4S)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

4-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]-2-methyl-benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide;

N-[3-chloro-4-[4-[(2S,4S)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[4-[(2S,4S)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazolium-2-carboxamide;

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[4-[(2S,4S)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazolium-2-carboxamide;

N-[3-chloro-4-[4-[(3R,4S)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

5-(2,3-Difluoro-4-methoxy-phenyl)-N-[4-[4-[(3R,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(3R,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide;

N-[3-chloro-4-(piperazin-1-carbonyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(4-guanidinobutyryl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(3-aminopropionyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(5-aminopentanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(3-cyanopropionyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(3-aminopropionylamino)piperidin-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-(azacyclobutane-3-yl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide;

N-[4-[4-[(1S,3R)-3-aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(2-aminoethylsulfonylamino)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-(4-piperidinyl)piperidin-4-carboxamide;

1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-(4-pyridylmethyl)piperidine-4-carboxamide;

5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4R)-4-fluoropyrrolidine-3-yl]piperidine-4-carboxamide;

5-[3-chloro-2-fluoro-4-(fluoromethoxy)phenyl]-N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazolium-2-carboxamide;

1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4R)-4-fluoropyrrolidine-3-yl]piperidine-4-carboxamide;

1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[[(3S)-pyrrolidine-3-yl]methyl]piperidine-4-carboxamide;

N-[4-[4-(2-aminoethoxy)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(azacyclobutane-3-ylmethoxy)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(4-aminobutyryl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[(2S)-2-aminopropyl]-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide;

N-[4-[4-[1-(2-aminoethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[1-[2-(dimethylamino)acetyl]piperidin-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[4-[4-(4-hydroxypiperidin-4-carbonyl)piperazin-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(4-aminopiperidin-1-carbonyl)piperidin-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-[(3S)-pyrrolid-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2-(difluoromethyl)-3-fluoro-4-methoxy-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(pyrrolidone-3-ylsulfonylamino)piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidine-3-yl]methyl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-(4-piperidinylsulfonylamino)piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-[3-(dimethylamino)azacyclobutane-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(3-carbamoylpyrrolidine-1-carbonyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-(azacyclobutane-3-ylmethyl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide;

N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[1-(2-aminoethylsulfonyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-(azacyclobutane-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide;

N-[3-chloro-4-(4-methylsulfonylpiperazine-1-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(methanesulfonylamino)piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(2-aminoethylsulfonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(2-oxoimidazolidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[3-(2-aminoethyl)azacyclobutane-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2-pyrrolidone-3-ylacetyl)amino]piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-[(3S)-pyrrolid-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[3-fluoro-4-(fluoromethoxy)-2-methyl-phenyl]-1-methyl-imidazol-2-carboxamide;

5-[3-chloro-2-fluoro-4-(fluoromethoxy)phenyl]-N-[4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[(3S,4S)-3-amino-4-fluoro-pyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-(4-pyrrolidine-3-ylsulfonylpiperazine-1-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(3-aminobicyclo[1.1.1]pentane-1-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[[(1-methyl-4-piperidinyl)amino]carbamoyl]piperidin-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-[(3S)-pyrrolid-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2-cyano-3-fluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(5-oxopyrrolidone-3-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[3-(dimethylamino)propionylamino]piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

5-[3-chloro-4-(cyanomethoxy)phenyl]-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-(4-piperidinylmethyl)piperidin-4-carboxamide;

N-[4-[4-[3-(aminomethyl)azacyclobutane-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(methylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(3-aminoazacyclobutane-1-carbonyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]amino]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[3-[2-(2-aminoethoxy)ethoxy]propionyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(5-oxopyrrolidone-2-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(5-oxopyrrolidine-2-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-(4-aminopiperidin-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(methylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(6-oxopiperidin-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(2-azaspiro[3.3]heptane-6-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-5-(2-chloro-3-fluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[(2R,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazolium-2-carboxamide;

N-[3-chloro-4-[6-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]-2-azaspiro[3.3]heptane-2-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[3-[2-[[2-(dimethylamino)acetyl]amino]ethoxy]propionyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

5-(2-chloro-3-fluoro-4-methoxy-phenyl)-1-methyl-N-[3-methyl-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]imidazol-2-carboxamide;

N-[3-chloro-4-[3-[[[racemic-(3R)-pyrrolidine-3-carbonyl]amino]pyrrolidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[(1S)-2-amino-1-methyl-ethyl]-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]pyrrolidine-3-yl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-[(3S)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[2-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-2,6-diazaspiro[3.3]heptane-6-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2-fluoro-3,4-dimethoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothiopheno[3,4-d]imidazol-4-yl]valeryl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(2,5-dioxoimidazolidine-4-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[3-[3-(2-aminoethoxy)propionylamino]pyrrolidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

2-[4-[4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidinyl]acetic acid;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(2-methoxyethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(2-pyridinoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(4-pyridinoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(3,4-difluoro-5-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-pyrimidin-2-yloxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethyl)-2-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-9-methoxy-6,7-dihydro-5H-imidazo[5,1-a][2]benzoza-3-carboxamide;

N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-(azacyclobutane-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide;

5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[3-(2-aminoethoxy)propionyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidine-3-yl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-[2-[(2S)-pyrrolid-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

N-(2-aminoethyl)-1-[2-chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide;

N-(2-aminoethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide;

1-[2-chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-(4-piperidinyl)piperidin-4-carboxamide;

1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R)-pyrrolidine-3-yl]piperidine-4-carboxamide;

1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-(4-piperidinyl)piperidin-4-carboxamide;

1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[2-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R)-pyrrolidine-3-yl]piperidine-4-carboxamide;

N-[4-[3-[[3-(aminomethyl)cyclobutanecarbonyl]amino]azacyclobutane-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[3-[(2-aminoacetyl)amino]azacyclobutane-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-(3-carbamoylcyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(3-hydroxycyclobutanecarbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(3-methoxypropionyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[3-(3-amino-3-oxo-propoxy)propionyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; and

N-[4-[4-(5-amino-5-oxo-pentanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutical salt thereof, wherein the compound of formula (I) is selected from:

N-[3-chloro-4-[4-[racemic-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide;

5-[3-chloro-2-fluoro-4-(fluoromethoxy)phenyl]-N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazolium-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-(azacyclobutane-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-(2-pyrrolidone-3-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[2-(azacyclobutane-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide;

4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide;

1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-[2-[(3S)-pyrrolidone-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

5-[3-chloro-2-fluoro-4-(fluoromethoxy)phenyl]-N-[4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide;

N-[3-chloro-4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[4-[4-[2-(azacyclobutane-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-(azacyclobutane-3-ylmethyl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-[2-[(2S)-pyrrolid-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide;

N-[4-[4-[(2S,4S)-4-aminopyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide;

N-[3-chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-(azacyclobutane-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide;

N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

N-[3-chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide;

4-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]-2-methyl-benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide; and

5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazol-2-carboxamide.

In one embodiment, the present invention provides pharmaceutical salts of compounds of formula (I) as described herein, particularly those selected from hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid), and trifluoroacetate. In yet another specific embodiment, the present invention provides compounds according to formula (I) as described herein (i.e., referred to as "free base" or "free acid," respectively).

In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms 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 this disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, ^2H , ^3H , ^11C , ^13C , ^14C , ^13N , ^15N , ^15O , ^17O , ^18O , ^31P , ^32P , ^35S , ^18F , ^36Cl , ^123I , and ^125I . Certain isotopically labeled compounds of formula (I) (e.g., those containing radioisotopes) can be used for pharmaceutical and/or matrix tissue distribution studies. Radioactive isotopes tritium (i.e., ^3H ) and carbon-14 (i.e., ^14C ) are particularly useful for this because they are readily incorporated and detection methods are readily available. For example, compounds of formula (I) can be enriched with a given isotope of 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99%.

Replacing with a heavier isotope (such as deuterium, i.e., ^2H ) can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

The positron emission tomography (PET) studies that can be used to examine substrate acceptor occupancy are replaced with positron emission tomography (PET) studies using positron emission tomography isotopes (such as ^11C , ^18F , ^15O , and ^13N ). Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the examples presented below, using an appropriate isotopically labeled reagent instead of the previously used unlabeled reagent.

Preparation process

The preparation of compounds of formula (I) of the present invention can be carried out via a continuous or aggregate synthetic route. The synthesis of the compounds of the present invention is illustrated in the following scheme. The skills required for the reactions and purification of the resulting products are known to those skilled in the art. Unless otherwise stated, the substituents and notations used in the description of the following processes have the meanings given earlier herein. More specifically, compounds of formula (I) can be prepared by the methods given below, by the methods given in the examples, or by similar methods. Appropriate reaction conditions for each reaction step are known to those skilled in the art. Likewise, for information on reaction conditions reported in the literature affecting the reactions described, see, for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition, Richard C. Larock, John Wiley & Sons, New York, NY. 2018. We have found it convenient to carry out the reactions with or without a solvent. There are no particular limitations on the nature of the solvent used, as long as it does not adversely affect the reaction or the reagents involved and is at least partially capable of dissolving the reagents. The described reactions can occur over a wide temperature range, and precise reaction temperatures are not critical to the present invention. It is convenient to carry out the described reaction within a temperature range of -78°C to the reflux temperature. The reaction time required can also vary considerably, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, 0.5 hours to several days is generally sufficient to produce the described intermediates and compounds. The reaction sequence is not limited to that shown in the protocol; however, the order of reaction steps can be freely varied depending on the starting materials and their respective reactivity. The starting materials are commercially available or can be prepared by methods similar to those given below, by methods described in the specification or in the references cited in the examples, or by methods known in the art.

Unless otherwise stated, all substituents, especially ^R2 to ^R4, are as defined above. Furthermore, unless otherwise explicitly stated, all reactions, reaction conditions, abbreviations, and symbols have meanings commonly known to those skilled in the art of organic chemistry.

Option 1

Ra is an alkyl group, particularly Me, Et, or isobutyl.

Type I intermediate can be prepared according to Scheme 1. 5-Bromo-1-methyl-imidazolium can be acylated with isobutyl chloroformate under basic conditions (such as a DCM solution of DIPEA) to give Ia (step a). Acid Ib can be obtained by hydrolyzing Ia at room temperature using a suitable base and a suitable solvent (e.g., an aqueous solution of _K₂CO₃ and _EtOH ) (step b). Ib and amine Ic are amide-coupled with a condensing agent (such as CDI, DCC, HATU, HBTU, _T₃P ) in a suitable solvent (such as DMF, DMA, or dioxane) optionally in the presence of a base (e.g., _NET₃ , DIPEA, or DMAP) to give intermediate type I (step c).

Option 2

Ra is an alkyl group, particularly Me, Et, or isobutyl.

Wherein “structural unit X” is a cyclic amine with or without PG, and “PG” represents a suitable protecting group, such as a Cbz or Boc protecting group.

Intermediate VI or Example I can be prepared according to route 1 in Scheme 2. Intermediate I is hydrolyzed at room temperature using a suitable base and a suitable solvent (e.g., an EtOH/aqueous solution of LiOH or NaOH) to give intermediate II (step 1a). This intermediate is coupled with an amide of structural unit X and structural unit Y (intermediate XIII) using, for example, the method described in step 3b of Scheme 3, and then the PG of Y is deprotected (if necessary) to give intermediate IX or Example II (step 2a).

In route 3, the acid compound (intermediate type IV) can be amide-coupled with structural unit X-Y (intermediate type VII) using methods known in the art, such as those described in step C of scheme 1. The PG of X-Y is then deprotected (if necessary) to obtain intermediate type IX or example type II compound, using methods known in the art and, for example, those described in step 1C of scheme 2 (step 3a).

Compounds of type III can be prepared according to the three routes outlined in Scheme 3.

Option 3

Where X is a cyclic amine with or without PG, and "PG" represents a suitable protecting group, such as a Cbz or Boc protecting group.

The structural unit Q is an amine with or without PG, where "PG" represents a suitable protecting group, such as a Cbz or Boc protecting group.

In Route 2, the structural unit Y-Q is an acid (Y)-amine (Q) compound with or without PG, where “PG” represents a suitable protecting group, such as a Cbz or Boc protecting group.

In Route 3, the structural unit X-Y-Q is a haloalkane (Y) compound with or without PG, which is attached to two amines (X-cyclic amine and Q), where “PG” represents a suitable protecting group, such as a Cbz or Boc protecting group.

In route 1, the removal of the protecting group from intermediate type IX (if necessary) can be achieved by applying methods known in the art and, for example, the method described in step 1C of scheme 2. Then, amide coupling is performed with structural unit Q (Ig) using, for example, the method described in step 3b of scheme 3, to obtain example type III (step 1a).

In route 2, the removal of the protecting group from intermediate type VI (if necessary) can be achieved by applying methods known in the art and, for example, the method described in step 1C of scheme 2. Then, amide coupling is performed with structural unit Y-Q (intermediate type X) using, for example, the method described in step 3b of scheme 3, to obtain example type III (step 2a).

In route 3, the amide coupling between the acid compound (intermediate type IV) and the structural unit X-Y-Q (intermediate type VIII) can be achieved using, for example, the method described in step 3b of scheme 3. The protecting group is then removed (if necessary) to obtain example type III, applying methods known in the art and, for example, the method described in step 1C of scheme 2.

In one aspect, the present invention provides a method for preparing the compound of formula (I) described herein, wherein the method is as described in any one of embodiments 1 to 5 above.

In another aspect, the present invention provides a pharmaceutical salt of the compound of formula (I) described herein, prepared according to the method disclosed herein.

Using the compounds of the present invention

As shown in the experimental section, the compound of formula (I) and its medicinal salts have valuable pharmacological properties for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, especially species of Acinetobacter, and most particularly Acinetobacter baumannii, particularly bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

Compounds of formula (I) and their pharmaceutical 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.

Compounds of formula (I) and their pharmaceutical salts can be used as antibiotics, i.e., as antimicrobial drug components suitable for the treatment and prevention of bacterial infections, especially bacterial infections caused by species of Acinetobacter, and even more particularly for the treatment and prevention of bacterial infections caused by Acinetobacter baumannii.

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

In one aspect, the present invention provides compounds of formula (I) as described herein, or pharmaceutical salts thereof, which are used as therapeutically active substances.

In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, which is used as an antibiotic.

In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, for the treatment or prevention of hospital-acquired infections and the resulting diseases.

In a particular implementation, the hospital infection and the resulting disease are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection or a combination thereof.

In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, for the treatment or prevention of infections and diseases caused by Gram-negative bacteria.

In a particular embodiment, the infection caused by Gram-negative bacteria and the resulting disease are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection or a combination thereof.

In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, for the treatment or prevention of infections and diseases caused by Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof.

In another aspect, the present invention provides a method for treating or preventing infections and diseases caused by Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof, the method comprising administering to a mammal a compound of formula (I) as described herein or a pharmaceutical salt thereof.

In another aspect, the present invention provides the use of compounds of formula (I) as described herein, or pharmaceutical salts thereof, as antibiotics.

On the other hand, the present invention provides the use of compounds of formula (I) as described herein or pharmaceutical salts thereof for the treatment or prevention of infections and diseases caused by Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof.

In another aspect, the present invention provides the use of compounds of formula (I) as described herein or pharmaceutical salts thereof for the preparation of medicaments for the treatment or prevention of infections and diseases caused by Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof.

In a particular embodiment, the infection and the resulting disease caused by Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or a combination thereof are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection or a combination thereof.

On the other hand, the present invention provides compounds of formula (I) as defined above or pharmaceutical salts thereof for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more particularly species of Acinetobacter, and most particularly Acinetobacter baumannii, especially bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

On the other hand, the present invention provides a method for treating or preventing infections and diseases caused by pathogens, particularly bacteria, more particularly species of Acinetobacter, especially Acinetobacter baumannii, particularly bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, the method comprising administering to a mammal a compound of formula (I) as defined above or a pharmaceutical salt thereof.

On the other hand, the present invention provides the use of compounds of formula (I) as defined above, or pharmaceutical salts thereof, for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more particularly species of Acinetobacter, and most particularly Acinetobacter baumannii, especially bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

On the other hand, the present invention provides the use of compounds of formula (I) as defined above, or pharmaceutical salts thereof, in the preparation of medicaments for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more particularly species of Acinetobacter, and most particularly Acinetobacter baumannii, especially bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections. Such medicaments comprise compounds of formula (I) as defined above, or pharmaceutical salts thereof.

Pharmaceutical composition and administration

In one aspect, the present invention provides pharmaceutical compositions comprising a compound of formula (I) as defined above, or a pharmaceutical salt thereof, and one or more pharmaceutical excipients. Exemplary pharmaceutical compositions are described in Examples A through D.

On the other hand, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) as defined above or a pharmaceutical salt thereof and one or more pharmaceutical excipients for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more particularly species of Acinetobacter, and most particularly Acinetobacter baumannii, especially bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

Compounds of formula (I) and their pharmaceutical salts can be used as medicines (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered orally, such as orally (e.g., in the form of tablets, coated tablets, sugar lozenges, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), intranasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration can also be made extraintestinally, such as intramuscularly or intravenously (e.g., in the form of injectable or infusion solutions).

Compounds of formula (I) and their pharmaceutical salts can be processed with pharmaceutically inert inorganic or organic excipients to produce tablets, coated tablets, sugar tablets, and hard gelatin capsules. Lactose, corn starch or their derivatives, talc, stearic acid or its salts, etc., can be used as excipients for tablets, sugar tablets, and hard gelatin capsules.

Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

Suitable excipients for the production of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, glucose, etc.

Suitable excipients for injection solutions include, for example, water, alcohol, polyol, glycerin, and vegetable oil.

Suitable excipients for suppositories include, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols.

In addition, pharmaceutical preparations may contain preservatives, solubilizers, thickeners, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for altering osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other substances with therapeutic value.

Dosage can vary within a wide range to suit the various requirements of each specific situation. Generally, a daily oral dose of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g., about 300 mg per person), should be appropriate, preferably divided into 1-3 individual doses (which may consist of, for example, the same amount). However, it will be apparent that, when indicated, the upper limits given herein may be exceeded.

Co-administration of compound (I) with other pharmaceutical agents

Compounds of formula (I) or salts thereof, or compounds disclosed herein or pharmaceutical salts thereof, may be used alone or in combination with other pharmaceutical agents for treatment. For example, a second agent in a pharmaceutical combination formulation or dosing regimen may have an activity complementary to that of a compound of formula (I) such that they do not adversely affect each other. Compounds may be administered together or separately in a single pharmaceutical composition. In one embodiment, a compound or pharmaceutical salt may be administered co-administered with an antibiotic, particularly with an antibiotic for the treatment or prevention of infections and diseases caused by Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

The term "co-administration" means the simultaneous or sequential administration of a compound of formula (I) or a salt thereof, or a compound disclosed herein or a pharmaceutically acceptable salt thereof, with one or more other active pharmaceutical ingredients (including antibiotics). If the administrations are not simultaneous, the compounds should be administered at approximately the same time interval. Furthermore, it is irrelevant whether the compounds are administered in the same dosage form; for example, one compound may be administered intravenously while another may be administered orally.

Generally, any agent with antimicrobial activity can be used together. Specific examples of such agents include carbapenems (meropenem), fluoroquinolones (ciprofloxacin), aminoglycosides (amikacin), tetracyclines (tigecycline), colistin, sulbactam, sulbactam + Durlobactam, cefdil (Fetroja), macrocyclic peptides (as illustrated in WO2017072062 A1, WO 2019185572 A1 and WO 2019206853 A1), and macrolides (erythromycin).

In one aspect, the present invention provides pharmaceutical compositions described herein that further comprise additional therapeutic agents.

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

In one embodiment, the additional therapeutic agent is an antibiotic for treating or preventing infections and diseases caused by Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof.

In one embodiment, the additional therapeutic agent is an antibiotic selected from carbapenems (meropenem), fluoroquinolones (ciprofloxacin), aminoglycosides (amikacin), tetracyclines (tigecycline), colistin, sulbactam, sulbactam + Durlobactam, cefdil (Fetroja), macrocyclic peptides (as illustrated in WO 2017072062 A1, WO 2019185572 A1 and WO 2019206853 A1), and macrolides (erythromycin).

Example

The invention will be more fully understood by referring to the following embodiments. However, the claims should not be construed as limiting the scope of the embodiments.

In the case of preparation examples obtained as mixtures of enantiomers, pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art (such as chiral chromatography (e.g., chiral SFC) or crystallization).

Unless otherwise stated, all reaction examples and intermediates were prepared under an argon atmosphere.

The abbreviations used in this article are as follows:

ACN or MeCN Acetonitrile

BINAP 2,2'-bis(diphenylphosphine)-1,1'-binaphthylene

CFU (colony forming unit)

d day

DCM (Dichloromethane)

DIPEA (N,N-diisopropylethylamine)

EtOAc or EA Ethyl acetate

FA Formic acid

h(s)or hr(s) hours

HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium

3-Hexafluorophosphate

HPLC: High Performance Liquid Chromatography

HPLC-UV: High-performance liquid chromatograph with ultraviolet detector

IC50 (Half-maximum inhibition concentration)

IC90 90% Inhibition Concentration

PE (petroleum ether)

_PdCl₂ (DPPF)[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro

_Pd₂ (dba) _₃tris (dibenzylacetone)dipalladium(0)

PG (Protecting Group)

Precat (Pre-catalyst)

prep-HPLC (Preparative High Performance Liquid Chromatography)

RBF round-bottom flask

rt Room temperature

sat saturation

SEM: 2-Methoxyethyl(trimethyl)silane

FA Formic acid

TFA (Trifluoroacetic acid)

wt

X-PHOS 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

Intermediate Type I: 308

4-[(5-bromo-1-methylimidazol-2-carbonyl)amino]-2-chlorobenzoate methyl ester

Step 1: Isobutyl 5-bromo-1-methyl-imidazolium-2-carboxylate

A solution of isobutyl chloroformate (22.1 g, 161 mmol) in DCM (60 mL) was slowly added dropwise over 30 minutes to a solution of 5-bromo-1-methyl-1H-imidazolium (20 g, 124 mmol) and DIPEA (32.1 g, 43.4 mL, 248 mmol) in 140 mL of DCM. The reaction mixture was stirred at -70 °C for 2 hours, then slowly heated to room temperature and stirred overnight. The solution was then washed with water and concentrated under vacuum. The crude product was then purified by rapid column chromatography to give a yellow oily solution of isobutyl 5-bromo-1-methyl-1H-imidazolium-2-carboxylate (29 g, 89.4% yield). MS (ESI, m/z): 261.2 [M+H] ⁺

Step 2: 5-Bromo-1-methyl-imidazol-2-carboxylic acid

A solution of lithium hydroxide monohydrate (9.32 g, 222 mmol) in water (60 mL) was added to a solution of 5-bromo-1-methyl-1H-imidazolium-2-carboxylic acid (29 g, 111 mmol) in MeOH (5 mL) and THF (120 mL). The mixture was stirred at room temperature for 3 hours. The organic solvent was removed under reduced pressure. 12N HCl aqueous solution was added with stirring until the pH reached 4–5. The white solid was filtered, washed with MeOH, and dried to give 5-bromo-1-methyl-imidazolium-2-carboxylic acid (20.5 g, 90% yield) as a white solid. MS (ESI, m/z): 204.8 [M+H] ⁺

Step 3: Methyl 4-[(5-bromo-1-methylimidazol-2-carbonyl)amino]-2-chlorobenzoate

A mixture of 5-bromo-1-methyl-1H-imidazol-2-carboxylic acid (13 g, 63.4 mmol), methyl 2-chloro-4-(methylamino)benzoate (11.8 g, 63.4 mmol), HATU (24.1 g, 63.4 mmol), and DIPEA (24.6 g, 33.2 mL) in DMF (30 mL) was stirred overnight at room temperature. The mixture was then poured into water. The aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phases were washed with water, dried over _{anhydrous Na₂SO₄} , and concentrated under vacuum. A solid precipitated from the concentrated solution. The solid was collected, washed with MeOH, and dried to give a pale yellow solid of methyl 4-[(5-bromo-1-methyl-imidazol-2-carbonyl)amino]-2-chlorobenzoate (18 g, 76% yield). MS (ESI, m/z): 371.8 [M+H] ^⁺

Similar to intermediate 308, the following type I intermediates were prepared.

Intermediate Type II: 313

4-[(5-bromo-1-methylimidazol-2-carbonyl)amino]-2-chlorobenzoic acid

A solution of lithium hydroxide monohydrate (2.57 g, 61.2 mmol) in water (24 mL) was added to a solution of methyl 4-[(5-bromo-1-methylimidazol-2-carbonyl)amino]-2-chlorobenzoate (7.6 g, 20.4 mmol) in MeOH (2 mL) and THF (48 mL). The mixture was stirred overnight at room temperature. The mixture was then concentrated, and the aqueous layer was acidified with 6N HCl aqueous solution. A solid precipitated from the concentrated solution. The solid was collected, washed with water, and dried to give a white solid of 4-[(5-bromo-1-methylimidazol-2-carbonyl)amino]-2-chlorobenzoic acid (6 g, 82% yield). MS (ESI, m/z): 358.0 [M+H] ⁺

Similar to intermediate 313, the following type II intermediates were prepared.

Intermediate type III: 315

2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane

Step 1: 1-Bromo-4-(difluoromethoxy)-2,3-difluorobenzene

A solution of 4-bromo-2,3-difluorophenol (25 g, 120 mmol), sodium 2-chloro-2,2- _{difluoroacetate} (36.5 g, 239 mmol), and _K₂CO₃ (19.8 g, 144 mmol) in DMF (250 mL) and water (57 mL) was stirred at 100 °C for 3.0 h under _N₂ . The reaction mixture was poured into 1.5 L _H₂O and extracted with EtOAc (3 x 250 mL). The organic layers were combined, washed with saturated NaCl (1 x 200 mL), _dried over _Na₂SO₄ , and concentrated under vacuum. The crude material was purified by rapid chromatography (silica gel, 120 g, PE solution of 0% to 20% DCM) to give 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene (25.2 g, 97.3 mmol, 81.3% yield).

Step 2: 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane

Add a solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane) (24.5 g, 96.5 mmol), 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene (25 g, 96.5 mmol), _PdCl₂ (DPPF) _{-CH₂Cl₂ adduct} (3.53 g, 4.83 mmol), and potassium acetate (18.9 g, 193 mmol) in dioxane (150 mL) to 250 mL of RBF. Stir the mixture at 80 °C under _N₂ for 15 hours. Concentrate the crude reaction mixture under vacuum. Pour the reaction mixture into 50 mL of _H₂O and extract with EtOAc (3 x 50 mL). Combine the organic layers and wash with saturated NaCl (1 x 50 mL). Dry the organic layers _{with Na₂SO₄} and concentrate under vacuum. The crude material was purified by rapid chromatography (silica gel, 330 g, PE solution of 0% to 20% DCM) to give 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (25 g, 81.7 mmol, 84.6% yield).

Similar to intermediate 315, the following type III intermediates were prepared.

Intermediate type III: 319

2-[2,3-Difluoro-4-(fluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane

Step 1: 1-Bromo-2,3-difluoro-4-(fluoromethoxy)benzene

Add a 3 mL solution of 4-bromo-2,3-difluorophenol (150 mg, 718 μmol, equivalent: 1), fluoromethyl 4-methylbenzenesulfonate (176 mg, 861 μmol), and _Cs₂CO₃ (351 mg, 1.08 mmol) in DMF to a 5 mL microwave _- safe vial. Cap the vial and microwave overnight at 90 °C. Pour the reaction mixture into 50 mL of _H₂O and extract with EtOAc (3 x 25 mL). Combine the organic layers, wash with saturated NaCl (1 x 50 mL ₎ , dry with _Na₂SO₄ , and concentrate under vacuum to give 1-bromo-2,3-difluoro-4-(fluoromethoxy)benzene (153 mg, 635 μmol, 88.4% yield).

Step 2:

2-[2,3-Difluoro-4-(fluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane

Add a solution of bis(pinacol)diboron (161 mg, 635 μmol), 1-bromo-2,3-difluoro-4-(fluoromethoxy)benzene (153 mg, 635 μmol), _PdCl₂ (DPPF) _-CH₂Cl₂ adduct (46.5 mg, 63.5 μmol ₎ , and potassium acetate (125 mg, 1.27 mmol) in dioxane (3 mL) to a 5 mL microwave-safe vial. Place the vial under nitrogen atmosphere, cap, and microwave at 80 °C overnight. Concentrate the crude reaction mixture under vacuum. Pour the reaction mixture into 25 mL of _H₂O and extract with EtOAc (3 x 25 mL). The organic layers were combined, washed with saturated NaCl (1 x 25 mL), dried with _Na₂SO₄ and concentrated under vacuum to give 2-[2,3-difluoro- _4- (fluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxoborane (180 mg, 625 μmol, 98.4% yield).

Similar to intermediate 319, the following type III intermediates were prepared.

Intermediate type III: 322

4,4,5,5-Tetramethyl-2-(2,3,5-trifluoro-4-methoxy-phenyl)-1,3,2-dioxane

Step 1: 4-Bromo-2,3,6-Trifluorophenol

In a 100 mL round-bottom flask, 2,3,6-trifluorophenol (215 mg, 1.45 mmol) was mixed with _CHCl3 (10 mL) to provide a colorless solution. NBS (284 mg, 1.6 mmol) was added at 0 °C. The reaction was heated to room temperature with stirring for 2 hours. The crude reaction mixture was concentrated under vacuum to give 4-bromo-2,3,6-trifluorophenol (330 mg, 1.45 mmol, 100% yield), which was used directly in the next step. (ESI, m/z): 227.0 [MH]-.

Step 2: 1-Bromo-2,3,5-trifluoro-4-methoxybenzene

In a 100 mL round-bottom flask, 4-bromo-2,3,6-trifluorophenol ( ₃₃₀ mg, 1.45 mmol), MeI (413 mg, 182 μl, 2.91 mmol), and _K₂CO₃ (301 mg, 2.18 mmol) were mixed with acetonitrile (10 mL) to give a pale yellow solution. The reaction mixture was heated to 50 °C and stirred for 2 hours. The reaction mixture was filtered through glass fiber paper. The crude material was purified by rapid chromatography to give 1-bromo-2,3,5-trifluoro-4-methoxybenzene (220 mg, 913 μmol, 62.8% yield).

Step 3: 4,4,5,5-Tetramethyl-2-(2,3,5-trifluoro-4-methoxy-phenyl)-1,3,2-dioxane

Add a solution of 1-bromo-2,3,5-trifluoro-4-methoxybenzene (220 mg, 913 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane) (255 mg, 1 mmol), _Pd₂ (dba) _₃ (83.6 mg, 91.3 μmol), X-PHOS (87 mg, 183 μmol), and potassium acetate (269 mg, 171 μl, 2.74 mmol) in dioxane (10 mL) to a ₁₀₀ mL microwave-safe vial. Place the vial under nitrogen, cap it, and microwave at 100 °C for 2 hours. The reaction mixture is used directly in the next step without further purification.

Intermediate type III: 323

2,3-Difluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)aniline

Step 1: 4-Bromo-2,3-difluoro-N,N-dimethylaniline

In a 100 mL round-bottom flask, 4-bromo-2,3-difluoroaniline (300 mg, 1.44 mmol), formaldehyde (433 mg, 397 μl, 14.4 mmol), and formic acid (6.64 g, 5.53 mL, 144 mmol) were mixed to obtain a pale red solution. The reaction mixture was heated to 50 °C and stirred for 3 hours. The crude reaction mixture was concentrated under vacuum. The reaction mixture was poured into 50 _mL of saturated NaHCO3 and extracted with EtOAc (3 x 25 mL). The organic layers were combined, washed with saturated NaCl (1 x 25 mL), dried over _{Na2SO4 ,} and concentrated under vacuum. The crude material was purified by rapid chromatography to give 4-bromo-2,3-difluoro-N,N-dimethylaniline (270 mg, 1.14 mmol, 79.3% yield). (ESI, m/z): 238.0 [M+H]+.

Step 2: 2,3-Difluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)aniline

In a 100 mL round-bottom flask, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane) (70.5 mg, 277 μmol), 4-bromo-2,3-difluoro-N,N-dimethylaniline (65.5 mg, 277 μmol), _PdCl₂ (DPPF) _{-CH₂Cl₂ adduct} (20.3 mg, 27.7 μmol), and potassium acetate (81.7 mg, 832 μmol) were mixed with dioxane (12 mL) and heated under _N₂ to give a light brown solution. The reaction mixture was heated to 100 °C and stirred for 5 hours. The reaction mixture was used directly in the next step.

Intermediate type III: 324

2,3-Difluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzamide

Step 1: 4-Bromo-2,3-difluoro-N,N-dimethylbenzamide

In a 100 mL round-bottom flask, 4-bromo-2,3-difluorobenzoic acid (300 mg, 1.27 mmol), dimethylamine (in THF) (1.9 mL, 3.8 mmol), and DIEA (327 mg, 442 μl, 2.53 mmol) were mixed with DMF (5 mL) to obtain a colorless solution. HATU (578 mg, 1.52 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 100 mL of _H₂O and extracted with EtOAc (3 x 25 mL). The organic layers were combined, washed with saturated NaCl ( ₁ x 25 mL), dried over _Na₂SO₄ , and concentrated under vacuum to give 4-bromo-2,3-difluoro-N,N-dimethylbenzamide (334 mg, 1.26 mmol, 99.9% yield). (ESI, m/z): 264.0 [M+H]⁺.

Step 2: 2,3-Difluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzamide

Add a 6 mL solution of dioxane containing bis(pinacol)diboron (70.7 mg, 278 μmol), 4-bromo-2,3-difluoro-N,N-dimethylbenzamide (70 mg, 265 μmol), _Pd₂ (dba) _₃ (24.3 mg, 26.5 μmol), X-PHOS (25.3 mg, 53 μmol), and potassium acetate (78 mg, 795 μmol) to a 25 mL microwave-safe vial. Cap the vial and microwave at 100 °C for 3 hours under _N₂ . Use the reaction mixture directly for the next step.

Intermediate type III: 325

2-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy]acetonitrile

Step 1: 2-(4-bromo-2-chloro-phenoxy)acetonitrile

A mixture of 4-bromo-2-chlorophenol (3 g, 14.5 mmol), 2-bromoacetonitrile (2.08 g, _17.4 mmol), and _K₂CO₃ (3 g, 21.7 mmol) in acetone (30 mL) was stirred at 60 °C for 3 hours and then filtered. The solid was washed with EtOAc. The organic phase was washed with water, dried, and concentrated to give the title compound as a yellow oil (3.5 g, 98.2% yield).

Step 2: 2-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy]acetonitrile

A mixture of 2-(4-bromo-2-chlorophenoxy)acetonitrile (3.5 g, 14.2 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1,3,2-dioxane (3.61 g, 14.2 mmol), potassium acetate (2.79 g, 28.4 mmol), and a 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex (1.74 g, 2.13 mmol) in 1,4-dioxane (30 mL) was stirred overnight at 80 °C. The mixture was then concentrated. Water (10 mL) was added. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the residue was purified by rapid column chromatography to give the title compound (2.8 g, 67.2% yield). MS(ESI, m/z): 293.7 [M+H]+

Similar to intermediate 325, the following type III intermediates were prepared:

Intermediate type IV: 341

2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoic acid

Step 1: Methyl 2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoate (intermediate V type)

A mixture of methyl 4-[(5-bromo-1-methylimidazolium-2-carbonyl)amino]-2-chlorobenzoate (intermediate 308, 1 g, 2.68 mmol), (2,3-difluoro-4-methoxyphenyl)boronic acid (504 _mg , 2.68 mmol), _Na₂CO₃ (853 mg, 8.05 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (350 mg, 537 μmol) in 1,4-dioxane solution (15 mL) and water (1.5 mL) was irradiated at 100 °C for 60 min in a microwave. This process was repeated a total of 8 times. The reaction mixtures were combined and concentrated under vacuum. Water (40 mL) was added. The aqueous phase was extracted with DCM. The combined organic phases were washed with water, dried over _{anhydrous Na₂SO₄} , and concentrated, and the solid was dried to give the title compound (8.3 mg) as a brown solid. MS(ESI, m/z): 435.9 [M+H] ⁺

Step 2: 2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoic acid

A solution of lithium hydroxide monohydrate (3.2 g, 76.2 mmol) in water (24 mL) was added to a solution of methyl 2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoate (8.3 g, 19 mmol) in MeOH (2 mL), THF (48 mL), and water (24 mL). The mixture was stirred overnight at room temperature. The mixture was then concentrated and acidified with 6N HCl under stirring until pH 3–4. Some solid precipitated from the concentrated solution. The solid was filtered and dried to give the title compound (7 g, 87%) as a brown solid. MS (ESI, m/z): 422.3 [M+H] ⁺

Similar to intermediate 341, the following type IV intermediates were prepared.

Intermediate type VI: 362

1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxylic acid

Step 1: Methyl 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxylate

A mixture of 2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoic acid (intermediate 341, 3 g, 7.11 mmol), methyl piperidine-4-carboxylate (1.22 g, 8.54 mmol), DIPEA (2.76 g, 3.73 mL, 21.3 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane 2,4,6-trioxide (3.39 g, 10.7 mmol) in DMF (10 mL) was stirred overnight at 25 °C. The mixture was then poured into water. The aqueous phase was extracted with DCM. The combined organic phases were dried over _{anhydrous Na₂SO₄} and concentrated to give the title compound (3 g, 77.1%) as a black oil. MS(ESI, m/z): 547.47 [M+H] ⁺

Step 2: 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxylic acid

A mixture of methyl 1-(2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamido)benzoyl)piperidin-4-carboxylate (3.5 g, 6.4 mmol) and lithium hydroxide monohydrate (1.07 g, 25.6 mmol) in THF (12 mL), water (6 mL), and MeOH (0.5 mL) was stirred overnight at room temperature. The mixture was then acidified with 6N HCl under stirring until pH 2–3. The mixture was concentrated, and the aqueous phase was extracted with DCM. The combined organic phases were washed with water, dried, and concentrated to give the title compound (2.8 g, 82% yield) as a black solid. MS (ESI, m/z): 533.60 [M+H] ⁺

Similar to intermediate 362, the following type VI intermediates were prepared:

Intermediate type VI: 373

N-[4-(4-aminopiperidin-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide

Step 1: N-[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-4-piperidinyl]tert-butyl carbamate

A mixture of piperidine-4-ylcarbamate tert-butyl ester (684 mg, 3.41 mmol), 2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoic acid (intermediate 341, 1.2 g, 2.85 mmol), HATU (1.3 g, 3.41 mmol), and DIPEA (1.1 g, 1.49 mL, 8.54 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. The mixture was then poured into water. The solid was collected and dried to give the title compound as a brown solid (1.5 g, 87.3% yield). MS (ESI, m/z): 604.3 [M+H] ⁺

Step 2: N-[4-(4-aminopiperidin-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide

A solution of N-[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-4-piperidinyl]tert-butyl carbamate (1.5 g, 2.48 mmol) in DCM (10 mL) and TFA (10 mL) was stirred for 1 hour at room temperature. The solution was alkalized with _NH₃ · _H₂O until pH 8–9 under ice cooling. The aqueous layer was extracted with DCM. The organic layer _was dried over anhydrous _Na₂SO₄ and concentrated to give the title compound (900 mg, 66%) as a black solid. MS (ESI, m/z): 504.2 [M+H] ^⁺

Similar to intermediate 373, the following type VI intermediates were prepared:

Intermediate type VI: 392

N-(3-chloro-4-(piperazin-1-carbonyl)phenyl)-5-(2,3-difluoro-4-(fluoromethoxy)phenyl)-1-methyl-1H-imidazol-2-carboxamide

Step 14-(2-chloro-4-(5-(2,3-difluoro-4-(fluoromethoxy)phenyl)-1-methyl-1H-imidazol-2-carboxamido)benzoyl)piperazine-1-carboxylic acid tert-butyl ester

Add a solution of tert-butyl 4-(4-(5-bromo-1-methyl-1H-imidazol-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxylate (1 g, 1.9 mmol), 2-(2,3-difluoro-4-(fluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (602 mg, 2.09 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (124 mg, 190 μmol), and _Na₂CO₃ (604 mg, 5.69 mmol) in _dioxane (18 mL)/water (3 mL) to a 25 mL microwave-safe vial. Cap the vial and microwave at 100 °C for 2 hours under _N₂ . Concentrate the crude reaction mixture under vacuum. The crude material was purified by rapid chromatography to give tert-butyl 4-(2-chloro-4-(5-(2,3-difluoro-4-(fluoromethoxy)phenyl)-1-methyl-1H-imidazol-2-carboxamido)benzoyl)piperazine-1-carboxylate (759 mg, 1.25 mmol, 65.8% yield). MS (ESI, m/z): 608.2 [M+H] ⁺

Step 2

Intermediate 392

N-(3-chloro-4-(piperazin-1-carbonyl)phenyl)-5-(2,3-difluoro-4-(fluoromethoxy)phenyl)-1-methyl-1H-imidazol-2-carboxamide

In a 100 mL round-bottom flask, tert-butyl 4-(2-chloro-4-(5-(2,3-difluoro-4-(fluoromethoxy)phenyl)-1-methyl-1H-imidazol-2-carboxamido)benzoyl)piperazine-1-carboxylate (759 mg, 1.25 mmol) was mixed with THF (8 mL) to give a dark brown solution. HCl (4.16 mL, 49.9 mmol) was added. The reaction was stirred at room temperature for 10 min. The crude reaction mixture was concentrated under vacuum to give N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-5-(2,3-difluoro-4-(fluoromethoxy)phenyl)-1-methyl-1H-imidazol-2-carboxamide (634 mg, 80% yield), which was used directly in the next step. MS (ESI, m/z): 508.2 [M+H] ⁺

Similar to intermediate 392, the following type VI intermediates were prepared:

Intermediate type VII: 402

N-[2-(4-piperidinoxy)ethyl]carbamate tert-butyl ester

Step 1: 4-[2-(tert-butoxycarbonylamino)ethoxy]piperidine-1-carboxylic acid benzyl ester

Sodium hydride (170 mg, 4.25 mmol) was added fractionally to a DMF (10 mL) solution of 4-hydroxypiperidine-1-carboxylate (500 mg, 2.13 mmol) at 0 °C. The reaction mixture was stirred for 30 min, and then 2,2-dioxide of 1,2,3-oxathiazolidin-3-carboxylate tert-butyl ester (474 mg, 2.13 mmol) was added. The reaction mixture was slowly heated to room temperature and stirred overnight. The reaction mixture was washed with brine and extracted with DCM. The organic layer was dried over _{anhydrous Na₂SO₄} and concentrated under vacuum to give 4-(2-((tert-butoxycarbonyl)amino)ethoxy)piperidine-1-carboxylate (760 mg, 94.5% yield). MS (ESI, m/z): 379.2 [M+H] ^⁺ .

Step 2: N-[2-(4-piperidinoxy)ethyl]carbamate tert-butyl ester

Pd(OH) _₂ (300 mg) was added to a solution of 4-(2-((tert-butoxycarbonyl)amino)ethoxy)piperidine-1-carboxylic acid benzyl ester (760 mg, 2.01 mmol) in EtOH (20 mL), and the reaction was stirred at room temperature under a hydrogen atmosphere for 6 hours. The mixture was filtered, and the filtrate was concentrated under vacuum to give tert-butyl (2-(piperidine-4-yloxy)ethyl)carbamate (320 mg, 65.2% yield). MS (ESI, m/z): 245.1 [M+H] ^⁺ .

Intermediate type VII: 403

3-(4-piperidinyloxymethyl)azacyclobutane-1-carboxylic acid tert-butyl ester

Step 1: tert-butyl 3-(4-piperidinyloxymethyl)azacyclobutane-1-carboxylate

At 0 °C, sodium hydride (320 mg, 8.01 mmol) was added fractionally to a DMF (10 mL) solution of tert-butyl 3-(hydroxymethyl)azacyclobutane-1-carboxylate (500 mg, 2.67 mmol). The reaction mixture was stirred for 30 min, followed by the addition of 4-fluoropyridine hydrochloride (357 mg, 2.67 mmol). The reaction mixture was slowly heated to 60 °C and stirred for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over _{anhydrous Na₂SO₄} and concentrated under vacuum to give tert-butyl 3-((pyridin-4-yloxy)methyl)azacyclobutane-1-carboxylate (600 mg, 85% yield). MS (ESI, m/z): 265.1 [M+H] ^⁺ .

Step 2: 3-[(1-phenylpyridin-1-onthiol-4-yl)oxymethyl]azacyclobutane-1-carboxylic acid tert-butyl; chloride

To a MeCN (10 mL) solution of tert-butyl 3-((pyridin-4-yloxy)methyl)azacyclobutane-1-carboxylate (600 mg, 2.27 mmol), (chloromethyl)benzene (287 mg, 2.27 mmol) was added. The reaction mixture was stirred at 70 °C for 15 h. The reaction mixture was cooled to room temperature and concentrated under vacuum to give 1-benzyl-4-((1-(tert-butoxycarbonyl)azacyclobutane-3-yl)methoxy)pyridin-1-chloroonium chloride (882 mg, 99.4% yield). MS (ESI, m/z): 355.2 [M] ⁺ .

Step 3: 3-[(1-benzyl-3,6-dihydro-2H-pyridin-4-yl)oxymethyl]azacyclobutane-1-carboxylic acid tert-butyl ester

Sodium borohydride (387 mg, 10.2 mmol) was added fractionally to a MeOH solution of 1-benzyl-4-((1-(tert-butoxycarbonyl)azacyclobutane-3-yl)methoxy)pyridine-1-chloroonium chloride (800 mg, 2.05 mmol) cooled in an ice bath. The reaction was slowly heated to room temperature and stirred overnight. The reaction was quenched with ammonium chloride and washed with brine. The mixture was extracted with EtOAc, and the organic layer was dried over anhydrous _Na₂SO₄ and concentrated under vacuum to give _tert -butyl 3-(((1-benzyl-1,2,3,6-tetrahydropyridine-4-yl)oxy)methyl)azacyclobutane-1-carboxylate (700 mg, 95.4% yield). MS (ESI, m/z): 359.2 [M+H] ^⁺ .

Step 4: tert-butyl 3-(4-piperidinyloxymethyl)azacyclobutane-1-carboxylate

Pd(OH) _₂ (350 mg) was added to a solution of tert-butyl 3-(((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)methyl)azacyclobutane-1-carboxylate (700 mg, 1.95 mmol) in 20 mL of EtOH. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give tert-butyl 3-((piperidin-4-yloxy)methyl)azacyclobutane-1-carboxylate (430 mg, 81.4% yield). MS (ESI, m/z): 271.2 [M+H] ^⁺ .

Intermediate type VII: 404

(2-(azacyclobutane-3-yloxy)ethyl)tert-butyl carbamate

Step 1: 3-(2-((tert-butoxycarbonyl)amino)ethoxy)azacyclobutane-1-carboxylic acid benzyl ester

In a 100 mL round-bottom flask, NaH (255 mg, 6.37 mmol) was mixed with DMF (15 mL) to obtain a colorless solution. Benzyl 3-hydroxyazacyclobutane-1-carboxylate (1.1 g, 5.31 mmol) was added at 0 °C. The reaction was stirred at 0 °C for 30 min, then at room temperature for 30 min. Then, tert-butyl 1,2,3-oxathiazolidinedione-3-carboxylate 2,2-dioxide (1.42 g, 6.37 mmol) was added at 0 °C. The reaction was stirred overnight at room temperature. The reaction mixture was poured into 50 mL of _H₂O and extracted with EtOAc (3 x 50 mL). The organic layers were combined and washed with saturated NaCl (1 x 50 mL). The organic layer was dried _{with Na₂SO₄} and concentrated under vacuum to give 3-(2-((tert-butoxycarbonyl)amino)ethoxy)azacyclobutane-1-carboxylic acid benzyl ester (1.86 g, 100% yield).

Step 2: (2-(azacyclobutane-3-yloxy)ethyl)tert-butyl carbamate

In a 100 mL round-bottom flask, benzyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)azacyclobutane-1-carboxylate (350 mg, 999 μmol) was mixed with MeOH (30 mL) to give a colorless solution. Pd-C (21.3 mg, 200 μmol) was added. The reaction mixture was purged three times with hydrogen and then stirred at room temperature for 1 hour. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under vacuum to give tert-butyl (2-(azacyclobutane-3-yloxy)ethyl)carbamate (122 mg, 56.5% yield). (ESI, m/z): 217.3 [M+H]+.

Intermediate type VII: 405

(R)-(1-(piperazin-1-carbonyl)pyrrolidine-3-yl)tert-butyl carbamate

Step 1: (R)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carbonyl)piperazine-1-carboxylic acid benzyl ester

A mixture of (R)-3-(Boc-amino)pyrrolidine (0.5 g, 2.68 mmol), 1-Cbz-piperazine (0.59 g, 2.68 mmol), triphosgene (0.48 g, 0.810 mmol), and triethylamine (0.93 mL, 6.71 mmol) in DMF (15 mL) was stirred at 25 °C for 16 hours. The mixture was added to water (50 _mL ) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous _Na₂SO₄ and concentrated under reduced pressure. The residue was then purified by rapid column chromatography to give the title compound (178 mg) as a white solid. MS (ESI, m/z): 433.2 [M+H] ^⁺ .

Step 2: (R)-(1-(piperazin-1-carbonyl)pyrrolidine-3-yl)tert-butyl carbamate

A methanol (10 mL) solution of 4-[3-(tert-butoxycarbonylamino)pyrrolidine-1-carbonyl]piperazine-1-carboxylate (148.0 mg, 0.340 mmol) and Pd/C (20.0 mg, 15% w/w) was stirred at 25 °C for 6 hours under a hydrogen atmosphere. After filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure to give the title compound (100 mg) as a white solid, which was used directly in the next step without any purification. MS (ESI, m/z): 299.2 [M+H] ⁺ .

Intermediate type VII: 406

4-(4-piperidinylsulfonyl)piperazine-1-carboxylic acid tert-butyl ester

Step 1: 4-[(1-benzyloxycarbonyl-4-piperidinyl)sulfonyl]piperazine-1-carboxylic acid tert-butyl ester

A mixture of N,N-diisopropylethylamine (0.69 mL, 3.93 mmol), 1-Boc-piperazine (439.56 mg, 2.36 mmol), and 4-chlorosulfonylpiperidine-1-carboxylic acid benzyl ester (0.5 g, 1.57 mmol) in DCM (10 mL) was stirred at 25 °C for 3 hours under nitrogen. Water (5 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was then purified by rapid column chromatography to give the title compound (570 mg) as a white solid. MS (ESI, m/z): 490.2 [M+H] ⁺ .

Step 2: 4-(4-piperidinylsulfonyl)piperazine-1-carboxylic acid tert-butyl ester

A methanol (20 mL) solution of Pd/C (100.0 mg, 18% w/w) and 4-[(1-benzyloxycarbonyl-4-piperidinyl)sulfonyl]piperazine-1-carboxylic acid tert-butyl ester (570 mg, 1.22 mmol) was stirred at 25 °C for 12 hours under a hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure to give a colorless oily title compound (455 mg). MS (ESI, m/z): 334.2 [M+H] ⁺ .

Similar to 406, prepare the following type VII intermediates:

Intermediate type VII: 409

methyl 3-(3-oxo-3-piperazin-1-yl-propoxy)propionate (409) and 3-methoxy-1-(piperazin-1-yl)prop-1-one (409a)

Step 1: 4-(3-hydroxypropionyl)piperazine-1-carboxylic acid benzyl ester

A mixture of 1-Cbz-piperazine (5.0 g, 22.7 mmol), 3-hydroxypropionic acid (3.07 g, 34.05 mmol), 1-propylphosphonic anhydride solution, 50 wt% ethyl acetate (28.89 g, 45.4 mmol), and N,N-diisopropylethylamine (9.88 mL, 56.75 mmol) in DCM (113.5 mL) was stirred at 25 °C for 16 h. The mixture was added to water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (2.91 g) as a brown oil. MS (ESI, m/z): 293.1 [M+H] ⁺ .

Step 2: 4-[3-(3-methoxy-3-oxo-propoxy)propionyl]piperazine-1-carboxylic acid benzyl ester and 4-(3-methoxypropionyl)piperazine-1-carboxylic acid benzyl ester

Methyl acrylate (0.93 mL, 10.26 mmol) was added to a mixture of 4-(3-hydroxypropionyl)piperazine-1-carboxylate (2.5 g, 8.55 mmol) and sodium methoxide (1386.01 mg, 25.66 mmol) in THF (42.76 mL). The mixture was stirred at 25 °C for 12 hours. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were concentrated under reduced pressure. The crude product was then purified by rapid column chromatography to give a mixture of the title compounds (732 mg) in a yellow oil.

Step 3: Methyl 3-(3-oxo-3-piperazin-1-yl-propoxy)propionate and 3-methoxy-1-(piperazin-1-yl)prop-1-one

A mixture of 4-[3-(3-methoxy-3-oxo-propoxy)propionyl]piperazine-1-carboxylate and 4-(3-methoxypropionyl)piperazine-1-carboxylate (732 mg) and Pd/C (73 mg, 10% w/w) in methanol (20 mL) was stirred for 48 hours under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give a mixture of brown, colloidal title compounds (476 mg).

Intermediate type VII: 410

3-Cyclobutyl-5-(piperidin-4-ylmethyl)-1,2,4-oxadiazole

Step 1: 4-((3-cyclobutyl-1,2,4-oxadiazol-5-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester

A solution of (Z)-N'-hydroxycyclobutanemidine (4.68 g, 41 mmol, equivalent: 0.99) in DMF (70 mL) and pyridine (6.85 g, 7 mL, 86.5 mmol, equivalent: 2.09) at 50 °C was added dropwise over 30 minutes to a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (isopropyl carbonate) anhydride (13.64 g, 41.4 mmol) in DMF (7 mL). The mixture was stirred at the same temperature for 1 hour. The pale yellow clear solution was then heated to 100 °C and stirred overnight. The mixture was evaporated and absorbed by an HM-N column, dried, and purified by rapid chromatography to give a colorless oil of tert-butyl 4-((3-cyclobutyl-1,2,4-oxadiazol-5-yl)methyl)piperidin-1-carboxylate (8.866 g, 27.5 mmol, 66.6% yield). MS (ESI, m/z): 266.2[M-tBu+H] ⁺ .

Step 2: 3-Cyclobutyl-5-(piperidin-4-ylmethyl)-1,2,4-oxadiazole

To a solution of tert-butyl piperidine-1-carboxylate (27.55 g, 85.7 mmol, equivalent: 1) in dichloromethane (240 mL), a solution of 4 M HCl in dioxane (85 mL, 340 mmol) was added dropwise over 1.5 hours, and the mixture was stirred at room temperature for 2.5 hours, followed by evaporation. As the product began to crystallize, evaporation was stopped, 300 mL of diethyl ether was added, and the mixture was stirred at room temperature for 30 minutes. White crystals were filtered off, washed twice with 100 mL of diethyl ether, and dried under reduced pressure to give white crystalline 3-cyclobutyl-5-(piperidin-4-ylmethyl)-1,2,4-oxadiazole (21.618 g, 83.9 mmol, 97.8% yield). MS (ESI, m/z): 222.2 [M+H] ⁺ .

Intermediate type VIII: 411

(2-Amino-2-oxoethyl)(2-(piperazin-1-yl)ethyl)tert-butyl carbamate

Step 1: 4-(2-(1,3-dioxoisoindoline-2-yl)ethyl)piperazine-1-carboxylic acid benzyl ester

A mixture of N-(2-bromoethyl)phthalimide (5.0 g, 19.68 mmol), 1-Cbz-piperazine (5.2 g, 23.61 mmol), and triethylamine (4.11 mL, 29.52 mmol) in THF (30 mL) was stirred at 70 °C for 14 hours. _H₂O (100 mL) was added to the mixture, and extraction was performed with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give the title compound (4.29 g) as a brown oil. MS (ESI, m/z): 394.2 [M+H] ^⁺ .

Step 2: Benzyl 4-(2-aminoethyl)piperazine-1-carboxylate

A mixture of 4-[2-(1,3-dioxoisoindoline-2-yl)ethyl]piperazine-1-carboxylate (4.26 g, 10.83 mmol) and hydrazine hydrate (1.28 g, 21.7 mmol) in ethanol (50 mL) was stirred at 80 °C for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.78 g) as a white solid, which could be used in the next step without further purification. MS (ESI, m/z): 264.2 [M+H] ⁺ .

Step 3: 4-(2-((2-amino-2-oxoethyl)(tert-butoxycarbonyl)amino)ethyl)piperazine-1-carboxylic acid benzyl trifluoroacetate

2-Bromoacetamide (0.79 g, 5.7 mmol) was added to a mixture of 4-(2-aminoethyl)piperazine-1-carboxylic acid benzyl ester (1.5 g, 5.7 mmol) and N,N-diisopropylethylamine (4.96 mL, 28.48 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at 25 °C for 14 hours. Di-tert-butyl dicarbonate (2.49 g, 11.39 mmol) was added to the mixture. The mixture was stirred at 25 °C for 14 hours. Water (30 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with a saturated aqueous solution of _NaHCO3 (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Kromasil-C18 100x 21.2 mm 5 μm; 5%–95% ACN in _H₂O solution, 0.1% TFA as eluent) to give the title compound (237 mg) as a white solid. MS (ESI, m/z): 421.2 [M+H] ^⁺ .

Step 4: (2-Amino-2-oxoethyl)(2-(piperazin-1-yl)ethyl)tert-butyl carbamate

A mixture of 4-[2-[(2-amino-2-oxo-ethyl)-tert-butoxycarbonyl-amino]ethyl]piperazine-1-carboxylic acid benzyl trifluoroacetate (237.0 mg, 0.560 mmol) and Pd/C (47.4 mg, 20% w/w) in methanol (10 mL) was stirred at 25 °C for 14 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give a brown, colloidal title compound (122 mg). MS (ESI, m/z): 287.2 [M+H] ⁺ .

Similar to 411, prepare the following type VIII intermediates:

Intermediate type IX: 413

N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide

Similar to Example 11, steps 1-2, the title compound was obtained from N-[3-chloro-4-(piperazin-1-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide (intermediate 374) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. MS (ESI, m/z): 601.3 [M+H] ⁺

Intermediate X type: 415

2-(3-tert-butoxycarbonylazonylbutan-1-yl)acetic acid

Step 1: 1-(2-benzyloxy-2-oxo-ethyl)azacyclobutane-3-carboxylic acid tert-butyl ester

Benzyl 2-bromoacetate (1.4 g, 6.11 mmol) was added to a DCM solution of tert-butyl 3-carboxylate hydrochloride (910 mg, 4.7 mmol) and N,N-diisopropylethylamine (2.05 mL, 11.75 mmol). The mixture was stirred at 25 °C for 5 hours. After removing the solvent under vacuum, the crude product was purified by column chromatography to give the title compound (980 mg) as a colorless oil. MS (ESI, m/z): 306.2 [M+H] ⁺ .

Step 2: 2-(3-tert-butoxycarbonylazonylbutane-1-yl)acetic acid

Pd/C (50.0 mg, 6% w/w) was added to a methanol (5 mL) solution of 1-(2-benzyloxy-2-oxo-ethyl)azacyclobutane-3-carboxylic acid tert-butyl ester (900 mg, 2.95 mmol) under a nitrogen atmosphere. The mixture was stirred at 25 °C for 18 hours under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum to give the title compound (660 mg) as a white solid. MS (ESI, m/z): 216.2 [M+H] ⁺ .

Similar to intermediate 415, the following X-type intermediates were prepared:

Intermediate XI type: 394

4-(4-(5-bromo-1-methyl-1H-imidazol-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester

At room temperature, a mixture of 4-[(5-bromo-1-methylimidazol-2-carbonyl)amino]-2-chlorobenzoic acid (intermediate 313, 5.2 g, 14.5 mmol), tert-butyl piperazine-1-carboxylate (3.24 g, 17.4 mmol), HATU (6.62 g, 17.4 mmol), and DIPEA (5.62 g, 7.6 mL, 43.5 mmol) in DMF (5 mL) was stirred for 2 hours. The mixture was then poured into water. The aqueous layer was extracted with DCM. The organic layer was washed with water, dried, and concentrated to give the title compound as a solid (6.5 g, 85.1% yield). MS (ESI, m/z): 526.1 [M+H] ⁺

Similar to intermediate 394, the following type XI intermediates were prepared.

Intermediate XI type: 418

5-Bromo-N-[3-chloro-4-(piperazin-1-carbonyl)phenyl]-1-methyl-imidazol-2-carboxamide

At room temperature, 12N HCl (10 mL) was added to a THF (50 mL) suspension of 4-[4-[(5-bromo-1-methylimidazol-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carboxylate tert-butyl ester (intermediate 394, 6.5 g, 12.3 mmol) (50 mL). After stirring for 1 hour, the solution was alkalized with _NH₃ · _H₂O . The aqueous phase was extracted with DCM. The organic layer was washed with water, dried, and concentrated to give the title compound (5 g, 95% yield) as a yellow solid. MS (ESI, m/z): 426.2 [M+H] ^⁺

Similar to intermediate 418, the following type XI intermediates were prepared.

Intermediate XI type: 420

1-[4-[(5-bromo-1-methylimidazol-2-carbonyl)amino]-2-chloro-benzoyl]piperidine-4-carboxylic acid

Step 1: Methyl 1-[4-[(5-bromo-1-methylimidazol-2-carbonyl)amino]-2-chloro-benzoyl]piperidine-4-carboxylate

A mixture of 4-(5-bromo-1-methyl-1H-imidazol-2-carboxamido)-2-chlorobenzoic acid (intermediate 313, 2.8 g, 7.81 mmol), methyl piperidine-4-carboxylate (1.34 g, 9.37 mmol), HATU (3.86 g, 10.2 mmol), and DIPEA (5.05 g, 6.82 mL, 39 mmol) in DMF (15 mL) was stirred overnight at 25 °C. The mixture was then poured into water. The aqueous phase was extracted with DCM. The organic phase was dried and concentrated to give the crude product (1.9 g, 50.3% yield). MS (ESI, m/z): 483.1 [M+H] ⁺

Step 2: 1-[4-[(5-bromo-1-methyl-1H-imidazol-2-carbonyl)amino]-2-chloro-benzoyl]piperidine-4-carboxylic acid methyl 1-(4-(5-bromo-1-methyl-1H-imidazol-2-carboxamido)-2-chlorobenzoyl)piperidine-4-carboxylic acid was stirred for 3 hours in a solution of THF (24 mL), water (12 mL), and MeOH (1 mL). The solution was then concentrated, and the aqueous layer was acidified with _CH3COOH . The aqueous layer was extracted with DCM. The organic layer was washed with water, dried, and concentrated to give the title compound as a yellow oil (1.6 g, 86.7% yield). MS (ESI, m/z): 469.2 [M+H] ⁺

Intermediate XII type: 421

3-[[[1-[4-[(5-bromo-1-methyl-imidazol-2-carbonyl)amino]-2-chloro-benzoyl]piperidine-4-carbonyl]amino]methyl]azacyclobutane-1-carboxylic acid tert-butyl ester

At room temperature, a mixture of 1-(4-(5-bromo-1-methyl-1H-imidazol-2-carboxamido)-2-chlorobenzoyl)piperidin-4-carboxylic acid (intermediate 420, 1.6 g, 3.41 mmol), tert-butyl 3-(aminomethyl)azacyclobutane-1-carboxylate (1.9 g, 10.2 mmol), DIPEA (1.32 g, 1.78 mL, 10.2 mmol), and HATU (1.94 g, 5.11 mmol) in DMF (15 mL) was stirred for 1 hour. The mixture was then poured into water and the aqueous phase was extracted with DCM. The organic phase was washed with water, dried, and concentrated. The residue was purified by rapid column chromatography to give the title compound (1.8 g, 82.8% yield) as a yellow oil. MS (ESI, m/z): 637.2 [M+H] ⁺

Similar to intermediate 421, the following type XII intermediates were prepared:

Intermediate type XII: 431

5-Bromo-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide

Route 1:

At room temperature, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane 2,4,6-trioxide (7.28 g, 22.9 mmol) was added to a mixture of 4-(5-bromo-1-methyl-1H-imidazol-2-carboxamido)-2-chlorobenzoic acid (intermediate 313, 4.1 g, 11.4 mmol), N,N-dimethyl-2-(piperazin-1-yl)ethyl-1-amine (2.7 g, 17.2 mmol), and DIPEA (4.43 g, 5.99 mL, 34.3 mmol) in DMF (10 mL). After stirring for 20 minutes, the reaction was complete. The mixture was poured into water. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried, and concentrated. The residue was freeze-dried to give the title compound as a white solid (5.2 g, 91.4% yield). MS(ESI, m/z): 496.8 [M+H] ⁺

Route 2:

Step 1: (4-amino-2-chloro-phenyl)-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]methyl ketone

(Intermediate 433)

O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.93 g, 2.45 mmol) was added to a DMF (10 mL) solution of 1-(2-dimethylaminoethyl)piperazine (0.35 g, 2.24 mmol), 4-amino-2-chlorobenzoic acid (0.35 g, 2.04 mmol), and N,N-diisopropylethylamine (0.71 mL, 4.08 mmol). The mixture was stirred at 30 °C for 3 h. The mixture was diluted with water (60 mL) and extracted with EtOAc (75 mL x 2). The organic layer was washed with brine (50 mL x 2), dried over sodium sulfate, filtered, and concentrated under vacuum to give the title compound as a light brown oil (600 mg, 1.93 mmol, 94.63% yield). MS (ESI, m/z): 311.1 [M+H] ⁺ .

Step 2: 5-Bromo-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide

(Intermediate 432)

O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (303.49 mg, 0.800 mmol) was added to a DMF (3 mL) solution of (4-amino-2-chloro-phenyl)-[4-[2-(dimethylamino)ethyl]piperazin-1-yl] ketone (295.64 mg, 0.950 mmol), 5-bromo-1-methylimidazol-2-carboxylic acid (150 mg, 0.730 mmol), and N,N-diisopropylethylamine (0.23 mL, 1.33 mmol). The mixture was stirred at 30 °C for 3 hours. The mixture was diluted with water (60 mL) and extracted with EtOAc (75 mL x 2). The organic layer was washed with brine (50 mL x 2), dried over sodium sulfate, filtered, and concentrated under vacuum to give the title compound as a light brown solid (70 mg, 0.140 mmol, 19.22% yield). MS (ESI, m/z): 499.0 [M+H] ⁺ .

Intermediate type XIII: 434

(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-4-methylpyrrolidine-2-carboxylic acid and (2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-4-methylpyrrolidine-2-carboxylic acid

(2S)-1-tert-butoxycarbonyl-4-oxo-pyrrolidine-2-carboxylic acid (2 g, 8.72 mmol) in THF (20 mL) was added dropwise at -20 °C under nitrogen atmosphere to a solution of 1.5 M lithium in diethyl ether (8.72 mL, 13.09 mmol). The resulting mixture was stirred at the same temperature for 1 h, and then further stirred at 25 °C for 11 h. The reaction mixture was added to an aqueous solution of 1 N hydrochloric acid (50 mL) under ice cooling, and then extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (FA) to yield two final compounds: a dark green solid, P1, (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-4-methylpyrrolidine-2-carboxylic acid (50 mg, 0.200 mmol, 2.34% yield), MS (ESI, m/z): 190.0 [M+H-56] ⁺ , and a grayish-white solid, P2, (2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-4-methylpyrrolidine-2-carboxylic acid (600 mg, 2.45 mmol, 28.04% yield), MS (ESI, m/z): 190.0 [M+H-56] ⁺ .

Intermediate type XIII: 436

(2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-4-ethylpyrrolidine-2-carboxylic acid and (2S,4R)-1-tert-butoxycarbonyl-4-ethyl-4-hydroxy-pyrrolidine-2-carboxylic acid

At -20 °C under a nitrogen atmosphere, ethyl magnesium bromide (7.27 mL, 21.81 mmol, 3 M in diethyl ether) was added dropwise to a THF (50 mL) solution of (2S)-1-tert-butoxycarbonyl-4-oxo-pyrrolidine-2-carboxylic acid (2 g, 8.72 mmol). The resulting mixture was stirred at the same temperature for 1 hour, and then stirred further at 25 °C for 10 hours. The reaction mixture was added to a 1 N hydrochloric acid aqueous solution (100 mL) under ice cooling, and then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (FA) to give two final compounds: title compound P1 (2S,4S)-1-tert-butoxycarbonyl-4-ethyl-4-hydroxypyrrolidine-2-carboxylic acid (0.8 g, 3.09 mmol, 35.36% yield), grayish-white solid, MS (ESI, m/z): 282.0 [M+Na]+, and title compound P2 (2S,4R)-1-tert-butoxycarbonyl-4-ethyl-4-hydroxypyrrolidine-2-carboxylic acid (0.2 g, 0.770 mmol, 8.84% yield), grayish-white solid, MS (ESI, m/z): 282.0 [M+Na] ⁺ .

Intermediate type XIII: 12

(3S,4R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine-4-carboxylic acid

Step 1: (3S,4R)-1-tert-butoxycarbonyl-3-hydroxy-pyrrolidine-4-carboxylic acid (12)

Lithium hydroxide (0.46 g, 19.21 mmol) was added to a methanol (20 mL)/THF (20 mL)/water (20 mL) solution of (3S,4R)-3-hydroxypiperidine-1,4-dicarboxylic acid 1-(tert-butyl)-4-ethyl ester (2.1 g, 7.68 mmol) and the reaction mixture was stirred at 30 °C for 12 h. The crude product was adjusted to pH 7 with 1 N HCl aqueous solution and then lyophilized to give the title compound as a grayish-white solid (2.4 g, 9.79 mmol, 76.42% yield). The crude product was used directly without further purification. MS (ESI, m/z): 190.0 [M+H-56] ⁺ .

Intermediate 437

(3S,4S)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine-4-carboxylic acid

(3S,4S)-1-tert-butoxycarbonyl-3-hydroxy-pyrrolidine-4-carboxylic acid can be prepared using CAS [2166250-53-7], similar to intermediate 12.

Instance Type I: 13

N-[4-(4-aminopiperidin-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide carboxylate

The crude product of N-[4-(4-aminopiperidin-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide (intermediate 373, 200 mg) was purified by preparative HPLC to give the title compound (50 mg). MS (ESI, m/z): 504.2 [M+H] ⁺

Similar to Example 13, the following Example I type was prepared.

Instance Type I: 17

N-[4-[4-(2-aminoethyl)piperidin-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide carboxylate

Step 1

N-[3-chloro-4-[4-[2-(methylamino)ethyl]piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide

In a 100 mL round-bottom flask, 2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carbamate)benzoic acid (200 mg, 474 μmol), (2-(piperidin-4-yl)ethyl)carbamate tert-butyl ester (141 mg, 616 μmol), and DIPEA (184 mg, 248 μl, 1.42 mmol) were mixed with DMF to obtain a light brown solution. 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane 2,4,6-trioxide (603 mg, 948 μmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into 50 mL of _H₂O and extracted with EtOAc (3 x 25 mL). The organic layers were combined and washed with saturated NaCl (3 x 25 mL). The organic layer was dried over _Na₂SO₄ and concentrated under vacuum to give tert- _butyl (2-(1-(2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carbamate)benzoyl)piperidin-4-yl)ethyl)carbamate (295 mg, 98.4% yield). MS (ESI, m/z): 632.1 [M+H]+.

Step 2

N-[4-[4-(2-aminoethyl)piperidin-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide carboxylate

In a 100 mL round-bottom flask, tert-butyl (295 mg, 467 μmol) of (2-(1-(2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamido)benzoyl)piperidin-4-yl)ethyl)carbamate (3 mL) was mixed with THF to give a pale yellow solution. 4 M HCl (3.5 mL, 14 mmol) was added to dioxane. The reaction was stirred at room temperature for 20 min. The crude reaction mixture was concentrated under vacuum. The crude material was purified by preparative HPLC to give N-(4-(4-(2-aminoethyl)piperidin-1-carbonyl)-3-chlorophenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamide carbamate (270 mg, 98.1% yield). MS(ESI,m/z): 532.2[M+H]+.

Similar to Example 17, the following Type II and Type III instances were prepared.

Example Type II: 28

N-[(1S)-2-amino-1-methyl-ethyl]-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide trifluoroacetate

Step 1: N-[(2S)-2-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]propyl]tert-butyl carbamate

At room temperature, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane 2,4,6-trioxide (358 mg, 1.13 mmol) was added to a mixture of 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidin-4-carboxylic acid (intermediate 362, 300 mg, 563 μmol), (S)-(2-aminopropyl)carbamate tert-butyl ester (98.1 mg, 563 μmol), and DIPEA (218 mg, 295 μl, 1.69 mmol) in DMF (2 mL). After stirring for 1 hour, the mixture was poured into water. The aqueous phase was extracted with DCM. The combined organic phases were concentrated, and the residue was used in the next reaction without further purification. MS(ESI, m/z): 689.1 [M+H] ⁺

Step 2: N-[(1S)-2-amino-1-methyl-ethyl]-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; 2,2,2-trifluoroacetic acid

At room temperature, a solution of (S)-(2-(1-(2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamido)benzoyl)piperidin-4-carboxamido)propyl)tert-butyl carbamate (TFA, 5 mL) and _CH₂Cl₂ ( ₅ mL) was stirred for 2 hours. The mixture was then concentrated. Water (10 mL) was added. The mixture was alkalized to pH 8-9 with _NH₃ · _H₂O . The aqueous phase was extracted with DCM. The organic phase was dried over anhydrous _Na₂SO₄ and concentrated. The residue was purified by preparative HPLC to give the title compound (61 mg). _MS (ESI, m/z): 589.4 [M+H] ^⁺

Similar to Example 28, prepare the following Type II or Type III examples, where deprotection step 2 is only applicable to intermediates derived from Boc-protected amines.

Example Type II: 11

N-[3-chloro-4-[4-[(2-pyrrolidone-3-ylacetyl)amino]piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide carboxylate

Step 1: 3-[2-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-4-piperidinyl]amino]-2-oxo-ethyl]pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of N-[4-(4-aminopiperidin-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide (intermediate 373, 200 mg, 397 μmol), 2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)acetic acid (182 mg, 794 μmol), HATU (226 mg, 595 μmol), and DIPEA (154 mg, 208 μl, 1.19 mmol) in DMF (5 mL) was stirred overnight. The mixture was then poured into water. The aqueous layer was extracted with DCM. The organic layer was washed with water, dried over _{anhydrous Na₂SO₄} , and concentrated under vacuum to give a crude product (200 mg), which was used directly for the next reaction. MS (ESI, m/z): 715.1 [M+H] ^⁺

Step 2: N-[3-chloro-4-[4-[(2-pyrrolidone-3-ylacetyl)amino]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide; formate

At room temperature, a mixture of 3-[2-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-4-piperidinyl]amino]-2-oxo-ethyl]pyrrolidine-1-carboxylate (200 mg, 280 μmol) in DCM (2 mL) and TFA (3 mL) was stirred for 1 hour. Under ice cooling, Et ₃ N was added with stirring until pH 8–9. Water (10 mL) was then added. The aqueous layer was extracted with DCM. The organic layer was concentrated to give a crude product, which was purified by preparative HPLC to give the title compound (62 mg). MS (ESI, m/z): 615.1 [M+H] ⁺

Similar to Example 11, prepare the following Type II or Type III instances.

Example Type II: 235

N-[3-chloro-4-[4-(4-piperidinylsulfonylamino)piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide carboxylate

Step 1: 4-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-4-piperidinyl]aminosulfonyl]tert-butyl piperidine-1-carboxylate

A mixture of N-[4-(4-aminopiperidin-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide (intermediate 373, 300 mg, 595 μmol), tert-butyl 4-(chlorosulfonyl)piperidin-1-carboxylate (253 mg, 893 μmol), and Et ₃ N (120 mg, 166 μl, 1.19 mmol) in DCM (5 mL) was stirred overnight. The organic layer was washed with water, dried over _{anhydrous Na₂SO₄} , and concentrated under vacuum to give a crude product (300 mg), which was used in the next step without further purification. MS (ESI, m/z): 750.8 [M+H] ^⁺

Step 2: N-[3-chloro-4-[4-(4-piperidinylsulfonylamino)piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide; formate

300 mg (399 μmol) of 4-(N-(1-(2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamido)benzoyl)piperidin-4-yl)aminosulfonyl)piperidin-1-carboxylic acid tert-butyl ester (TFA) was dissolved in DCM (5 mL) and TFA (5 mL). The solution was stirred for 2 hours. Under ice cooling, water (5 mL) was added, followed by Et ₃ N until pH 8–9. The aqueous layer was extracted with DCM. The organic layer was concentrated to give a crude product, which was purified by preparative HPLC to give the title compound (126 mg). MS (ESI, m/z): 651.0 [M+H] ⁺

Similar to Example 235, prepare the following Type II and Type III examples.

Example Type II: 243

N-[3-chloro-4-[4-[3-(methylamino)propionyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide

A mixture of N-(3-chloro-4-(piperazin-1-carbonyl)phenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamide (intermediate 374, 250 mg, 510 μmol), 2-chloro-N-methylethyl-1-amine (57.3 mg, 612 μmol), sodium iodide (76.5 mg, 510 _μmol ), and _K₂CO₃ (141 mg, 1.02 mmol) in DMF (2 mL) was stirred at 85 °C for 3 hours. The mixture was then poured into water. The aqueous layer was extracted with DCM. The organic layer was washed with water and concentrated. The residue was purified by preparative HPLC to give the title compound (42 mg). MS (ESI, m/z): 547.2 [M+H] ^⁺

Similar to Example 243, prepare the following Type II examples.

Example Type II: 245

N-(azacyclobutane-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide trifluoroacetate

Step 1: 3-[[[1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]methyl]azacyclobutane-1-carboxylic acid tert-butyl ester

A mixture of 3-((1-(4-(5-bromo-1-methyl-1H-imidazol-2-carboxamido)-2-chlorobenzoyl)piperidin-4-carboxamido)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester (intermediate 421, 530 mg, 831 μmol), 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (intermediate 315, 305 mg, 997 μmol), _Na₂CO₃ (440 mg, 4.15 mmol) _, and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (54.1 mg, 83.1 μmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was microwaved at 100 °C for 50 min. The mixture was then concentrated, and the residue was purified by rapid column chromatography to give the title compound as a yellow oil (400 mg, 65.3% yield). MS (ESI, m/z): 737.8 [M+H] ⁺

Step 2: N-(azacyclobutane-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; 2,2,2-trifluoroacetate

At room temperature, _CF3COOH (6 mL) was added to a solution of tert-butyl 3-[[[1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]methyl]azacyclobutane-1-carboxylate (400 mg, 543 μmol) in DCM (10 mL). The solution was stirred for 40 min. Under ice cooling, _NH3 · _H2O was added until pH 8–9 was reached. The solution was concentrated, and the aqueous layer was extracted with DCM. The organic layer was concentrated to give a crude product, which was purified by preparative HPLC to give the title compound (21 mg). MS (ESI, m/z): 637.3 [M+H] ⁺

Similar to Example 245, the following Type II examples were prepared:

Example Type II: 269

5-[3-chloro-4-(cyanomethoxy)phenyl]-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazolium-2-carboxamide trifluoroacetate

A mixture of 5-bromo-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazolium-2-carboxamide (intermediate 431, 200 mg, 402 μmol), 2-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenoxy]acetonitrile (intermediate 325, 118 mg, 402 μmol), _Na₂CO₃ (128 mg, 1.21 mmol) _, and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (26.2 mg, 40.2 μmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was irradiated at 100 °C for 1 hour in a microwave. The mixture was filtered and concentrated. Water was added, and the aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude product was purified by preparative HPLC to obtain the desired product (29 mg) as a light brown powder. MS (ESI, m/z): 584.3 [M+H] ⁺

Similar to Example 269, the following Type II examples were prepared:

Example Type II: 279

N-(4-(4-(3-(3-amino-3-oxopropoxy)propionyl)piperazine-1-carbonyl)-3-chlorophenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamide

Step 1: N-[3-chloro-4-[4-(3-methoxypropionyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide

A mixture of 2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoic acid (500.0 mg, 0.950 mmol), methyl 3-(3-oxo-3-piperazin-1-yl-propoxy)propionate and 3-methoxy-1-(piperazin-1-yl)prop-1-one (467 mg), N,N-diisopropylethylamine (0.41 mL, 2.37 mmol), and a solution of 1-propylphosphonic anhydride, along with 50 wt.% ethyl acetate (1207 mg, 1.9 mmol), in DMF (6 mL) was stirred at 25 °C for 16 hours. The mixture was then added to water (15 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated _NaHCO3 aqueous solution (15 mL), dried over _{anhydrous Na2SO4} , and concentrated under reduced pressure to give a brown, gelatinous crude product (637 mg). 200 mg of the crude product was purified by preparative HPLC (column: Kromasil-C18 100 x 21.2 mm 5 μm; 5%-95% ACN in _H2O solution, 0.1% FA as eluent). The desired fraction was lyophilized to give a white solid final compound, methyl 3-[3-[4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazin-1-yl]-3-oxo-propoxy]propionate (22 mg). MS (ESI, m/z): 576.2 [M+H] ⁺ ;

Step 2: N-(4-(4-(3-(3-amino-3-oxopropoxy)propionyl)piperazine-1-carbonyl)-3-chlorophenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamide

A mixture of methyl 3-[3-[4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazin-1-yl]-3-oxo-propoxy]propionate (220 mg, 0.34 mmol) and ammonia (5.0 mL, 0.340 mmol) was stirred at 40 °C for 12 hours. The mixture was added to water (100 mL) and extracted with ethyl acetate (50 mL × ₃ ). The combined organic layers were dried over anhydrous _Na₂SO₄ and concentrated under reduced pressure. The mixture was purified by preparative HPLC (column: Kromasil-C18 100 x 21.2 mm 5 μm; 5%-95% ACN in _H₂O solution, 0.1% FA as eluent) to give the title compound (61.2 mg) as a white solid. MS(ESI,m/z): 633.2[M+H] ⁺ .

Similar to Example 279, the following Type II examples were prepared:

Instance Type III: 281

N-(2-aminoethyl)-4-(2-chloro-4-(5-(4-(cyanomethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazol-2-carboxamido)benzoyl)piperazine-1-carboxamide 2,2,2-trifluoroacetate

Step 1:

(2-(4-(2-chloro-4-(5-(4-(cyanomethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazol-2-carboxamido)benzoyl)piperazine-1-carboxamido)cyclobutyl)tert-butyl carbamate

A solution of triethylamine (0.06 mL, 0.400 mmol), N-Boc-ethylenediamine (64.68 mg, 0.400 mmol), and triethylamine (0.06 mL, 0.400 mmol) in DMF (1.45 mL) was stirred at 25 °C for 1 hour. Then, a solution of N-[3-chloro-4-(piperazin-1-carbonyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1H-imidazol-2-carboxamide and a solution of 2,2,2-trifluoroacetic acid (124.13 mg, 0.200 mmol) in DMF (2 mL) were added. The reaction was quenched with water (20 _mL ), and the resulting solution was extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous _Na₂SO₄ and concentrated under vacuum to give the title compound (150 mg) as a pale brown solid. MS (ESI, m/z): 701.2[M+H] ⁺ .

Step 2:

N-(2-aminoethyl)-4-(2-chloro-4-(5-(4-(cyanomethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazol-2-carboxamido)benzoyl)piperazine-1-carboxamide 2,2,2-trifluoroacetate

A solution of N-[2-[[4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]amino]ethyl]tert-butyl carbamate (150 mg, 0.110 mmol) and trifluoroacetic acid (1.0 mL, 12.98 mmol) in DCM (5 mL) was stirred at 25 °C for 1 hour. After vacuum concentration, the residue was purified by preparative HPLC (column: Kromasil-C18 100 x 21.2 mm 5 μm; 5%-95% ACN in _H₂O solution, 0.1% TFA as eluent) to give the title compound (17 mg) as a white solid. MS (ESI, m/z): 601.2 [M+H] ^⁺ .

Similar to Example 281, the following Type III examples were prepared:

Instance Type III: 288

2-[4-[4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidinyl]acetic acid trifluoroacetic acid

Step 1: 2-[4-[4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidinyl]methyl acetate

A mixture of N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide (intermediate 413, 400 mg, 666 μmol), methyl 2-bromoacetate (122 mg, 799 μmol), and Et ₃ N (337 mg, 464 μl, 3.33 mmol) in acetonitrile (10 mL) was stirred at 85 °C for 2 hours and then concentrated. Water (5 mL) was added. The aqueous layer was extracted with DCM. The organic layer was washed with water, dried over anhydrous _Na₂SO₄ , and concentrated. The residue (400 mg) was used in the next step without further purification. _MS (ESI, m/z): 673.3 [M+H] ^⁺

Step 2: 2-[4-[4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidinyl]acetic acid trifluoroacetic acid

A solution of lithium hydroxide monohydrate (125 mg, 2.97 mmol) was added to a solution of methyl 2-[4-[4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidinyl]acetate (400 mg, 594 μmol) in THF (24 mL), MeOH (1 mL), and water (12 mL). The mixture was stirred overnight at room temperature. The mixture was then concentrated and acidified with HCl until pH 3–4. The aqueous layer was extracted with a 1:6 iPrOH:DCM mixture. The organic layer was concentrated, and the residue was purified by preparative HPLC to give the title compound (30 mg) as a white powder. MS (ESI, m/z): 659.3 [M+H] ⁺

Similar to Example 288, prepare the following Type III examples.

Instance Type III: 290

N-[4-[4-[1-(2-aminoethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide carboxylate

Step 1: N-[2-[4-[4-[2-fluoro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidinyl]ethyl]tert-butyl carbamate

In a 100 mL round-bottom flask, N-(3-chloro-4-(4-(piperidin-4-carbonyl)piperazin-1-carbonyl)phenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamide (55 mg, 91.5 μmol), tert-butyl (2-oxoethyl)carbamate (58.3 mg, 366 μmol), and sodium cyanoborohydride (28.8 mg, 458 μmol) were mixed with MeOH (5 mL) to obtain a colorless solution. The reaction mixture was heated to 40 °C and stirred for 1 hour. The crude reaction mixture was concentrated under vacuum. The reaction mixture was poured into 25 mL of saturated NaHCO3 and extracted with EtOAc (3 x 25 mL). The organic layer was dried _{with Na₂SO₄} and concentrated under vacuum to give (2-(4-(4-(2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidin-1-yl)ethyl)tert-butyl carbamate (68 mg, 8% yield). MS (ESI, m/z): 744.2 [M+H] ^⁺

Step 2: N-[4-[4-[1-(2-aminoethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide carboxylate

In a 100 mL round-bottom flask, 68 mg (91.4 μmol) of (2-(4-(2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carbamate)benzoyl)piperazine-1-carbonyl)piperidin-1-yl)ethyl)tert-butyl carbamate was mixed with 3 mL of THF to give a colorless solution. A dioxane solution of 1.14 mL (4.57 mmol) was added. The reaction was stirred at room temperature for 30 minutes. The crude reaction mixture was concentrated under vacuum. The crude material was purified by preparative HPLC to obtain N-(4-(4-(1-(2-aminoethyl)piperidine-4-carbonyl)piperazine-1-carbonyl)-3-chlorophenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazolium-2-carboxamide formate (19 mg, 29.5% yield). MS (ESI, m/z): 644.3 [M+H] ⁺

Similar to Example 290, the following Type III examples were prepared.

Instance Type III: 293

N-[3-chloro-4-[4-(2-pyrrolidone-1-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide carboxylate

Step 1 intermediate 447:

N-(3-chloro-4-(4-(2-chloroacetyl)piperazine-1-carbonyl)phenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamide

In a 100 mL round-bottom flask, N-(3-chloro-4-(piperazin-1-carbonyl)phenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamide (500 mg, 1.02 mmol) and DIPEA (264 mg, 357 μl, 2.04 mmol) were mixed with _CH₂Cl₂ (20 _mL ) to give a light brown solution. 2-Chloroacetyl chloride (138 mg, 1.22 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. The crude reaction mixture was concentrated under vacuum. The reaction mixture was poured into 50 mL of _H₂O and extracted with DCM (3 x 25 mL). The organic layers were combined and washed with saturated NaCl (1 x 50 mL). The crude reaction mixture was concentrated under vacuum to give N-(3-chloro-4-(4-(2-chloroacetyl)piperazin-1-carbonyl)phenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamide (530 mg, 936 μmol, 91.7% yield), which could be used directly in the next step. (ESI, m/z): 566.0 [M+H]+.

Step 2

N-[3-chloro-4-[4-(2-pyrrolidone-1-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide carboxylate

Add 3 mL of an acetonitrile solution of N-(3-chloro-4-(4-(2-chloroacetyl)piperazin-1-carbonyl)phenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazol-2-carboxamide (75 mg, 132 μmol), pyrrolidine (47.1 mg, 662 μmol), DIEA (17.1 mg, 23.1 μl, 132 μmol), and sodium iodide (3.97 mg, 26.5 μmol) to a 5 mL microwave-safe vial. Cap the vial and microwave at 80 °C for 30 minutes. Concentrate the crude reaction mixture under vacuum. The crude material was purified by preparative HPLC to obtain N-[3-chloro-4-[4-(2-pyrrolidone-1-ylacetyl)piperazin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide carboxylate (19 mg, 21.7% yield). (ESI, m/z): 601.3 [M+H]+.

Similar to Example 293, the following Type III instances were prepared:

Instance Type III: 299

N-[3-chloro-4-[4-[3-[2-[[2-(dimethylamino)acetyl]amino]ethoxy]propionyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide]

A mixture of N-[4-[4-[3-(2-aminoethoxy)propionyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide formate (246, 90 mg, 138 μmol), dimethylglycine (28.5 mg, 276 μmol), HATU (233 mg, 612 μmol), and DIPEA (158 mg, 214 μl, 1.22 mmol) in DMF (5 mL) was stirred overnight. The mixture was poured into water. The aqueous layer was extracted with DCM. The organic phase was washed with water, dried, and concentrated. The residue was purified by preparative HPLC to give the title compound (29 mg). MS (ESI, m/z): 690.3 [M+H] ⁺ .

Measurement Procedure

Antimicrobial susceptibility testing:

Determine the 90% growth-inhibiting concentration (IC90).

The in vitro antimicrobial activity of the compound was determined according to the following procedure:

This assay uses 10-point Iso-Sensitest broth medium to quantitatively measure the in vitro activity of compounds against Acinetobacter baumannii ATCC17978 or ATCC17961.

The stock compound in DMSO was serially diluted twice in 384-well microtiter plates (e.g., final concentrations ranging from 10 to 0.02 μM) and inoculated with 49 μl of bacterial suspension in Iso-Sensitest medium to achieve a final cell concentration of approximately 5 x 10⁵ ⁽⁵⁾ CFU/ml, with a final volume of 50 μl/well. The microtiter plates were incubated at 35 ± 2 °C.

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

Table 1 provides the 90% growth inhibition concentration (IC90) per liter of the compounds of the present invention against Acinetobacter baumannii strain ATCC17978 or ATCC17961, expressed in micromoles per liter.

In particular, the compounds of the present invention exhibit an IC90 of ≤25 μmol/L (Acinetobacter baumannii ATCC17978 and/or ATCC17961).

More specifically, the compounds of the present invention exhibit an IC90 of ≤5 μmol/L (Acinetobacter baumannii ATCC17978 and/or ATCC17961).

Most notably, the compounds of the present invention exhibit an IC90 of ≤1 μmol/L (Acinetobacter baumannii ATCC17978 and/or ATCC17961).

Table 1

Example A

Compounds of formula (I) can be used as active ingredients in ways known per se to produce tablets with the following composition:

Example B

Compounds of formula (I) can be used as active ingredients in ways known per se to produce capsules with the following composition:

Example C

Compounds of formula (I) can be used as active ingredients in ways known per se to produce infusion solutions with the following composition:

Active ingredient: 100mg

Lactic acid 90% 100mg

An appropriate amount of NaOH or HCl is used to adjust the pH to 4.0.

Add appropriate amounts of sodium chloride or glucose to adjust the osmotic pressure to 290 mOsm/kg.

Water for Injection (WFI) Add to 100ml

Example D

Compounds of formula (I) can be used as active ingredients in ways known per se to produce infusion solutions with the following composition:

Active ingredient: 100mg

Hydroxypropyl-β-cyclodextrin 10mg

An appropriate amount of NaOH or HCl is used to adjust the pH to 7.4.

Add appropriate amounts of sodium chloride or glucose to adjust the osmotic pressure to 290 mOsm/kg.

Water for Injection (WFI) Add to 100ml

Claims (15)

1. Compound of formula (I) Or its medicinal salt, wherein: m is 1; ^R1 is selected from amino, amino- _C1 - _C6 -alkoxy-, group, and group _C1 - _C6 -alkyl- ^L2- ; wherein: The _C1 - _C6 -alkyl group is substituted with one or two substituents selected from the following: hydroxyl, amino, cyano, _C1 - _C6 -alkyl-NH-, ( _C1 - _C6 -alkyl) _2N- , amino- _C1 - _C6 -alkoxy- _C1 - _C6 -alkoxy-, carbamoyl, carbamoyl- _C1 - _C6 -alkoxy-, formamidinyl, ( _C1 - _C6 -alkyl) _{2NC1 - C6} -alkoxy-, ( _C1 - _C6 -alkyl) _2NC1 - _C6 - _alkyl -C(O)-NH- _C1 - _C6 -alkoxy-, _C2 - _C6 -alkynyl-NH-, carboxyl, and _C1 - _C6 -alkoxy. L ¹ is selected from -CH ₂ O-, -(CH ₂ ) _s C(O)-, -CH ₂ NHC(O)-, -CH ₂ C(O)NH-, -CH ₂ -, -NHC(O)-, -S(O) ₂ -, -S(O) ₂ NH-, -C(O)NH(CH ₂ ) ₂ -, and -NH-NHC(O)-; ^L2 is selected from covalent bonds, carbonyl groups, -S(O) _2- , -NHC(O)-, -C(O)NH-, and -S(O) _2NH- ; q is 0, 1, or 2; s can be 0, 1, or 4; B is selected from 3- to 8-membered heterocyclic groups, saturated monocyclic _C3 - _C6 -cycloalkyl groups, and 5- to 10-membered heteroaryl groups; and R ^5, in each occurrence, is independently selected from amino, hydroxyl, _C1 - _C6 -alkyl, amino- _C1 - _C6 -alkyl-, hydroxy- _C1 - _C6 -alkyl-, ( _C1 - _C6 -alkyl) _2N- , ( _C1 - _C6 -alkyl) _2NC1 - _{C6 -} alkyl-, ( _C1 - _{C6 -} alkyl) _2NC1 - _C6 -alkyl-C(O)-, oxo, carbamoyl, carbamoyl- _C1 - _C6 -alkyl, carboxyl, carboxyl- _C1 - _C6 -alkyl, halogen, aminoalkyl-S(O) _2- , and groups wherein: ^L3 is a covalent bond or a carbonyl group; r is 0 or 1; C is a saturated monocyclic _C3 - _C6 -cycloalkyl group or a 3- to 8-membered heterocyclic group; and ^R6 is a hydroxyl group; n is 1; ^R2 is a halogen or a _C1 - _C6 -alkyl group; ^R3 is a _C1 - _C6 -alkyl group; p is 1, 2, 3 or 4; ^R4, in each occurrence, is independently selected from halogens, _C1 - _C6 -alkyl, _C1 - _C6 -alkoxy, cyano, halo- _C1 - _C6 -alkyl, cyano- _C1 - _C6 -alkyl, ( _C1 - _C6 -alkyl) _2N- , halo- _C1 - _C6 -alkoxy, cyano- _C1 - _C6 -alkoxy, _C1 - _C6 -alkoxy- _C1 - _C6 -alkoxy-, ( _C1 - _C6 -alkyl) _2NC (O)-, and 5- to 10-membered heteroaryloxy groups; and A is a 3- to 8-membered heterocyclic group; Each heterocyclic group contains 1, 2, or 3 heteroatoms selected from N, O, and S; each heteroaryl group contains 1, 2, 3, or 4 heteroatoms selected from O, S, and N. 2. The compound of formula (I) according to claim 1, or a pharmaceutical salt thereof, wherein: m is 1; and ^R1 is a group where: ^L1 is selected from carbonyl, _-CH2C (O)-, _-CH2NHC (O)- and -NHC(O)-; q is 0 or 1; B is a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and ^R5 is selected from amino, hydroxyl, and hydroxy- _C1 - _C6 -alkyl-. 3. The compound of formula (I) according to claim 1, or a pharmaceutical salt thereof, wherein: m is 1; and ^R1 is a group where: ^L1 is selected from carbonyl, _-CH2C (O)-, _-CH2NHC (O)- and -NHC(O)-; q is 0 or 1; B is selected from aziridine, pyrrolidinyl, 3-azirbicyclo[3.1.0]hexyl, and piperidinyl; and ^R5 is selected from amino, hydroxy, and hydroxymethyl. 4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutical salt thereof, wherein n is 1 and ^R2 is selected from chlorine and methyl. 5. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutical salt thereof, wherein the compound of formula (I) is a compound of formula (II): 6. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutical salt thereof, wherein ^R3 is methyl. 7. The compound of formula (I) or a pharmaceutical salt thereof according to any one of claims 1 to 3, wherein p is 2 or 3 and ^R4 is independently selected from halogen, _C1 - _C6 -alkoxy, halogenated- _C1 - _C6 -alkoxy and cyano- _C1 - _C6 -alkoxy each time it appears. 8. The compound of formula (I) or a pharmaceutical salt thereof according to any one of claims 1 to 3, wherein p is 2 or 3 and ^R4 is independently selected from fluorine, chlorine, methoxy, _FCH2O- , _F2CHO- and _CNCH2O- each time it appears. 9. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutical salt thereof, wherein the compound of formula (I) is a compound of formula (III): in: R ^4a is selected from hydrogen, halogen, _C1 - _C6 -alkyl, cyano, and halo- _C1 - _C6 -alkyl; R ^4b is selected from hydrogen, halogen, cyano, and _C1 - _C6 -alkoxy groups; R ^4c is selected from halogens, _C1 - _C6 -alkoxy groups, cyano- _C1 - _C6 -alkyl groups, cyano- _C1 - _C6 -alkoxy groups, ( _C1 - _C6 -alkyl) _2N- groups, halo- _C1 - _C6 -alkoxy groups, _C1 - _C6 -alkoxy- _C1 - _C6 -alkoxy groups, ( _C1 - _C6 -alkyl) _2NC (O)- groups, and 5- to 10-membered heteroaryloxy groups containing 1, 2, 3, or 4 heteroatoms selected from O, S, and N; and R ^4d is selected from hydrogen and halogens. 10. The compound of formula (III) according to claim 9, or a pharmaceutical salt thereof, wherein: R ^4a is a halogen; R ^4b is selected from hydrogen and halogens; ^R4c is selected from _C1 - _C6 -alkoxy, cyano- _C1 - _C6 -alkoxy, and halo- _C1 - _C6 -alkoxy; and R ^4d is hydrogen. 11. The compound of formula (III) according to claim 9, or a pharmaceutical salt thereof, wherein: R ^4a is selected from fluorine and chlorine; R ^4b is selected from hydrogen, fluorine, and chlorine; R ^4c is selected from methoxy, FCH ₂ O-, F ₂ CHO-, and CNCH ₂ O-; and R ^4d is hydrogen. 12. A compound or a pharmaceutical salt thereof, wherein the compound is selected from: N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[3-(dimethylamino)propyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-[2-(aminomethyl)morpholine-4-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-[(2S,4S)-4-aminopyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(2S)-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(2S)-piperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(3S)-piperidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-(2-aminoethyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(methylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(2R)-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-(3-amino-2-hydroxy-propyl)-1-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-N-[3-methyl-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]imidazol-2-carboxamide; N-[3-chloro-4-[4-[(3S)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(1,1-dioxo-1,4-thiazinyl-4-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-N-[3-methyl-4-[4-[2-(methylamino)acetyl]piperazine-1-carbonyl]phenyl]imidazol-2-carboxamide; N-[3-chloro-4-[4-(morpholin-4-carbonyl)piperidin-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-N-[3-methyl-4-[4-(morpholin-4-carbonyl)piperidine-1-carbonyl]phenyl]imidazol-2-carboxamide; N-[3-chloro-4-[4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazolium-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[4-(1,1-dioxo-1,4-thiazin-4-carbonyl)piperidine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-[(2R)-2-(aminomethyl)morpholine-4-carbonyl]piperidine-1-carbonyl]-3-methyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(thiomorpholine-4-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-(3-aminoazacyclobutane-1-carbonyl)piperidine-1-carbonyl]-3-methyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-(aminomethyl)piperidin-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(5-hydroxypiperidin-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-(2-Aminoethyl)-4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-(4-piperazin-1-ylsulfonylpiperidin-1-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-[[(2S)-pyrrolidine-2-carbonyl]amino]ethyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-[(2S)-2-(aminomethyl)morpholine-4-carbonyl]piperidine-1-carbonyl]-3-methyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(4-piperidinylsulfonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-[2-[(2-amino-2-oxo-ethyl)amino]ethyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; (3R)-1-[2-[4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]pyrrolidine-3-carboxylic acid; 1-[2-[4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]azacyclobutane-3-carboxylic acid; 5-[3-chloro-4-(cyanomethoxy)-2-fluoro-phenyl]-N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[racemic-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazolium-2-carboxamide; N-[4-[4-(2-aminoethyl)piperidin-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxypyrrolidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-3-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-[2-(azacyclobutane-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-N-[3-chloro-4-[4-[2-[(3S)-pyrrolidine-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide; 5-[2-chloro-4-(difluoromethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[2-[(3S)-pyrrolidine-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(4-hydroxypyrrolidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidine-3-yl]methyl]piperidine-4-carboxamide; N-[4-[4-(2-aminoacetyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-[(2S)-azacyclobutane-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(2-pyrrolidone-1-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(2-pyrrolidone-3-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-[(2R)-pyrrolid-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-[(3R)-pyrrolidone-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-[(2S)-pyrrolid-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidine-3-yl]methyl]piperidine-4-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[[(3S)-pyrrolidine-3-yl]methyl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidin-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3-hydroxyazacyclobutane-3-yl)methyl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-[(2S)-pyrrolid-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-pyrrolidone-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-[(2S)-pyrrolid-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(3-hydroxyazacyclobutane-3-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-[1-(2-aminoethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-(azacyclobutane-3-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(pyrrolidone-3-ylmethyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidine-3-yl]piperidine-4-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[racemic-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-yl]piperidine-4-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(dimethylamino)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[2-[(3S)-pyrrolidine-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-(2,3,5-trifluoro-4-methoxy-phenyl)imidazol-2-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[racemic-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-yl]piperidine-4-carboxamide; N-[4-[3-(2-aminoethoxy)azacyclobutane-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidine-3-yl]methyl]piperidine-4-carboxamide; 5-[2-chloro-4-(difluoromethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(4-ethoxy-2,3-difluoro-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(5-hydroxypiperidin-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; 5-[2-chloro-4-(difluoromethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; 5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-[1-(azacyclobutane-3-carbonyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-3-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-(azacyclobutane-2-ylmethyl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-(3-hydroxyazacyclobutane-3-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-[2-(azacyclobutane-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[1-(4-hydroxypiperidin-4-carbonyl)piperidin-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-[(2S)-pyrrolid-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-3-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R)-pyrrolidine-3-yl]piperidine-4-carboxamide; 1-[2-chloro-4-[[5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidine-3-yl]piperidine-4-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-5-(4-ethoxy-2,3-difluoro-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[3-[3-(aminomethyl)azacyclobutane-1-carbonyl]azacyclobutane-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 3-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]propionic acid; 4-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]butyric acid; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazin-1-carbonyl]phenyl]-5-[4-(dimethylcarbamoyl)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[racemic-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide; N-[4-[4-[3-(aminomethyl)cyclobutanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(2-amino-2-oxo-ethyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[racemic-(3aR,6aS)-5-(piperidin-4-carbonyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolo-2-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(3-hydroxyazacyclobutane-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]azacyclobutane-3-yl]piperidine-4-carboxamide; N-[3-chloro-4-[3-(piperazin-1-carbonyl)azacyclobutane-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[racemic-(3aR,6aS)-5-[racemic-(3R)-pyrrolidine-3-carbonyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolo-2-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide; N-[3-chloro-4-[3-[[2-(dimethylamino)acetyl]amino]azacyclobutane-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[3-[racemic-(3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrolo-5-carbonyl]azacyclobutane-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide; N-[3-chloro-4-[racemic-(3aS,6aR)-2-[2-(dimethylamino)acetyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-(2,3,4-trifluorophenyl)imidazol-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(3-cyano-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[3-[racemic-(3aR,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrolo-5-carbonyl]pyrrolidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(3-cyano-2,4-difluoro-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-pyrrolidone-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[[2-(dimethylamino)acetyl]amino]piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 1-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]-2-ethyl-benzoyl]-N-[3-(prop-2-ynylamino)propyl]piperidine-4-carboxamide; 5-(2,3-Difluoro-4-methoxy-phenyl)-N-[4-[4-[4-[4-[3-(dimethylamino)propyl]piperazine-1-carbonyl]piperidine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazol-2-carboxamide; N-(2-aminoethyl)-1-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]-2-ethyl-benzoyl]piperidine-4-carboxamide; 1-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]-2-ethyl-benzoyl]-N-[2-[2-(dimethylamino)ethoxy]ethyl]piperidine-4-carboxamide; 5-[4-(difluoromethoxy)phenyl]-N-[4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazol-2-carboxamide; 5-(2-chloro-4-methoxy-phenyl)-N-[4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-5-(3-fluoro-4-isopropoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-[(3-cyclobutyl-1,2,4-oxadiazol-5-yl)methyl]piperidin-1-carbonyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide; 4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide; 4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide; N-[3-chloro-4-[4-[(3S,4S)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(2S,4S)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 4-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]-2-methyl-benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide; N-[3-chloro-4-[4-[(2S,4S)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[4-[(2S,4S)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazolium-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[4-[(2S,4S)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazolium-2-carboxamide; N-[3-chloro-4-[4-[(3R,4S)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 5-(2,3-Difluoro-4-methoxy-phenyl)-N-[4-[4-[(3R,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(3R,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]piperazine-1-carboxamide; N-[3-chloro-4-(piperazin-1-carbonyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(4-guanidinobutyryl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(3-aminopropionyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(5-aminopentanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(3-cyanopropionyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(3-aminopropionylamino)piperidin-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-(azacyclobutane-3-yl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[4-[4-[(1S,3R)-3-aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(2-aminoethylsulfonylamino)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-(4-piperidinyl)piperidin-4-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-(4-pyridylmethyl)piperidine-4-carboxamide; 5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; 5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4R)-4-fluoropyrrolidine-3-yl]piperidine-4-carboxamide; 5-[3-chloro-2-fluoro-4-(fluoromethoxy)phenyl]-N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazolium-2-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4R)-4-fluoropyrrolidine-3-yl]piperidine-4-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[[(3S)-pyrrolidine-3-yl]methyl]piperidine-4-carboxamide; N-[4-[4-(2-aminoethoxy)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(azacyclobutane-3-ylmethoxy)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(4-aminobutyryl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[(2S)-2-aminopropyl]-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[4-[4-[1-(2-aminoethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[1-[2-(dimethylamino)acetyl]piperidin-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[4-[4-(4-hydroxypiperidin-4-carbonyl)piperazin-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-(4-aminopiperidin-1-carbonyl)piperidin-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-pyrrolid-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2-(difluoromethyl)-3-fluoro-4-methoxy-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(pyrrolidone-3-ylsulfonylamino)piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; 5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidine-3-yl]methyl]piperidine-4-carboxamide; N-[3-chloro-4-[4-(4-piperidinylsulfonylamino)piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[3-(dimethylamino)azacyclobutane-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; 5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-(3-carbamoylpyrrolidine-1-carbonyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-(azacyclobutane-3-ylmethyl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-[1-(2-aminoethylsulfonyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-(azacyclobutane-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-chloro-4-(4-methylsulfonylpiperazine-1-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(methanesulfonylamino)piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(2-aminoethylsulfonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(2-oxoimidazolidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-[3-(2-aminoethyl)azacyclobutane-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(2-pyrrolidone-3-ylacetyl)amino]piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-pyrrolid-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[3-fluoro-4-(fluoromethoxy)-2-methyl-phenyl]-1-methyl-imidazol-2-carboxamide; 5-[3-chloro-2-fluoro-4-(fluoromethoxy)phenyl]-N-[4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-[(3S,4S)-3-amino-4-fluoro-pyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-(4-pyrrolidine-3-ylsulfonylpiperazine-1-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(3-aminobicyclo[1.1.1]pentane-1-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[[(1-methyl-4-piperidinyl)amino]carbamoyl]piperidin-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-pyrrolid-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2-cyano-3-fluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(5-oxopyrrolidone-3-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[3-(dimethylamino)propionylamino]piperidin-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; 5-[3-chloro-4-(cyanomethoxy)phenyl]-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-(4-piperidinylmethyl)piperidin-4-carboxamide; N-[4-[4-[3-(aminomethyl)azacyclobutane-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(methylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(3-aminoazacyclobutane-1-carbonyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]amino]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-[3-[2-(2-aminoethoxy)ethoxy]propionyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(5-oxopyrrolidone-2-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(5-oxopyrrolidine-2-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazolium-2-carboxamide; N-[4-(4-aminopiperidin-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(methylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(6-oxopiperidin-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(2-azaspiro[3.3]heptane-6-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-5-(2-chloro-3-fluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[(2R,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazolium-2-carboxamide; N-[3-chloro-4-[6-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]-2-azaspiro[3.3]heptane-2-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[3-[2-[[2-(dimethylamino)acetyl]amino]ethoxy]propionyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-1-methyl-N-[3-methyl-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]imidazol-2-carboxamide; N-[3-chloro-4-[3-[[racemic-(3R)-pyrrolidine-3-carbonyl]amino]pyrrolidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[(1S)-2-amino-1-methyl-ethyl]-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]pyrrolidine-3-yl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[(3S)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[2-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-2,6-diazaspiro[3.3]heptane-6-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazolium-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2-fluoro-3,4-dimethoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothiopheno[3,4-d]imidazol-4-yl]valeryl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(2,5-dioxoimidazolidine-4-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[3-[3-(2-aminoethoxy)propionylamino]pyrrolidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; 2-[4-[4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidinyl]acetic acid; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(2-methoxyethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(2-pyridinoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(4-pyridinoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(3,4-difluoro-5-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-pyrimidin-2-yloxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethyl)-2-fluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-9-methoxy-6,7-dihydro-5H-imidazo[5,1-a][2]benzoza-3-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-(azacyclobutane-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-(4-hydroxypiperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-[3-(2-aminoethoxy)propionyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidine-3-yl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-[(2S)-pyrrolid-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(piperidin-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; N-(2-aminoethyl)-1-[2-chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-(2-aminoethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; 1-[2-chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-(4-piperidinyl)piperidin-4-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R)-pyrrolidine-3-yl]piperidine-4-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-(4-piperidinyl)piperidin-4-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidinyl)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[2-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carboxamide; 1-[2-chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazol-2-carbonyl]amino]benzoyl]-N-[(3R)-pyrrolidine-3-yl]piperidine-4-carboxamide; N-[4-[3-[[3-(aminomethyl)cyclobutanecarbonyl]amino]azacyclobutane-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[3-[(2-aminoacetyl)amino]azacyclobutane-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-(3-carbamoylcyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxycyclobutanecarbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[3-chloro-4-[4-(3-methoxypropionyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; N-[4-[4-[3-(3-amino-3-oxo-propoxy)propionyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide; and N-[4-[4-(5-amino-5-oxo-pentanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazol-2-carboxamide. 13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutical salt thereof and a therapeutically inert carrier. 14. Use of the compound or pharmaceutical salt thereof according to any one of claims 1 to 12 for the preparation of a medicament for the treatment or prevention of infections caused by Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or combinations thereof. 15. The use according to claim 14, wherein the infection is caused by Acinetobacter baumannii.