Novel heterocyclic antibiotics

Abstract

The present invention provides novel heterocyclic compounds having the general formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 ~R 9 and p is as described herein: (I) TIFF2023539782000090.tif5972 Pharmaceutical compositions comprising the compounds, processes for making the compounds and methods of using the compounds as medicines, particularly methods of using the compounds as antibiotics for the treatment or prevention of bacterial infections and diseases resulting therefrom, are further provided.

Description

[Technical Field]

[0001] Field of Invention The present invention relates to novel heterocyclic compounds exhibiting antibacterial properties. The present invention also relates to methods of using the compounds for the treatment or prevention of bacterial infections and diseases resulting therefrom, particularly for the treatment or prevention of infections caused by Acinetobacter baumanni and diseases resulting therefrom. [Background technology]

[0002] Background of the Invention Acinetobacter baumanni is a Gram-negative, aerobic, and non-fermenting bacterium that has been recognized in recent decades as a novel pathogen with extremely limited treatment options.

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

[0004] Acinetobacter baumanni, due to the widespread use of antibiotics, offers a choice of resistance to all known antimicrobial agents and most frequently occurs in intensive care units and surgical wards, where infections such as bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections can occur.

[0005] Acinetobacter baumanni possesses a remarkable ability to upregulate and acquire resistance determinants, exhibiting environmental persistence that allows it to survive and spread in hospital environments. As a result, the organism frequently causes outbreaks of infection and becomes a healthcare-related pathogen specific to that environment.

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

[0007] According to the Infectious Diseases Society of America (IDSA) Task Force on Antimicrobial Availability (AATF), Acinetobacter baumanni has been, and remains, considered a prime example of the mismatch between unmet medical needs and the current antimicrobial research and development pipeline. Therefore, there is a strong need to identify compounds suitable for treating diseases and infections caused by Acinetobacter baumanni.

[0008] This invention provides novel compounds that exhibit activity against drug-sensitive and drug-resistant strains of Acinetobacter baumanni. [Overview of the project]

[0009] Summary of the Invention In the first aspect, the present invention relates to formula (I): [ka] (In the formula, R 1 ~R 9 (and p is as defined herein) The present invention provides compounds of or pharmaceutically acceptable salts thereof.

[0010] In one embodiment, the present invention provides a method for producing a compound of formula (I) as described herein, wherein the method is one of any one of schemes 1 to 4 described herein.

[0011] In a further embodiment, the present invention provides a compound of formula (I) as described herein, when produced according to the process described herein. In a further embodiment, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for use as therapeutic active substances.

[0012] In a further embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof and a therapeutically inactive carrier.

[0013] In a further embodiment, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for use as antibiotics.

[0014] In a further embodiment, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for use in the treatment or prevention of hospital-acquired infections and diseases resulting therefrom.

[0015] In a further embodiment, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for use in the treatment or prevention of infections caused by Gram-negative bacteria and diseases resulting therefrom.

[0016] In a further embodiment, the present invention provides compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof for use in the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0017] In a further embodiment, the present invention provides a method for the treatment or prevention of infections and diseases resulting from Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, comprising administering a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof to a mammal.

[0018] In a further embodiment, the present invention provides for the use of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof as an antibiotic.

[0019] In a further embodiment, the present invention provides the use of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof.

[0020] In a further embodiment, the present invention provides the use of compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for the preparation of pharmaceuticals useful for the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof. [Modes for carrying out the invention]

[0021] Detailed description of the invention definition Features, integers, characteristics, compounds, chemical parts, or groups described in relation to specific aspects, embodiments, or examples of the present invention should be understood to be applicable to any other aspects, embodiments, or examples described herein, unless they are incompatible. All features disclosed herein (including any appended claims, abstract, and drawings) and / or all steps of any method or process so so disclosed may be combined in any combination, except for combinations in which at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any of the embodiments described above. The present invention extends to any novel features or any novel combination of features disclosed herein (including any appended claims, abstract, and drawings) and any novel steps of any method or process so so disclosed.

[0022] The term "alkyl" refers to a monovalent or polyvalent, linear or branched saturated hydrocarbon group ("C1-C6-alkyl") having 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, alkyl groups include 1 to 3 carbon atoms, e.g., 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. Particularly preferred but non-limiting examples of alkyl groups include methyl and ethyl.

[0023] The term "alkoxy" refers to the alkyl group defined above, bonded to the parent molecule via an oxygen atom. Unless otherwise specified, alkoxy groups contain 1 to 6 carbon atoms ("C1-C6-alkoxy"). In some preferred embodiments, alkoxy groups contain 1 to 4 carbon atoms. In yet other embodiments, alkoxy groups contain 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred but non-limiting example of alkoxy is methoxy.

[0024] The term "halogen" or "halo" refers to fluoro(F), chloro(Cl), bromo(Br), or iodine(I). Preferably, the term "halogen" or "halo" refers to fluoro(F), chloro(Cl), or bromo(Br). Particularly preferred but non-limiting examples of "halogen" or "halo" are fluoro(F) and chloro(Cl).

[0025] As used herein, the term "cycloalkyl" refers to a monocyclic or bicyclic hydrocarbon group having 3 to 10 ring carbon atoms, being saturated or partially unsaturated ("C3- 10 (-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 bridging separating the two rings is either a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., a cycloalkyl moiety in which the two rings are linked via one 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 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and spiro[2.3]hexane-5-yl.

[0026] The term "aminoalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by an amino group. Preferably, "aminoalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group are replaced by amino groups. Preferred but non-limiting examples of aminoalkoxy are aminomethoxy and 1-aminoethoxy.

[0027] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic ring system, preferably a monocyclic ring system, having 3 to 14 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, where 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. A "bicyclic heterocyclyl" refers to a heterocyclic portion consisting of two rings having two common ring atoms, i.e., a spirocyclic portion, i.e., a heterocyclic portion in which the two rings are joined via one common ring atom, where the bridging separating the two rings is either a single bond or a chain of one or two ring atoms. Some non-restrictive examples of heterocyclyl groups include azetidine-3-yl, azetidine-2-yl, oxetan-3-yl, oxetan-2-yl, piperidyl, piperazinyl, pyrrolidinyl, 2-oxopyrrolidine-1-yl, 2-oxopyrrolidine-3-yl, 5-oxopyrrolidine-2-yl, 5-oxopyrrolidine-3-yl, 2-oxo-1-piperidyl, 2-oxo-3-piperidyl, 2-oxo-4-piperidyl, 6-oxo-2-piperidyl, 6-oxo-3-piperidyl, and 1-piperidinyl. Examples include 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, morpholino, morpholin-2-yl, morpholin-3-yl, pyrrolidinyl (e.g., pyrrolidine-3-yl), 3-azabicyclo[3.1.0]hexane-6-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2,6-diazaspiro[3.3]heptan-2-yl, and 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-yl.

[0028] The term "aryl" refers to a total of 6-10 ring members ("C6-C6"). 10 A monocyclic, bicyclic, or tricyclic carbocyclic ring system having an aryl group, where at least one ring in the system is aromatic. Particularly preferred, but not limited, examples of aryl groups are phenyl.

[0029] The term "heteroaryl" refers to a monovalent or polyvalent, monocyclic or bicyclic, preferably bicyclic, ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, more preferably 5 to 10 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5 to 10-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5 to 10-membered heteroaryl containing 1 to 2 heteroatoms independently selected from O and N. Some non-exclusive examples of heteroaryls include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyrimidine-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, and 1,2-benzoxazole Examples include sazole-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, oxazole-2-yl, oxazole-4-yl, oxazole-5-yl, thiazole-4-yl, and 1,2,4-oxadiazole-3-yl. Most preferably, "heteroaryl" refers to pyridyl and pyrimidinil.

[0030] The term "hydroxy" refers to the -OH group.

[0031] The term "amino" refers to the -NH2 group.

[0032] The term "cyano" refers to the -CN (nitrile) group.

[0033] The term "carbamoyl" refers to the -C(O)NH2 group.

[0034] The term "carbonyl" refers to a carbon radical that has two of the four covalent bonds shared with the oxygen atom (C=O).

[0035] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably a fluoro atom. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by a halogen atom, most preferably a fluoro atom. Non-limiting examples of haloalkyls are fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, 2-fluoroethyl, and 2,2-difluoroethyl. A particularly preferred but non-limiting example of a haloalkoxy is trifluoromethyl.

[0036] The term "cyanoalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a cyano group. Preferably, "cyanoalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by cyano groups. Most preferably, "cyanoalkyl" refers to an alkyl group in which one hydrogen atom of the alkyl group is replaced by a cyano group. A particularly preferred but non-limiting example of a cyanoalkyl is cyanomethyl.

[0037] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a halogen atom, preferably a fluoro atom. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group are replaced by a halogen atom, most preferably a fluoro atom. Particularly preferred but non-limiting examples of haloalkoxys are fluoromethoxy (FCH2O-), difluoromethoxy (F2CHO-), and trifluoromethoxy (F3CO-).

[0038] The term "cyanoalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a cyano group. Preferably, "cyanoalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group are replaced by cyano groups. Most preferably, "cyanoalkoxy" refers to an alkoxy group in which one hydrogen atom of the alkoxy group is replaced by a cyano group. A preferred but non-limiting example of a cyanoalkoxy is cyanomethoxy.

[0039] The term "carbamoyl alkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a carbamoyl group. Preferably, "carbamoyl alkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group are replaced by carbamoyl groups. Most preferably, "carbamoyl alkoxy" refers to an alkoxy group in which one hydrogen atom of the alkoxy group is replaced by a carbamoyl group.

[0040] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is 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 are replaced by a hydroxyl group. Preferred, but non-limiting, examples of hydroxyalkyls are hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), and 3-hydroxy-3-methylbutyl.

[0041] The adjective “aminoalkyl” refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by an amino group. Preferably, “aminoalkyl” refers to an alkyl group in which one, two, or three hydrogen atoms, most preferably one hydrogen atom, of the alkyl group are replaced by an amino group. Preferred but non-limiting examples of aminoalkyls are aminomethyl, aminoethyl (e.g., 2-aminoethyl), 3-amino-3-methyl-butyl, aminopentyl (e.g., 5-aminopentyl), and aminohexyl (e.g., 6-aminohexyl).

[0042] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a free base or free acid, and is not biologically or otherwise undesirable. Salts are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, lactic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic base or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts that can be derived from organic bases include, but are not limited to, 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, and polyimine resins. Specific pharmaceutically acceptable salts of the compound of formula (I) are hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid), and trifluoroacetate.

[0043] The compound of formula (I) may contain several chiral centers and may exist as an optically pure enantiomer, a mixture of enantiomers such as a racemate, an optically pure diastereoisomer, a mixture of diastereoisomers, a diastereoisomer racemate, or a mixture of diastereoisomer racemates.

[0044] According to the Cahn-Ingold-Prelog rule, an asymmetric carbon atom can have either an "R" or "S" configuration.

[0045] The term “treatment,” as used herein, includes: (1) suppressing a symptom, disorder, or condition (e.g., in the case of maintenance treatment, stopping, reducing, or delaying the onset or recurrence of at least one clinical symptom or asymptomatic disease); and / or (2) alleviating a condition (i.e., causing regression of a symptom, disorder, or condition, or at least one of its clinical symptoms or asymptomatics). The benefit to the patient to be treated is either statistically significant or at least recognizable to the patient or physician. However, it will be understood that when a medicine is administered to a patient to treat a disease, the outcome does not necessarily have to be an effective treatment.

[0046] As used herein, the term “prevention” includes preventing or delaying the onset of clinical symptoms of a condition, disorder, or condition in mammals, particularly in humans who are suffering from or susceptible to a condition, disorder, or condition but have not yet experienced or shown any clinical symptoms or asymptomatic symptoms of that condition, disorder, or condition.

[0047] 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, mice, cattle, horses, and pigs. In particularly preferred embodiments, the term “mammal” refers to humans.

[0048] The term "hospital-acquired infection" refers to hospital-acquired infections (HAIs), which are infections acquired in hospitals or other healthcare facilities. They are sometimes called healthcare-associated infections (HAIs or HCAIs) to emphasize both hospital and non-hospital settings. Such infections can be acquired in hospitals, nursing homes, rehabilitation facilities, outpatient clinics, or other clinical settings.

[0049] Compound of the present invention In the first aspect, the present invention relates to formula (I): [ka] (wherein, R 1 is independently selected, in each occurrence, from halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy; R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, 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)2N-C(O)-, and carbamoyl-C1-C6-alkoxy; R 7 is selected from hydrogen, C1-C6-alkyl, and halo-C1-C6-alkyl; R 8 is C1-C6-alkyl, amino-C1-C6-alkyl, amino-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)2N-C1-C6-alkyl-, C1-C6-alkyl-NH-C1-C6-alkyl-, amino-C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkyl-NH-C1-C6-alkoxy-C1-C6-alkyl-, (C1-C6-alkyl)2N-C1-C6-alkoxy-C1-C6-alkyl-, amino-C1-C6-alkoxy-C1-C6-alkyl-C(O)-, C1-C6-alkyl-NH-C1-C6-alkoxy-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)2N-C1-C6-alkoxy-C1-C6-alkyl-C(O)-, amino-C1-C6-alkyl-C(O)-NH-C1-C6-alkyl-, C1-C6-alkyl-NH-C1-C6-alkyl-C(O)-NH-C1-C6-alkyl-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-NH-C1-C6-alkyl-, and the group [ka] Selected from; R 9 These are selected from hydrogen and C1-C6-alkyl; R 10 These include halogens, cyano, amino, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, amino-C1-C6-alkyl-, C1-C6-alkyl-NH-C1-C6-alkyl-, (C1-C6-alkyl)2N-C1-C6-alkyl-, amino-C1-C6-alkyl-C(O)-, C1-C6-alkyl-NH-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, amino-C1-C6-alkyl-NH-C(O)-, amino-C1-C6-alkoxy-C1-C6-alkyl-C(O)-, hydroxy-C1-C6-alkyl, and groups [ka] Selected from; R 11 These are selected from halogen, cyano, amino, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, amino-C1-C6-alkyl-, C1-C6-alkyl-NH-C1-C6-alkyl-, (C1-C6-alkyl)2N-C1-C6-alkyl-, amino-C1-C6-alkyl-C(O)-, C1-C6-alkyl-NH-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, amino-C1-C6-alkyl-NH-C(O)-, amino-C1-C6-alkoxy-C1-C6-alkyl-C(O)-, and hydroxy-C1-C6-alkyl; A and B are independently 3-14 member heterocyclines, C3-C 10 -Cycloalkyl, 5-14 member heteroaryl, and C6-C 10 - Selected from the alphabet; L 1These are selected from covalent, carbonyl, -NH-C(O)-, C1-C6-alkyl, -C(O)-NH-C1-C6-alkyl-, -C1-C6-alkyl-NH-C(O)-, and -NH-C(O)-NH-C1-C6-alkyl-; L 2 These are selected from covalent, carbonyl, -NH-C(O)-, -C(O)-NH-, C1-C6-alkyl, -C(O)-NH-C1-C6-alkyl-, -C1-C6-alkyl-NH-C(O)-, and -NH-C(O)-NH-C1-C6-alkyl-; p is selected from 0, 1, 2, 3, or 4. (q and r are independently selected from 0, 1, 2, and 3.) The present invention provides compounds of or pharmaceutically acceptable salts thereof.

[0050] In one embodiment, the present invention relates to a compound of formula (I) of formula (II): [ka] (In the formula, R 1 ~R 9 (as defined herein) The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0051] In one embodiment, the present invention relates to a compound of formula (I) of formula (I-II): [ka] (In the formula, R 1 ~R 6 , R 8 and R 9 (as defined herein) The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0052] In one embodiment, the present invention relates to a compound of formula (I) of formula (I-III): [ka] (In the formula, R 1 ~R 4 , R 6 and R 8 (as defined herein) The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0053] In one embodiment, the present invention is R 1 However, it is a C1-C6-alkyl or halogen; p is 1. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0054] In a preferred embodiment, the present invention is R 1 However, it is a halogen; p is 1. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0055] In a particularly preferred embodiment, the present invention is R 1 But it is chloro; p is 1. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0056] In one embodiment, the present invention is R 2 However, it is hydrogen or halogen; R 3 However, it is hydrogen or halogen; R 4 However, these are selected from C1-C6-alkoxy, halo-C1-C6-alkoxy, cyano-C1-C6-alkoxy, and carbamoyl-C1-C6-alkoxy; R 5 However, it is hydrogen; R 6 However, it is hydrogen or halogen. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0057] In a preferred embodiment, the present invention is R 2 and R 3 However, all of them are halogens; R 4 However, these are selected from C1-C6-alkoxy and halo-C1-C6-alkoxy; R 5 and R 6 However, they are all hydrogen. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0058] In a particularly preferred embodiment, the present invention is R 2 and R 3 However, they are all fluoro; R 4 However, selected from methoxy and difluoromethoxy; R 5 and R 6 However, they are all hydrogen. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0059] In one embodiment, the present invention is R 7 This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein is a C1-C6 alkyl group.

[0060] In a preferred embodiment, the present invention is R 7 This specification provides compounds of formula (I) described herein, wherein the compound is methyl, or pharmaceutically acceptable salts thereof.

[0061] In one embodiment, the present invention is R 8However, C1-C6-alkyl, amino-C1-C6-alkyl, (C1-C6-alkyl)2N-C1-C6-alkyl-, amino-C1-C6-alkoxy-C1-C6-alkyl-, (C1-C6-alkyl)2N-C1-C6-alkoxy-C1-C6-alkyl-, amino-C1-C6-alkyl-C(O)-NH-C1-C6-alkyl-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-NH-C1-C6-alkyl-, and group [ka] Selected from; R 9 However, it is hydrogen; R 10 However, amino, hydroxy, C1-C6-alkyl, amino-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, amino-C1-C6-alkyl-NH-C(O)-, amino-C1-C6-alkoxy-C1-C6-alkyl-C(O)-, hydroxy-C1-C6-alkyl, and group [ka] Selected from; R 11 However, these are selected from hydroxy, amino, and amino-C1-C6-alkyl; A and B are independently 3-14 member heterocyclils and C3-C 10 - Selected from cycloalkyl groups; L 1 However, these are selected from covalent bonds, C1-C6-alkyl, -C(O)-NH-C1-C6-alkyl-, and -NH-C(O)-NH-C1-C6-alkyl-; L 2 However, these are selected from carbonyl, C1-C6-alkyl, -C(O)-NH-, and -NH-C(O)-; q and r are independently selected from 0 and 1, This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0062] In a preferred embodiment, the present invention is R 8 However, [ka] and; R 9 However, it is hydrogen; R 10 However, amino-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, amino-C1-C6-alkoxy-C1-C6-alkyl-C(O)-, and group [ka] Selected from; R 11 However, selected from hydroxyl and amino; A and B are independently 3-14 member heterocyclils and C3-C 10 - Selected from cycloalkyl groups; L 1 However, they are selected from covalent bonds and C1-C6-alkyl groups; L 2 However, it is selected from carbonyl, -C(O)-NH-, and -NH-C(O)-; q is 1; r is selected from 0 and 1. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0063] In a particularly preferred embodiment, the present invention is R 8 However, [ka] and; R 9 However, it is hydrogen; R 10 However, 2-aminoacetyl, 2-aminopropanoyl, 2-(dimethylamino)acetyl, 3-(2-aminoethoxy)propanoyl, and the base [ka] Selected from; R 11 However, selected from hydroxyl and amino; A is selected from azetidinil, cyclobutyl, pyrrolidinil, and piperidil; B is selected from cyclobutyl, pyrrolidinil, and piperidil; L 1 However, the bond is selected from covalent bonds and -(CH2)2-; L 2 However, it is selected from carbonyl, -C(O)-NH-, and -NH-C(O)-; q is 1; r is selected from 0 and 1. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0064] In one embodiment, the present invention is R 1 However, it is a C1-C6-alkyl or halogen; R 2 However, it is hydrogen or halogen; R 3 However, it is hydrogen or halogen; R 4 However, these are selected from C1-C6-alkoxy, halo-C1-C6-alkoxy, cyano-C1-C6-alkoxy, and carbamoyl-C1-C6-alkoxy; R 5 and R 9 However, they are all hydrogen; R 6 However, it is hydrogen or halogen; R 7 However, it is a C1-C6 alkyl group; R 8However, C1-C6-alkyl, amino-C1-C6-alkyl, (C1-C6-alkyl)2N-C1-C6-alkyl-, amino-C1-C6-alkoxy-C1-C6-alkyl-, (C1-C6-alkyl)2N-C1-C6-alkoxy-C1-C6-alkyl-, amino-C1-C6-alkyl-C(O)-NH-C1-C6-alkyl-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-NH-C1-C6-alkyl-, and group [ka] Selected from; R 10 However, amino, hydroxy, C1-C6-alkyl, amino-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, amino-C1-C6-alkyl-NH-C(O)-, amino-C1-C6-alkoxy-C1-C6-alkyl-C(O)-, hydroxy-C1-C6-alkyl, and group [ka] Selected from; R 11 However, these are selected from hydroxy, amino, and amino-C1-C6-alkyl; A and B are independently 3-14 member heterocyclils and C3-C 10 - Selected from cycloalkyl groups; L 1 However, these are selected from covalent bonds, C1-C6-alkyl, -C(O)-NH-C1-C6-alkyl-, and -NH-C(O)-NH-C1-C6-alkyl-; L 2 However, these are selected from carbonyl, C1-C6-alkyl, -C(O)-NH-, and -NH-C(O)-; p is 1; q and r are independently selected from 0 and 1, This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0065] In a preferred embodiment, the present invention is, R 1 、R 2 、and R 3 are each independently halogen; R 4 is selected from C1-C6-alkoxy and halo-C1-C6-alkoxy; R 5 、R 6 and R 9 are all hydrogen; R 7 is C1-C6-alkyl; R 8 is the group

Chemical formula

Chemical formula

[0066] In a particularly preferred embodiment, the present invention is, R1 But it is chloro; R 2 and R 3 However, all of them are fluoro, R 4 However, selected from methoxy and difluoromethoxy; R 5 , R 6 and R 9 However, they are all hydrogen; R 7 However, it is methyl; R 8 However, [ka] and; R 10 However, 2-aminoacetyl, 2-aminopropanoyl, 2-(dimethylamino)acetyl, 3-(2-aminoethoxy)propanoyl, and the base [ka] Selected from; R 11 However, selected from hydroxyl and amino; A is selected from azetidinil, cyclobutyl, pyrrolidinil, and piperidil; B is selected from cyclobutyl, pyrrolidinil, and piperidil; L 1 However, the bond is selected from covalent bonds and -(CH2)2-; L 2 However, it is selected from carbonyl, -C(O)-NH-, and -NH-C(O)-; q is 1; r is selected from 0 and 1; p is 1. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0067] In one embodiment, the present invention is R 1The present specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the compounds are C1-C6-alkyl or halogen.

[0068] In one embodiment, the present invention is R 2 The present specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the compound is hydrogen or a halogen.

[0069] In one embodiment, the present invention is 3 The present specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the compound is hydrogen or a halogen.

[0070] In one embodiment, the present invention is R 4 The present invention provides compounds of formula (I) as described herein, selected from C1-C6-alkoxy, halo-C1-C6-alkoxy, cyano-C1-C6-alkoxy, and carbamoyl-C1-C6-alkoxy, or pharmaceutically acceptable salts thereof.

[0071] In one embodiment, the present invention is R 5 This specification provides compounds of formula (I) described herein, wherein the compound is hydrogen, or pharmaceutically acceptable salts thereof.

[0072] In one embodiment, the present invention is R 6 The present specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the compound is hydrogen or a halogen.

[0073] In one embodiment, the present invention is R 7 This specification provides compounds of formula (I) described herein, wherein is hydrogen or a C1-C6-alkyl group, or pharmaceutically acceptable salts thereof.

[0074] In one embodiment, the present invention is R 8However, C1-C6-alkyl, amino-C1-C6-alkyl, (C1-C6-alkyl)2N-C1-C6-alkyl-, amino-C1-C6-alkoxy-C1-C6-alkyl-, (C1-C6-alkyl)2N-C1-C6-alkoxy-C1-C6-alkyl-, amino-C1-C6-alkyl-C(O)-NH-C1-C6-alkyl-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-NH-C1-C6-alkyl-, and group [ka] The following compounds of formula (I) described herein, selected from the above, are provided, or pharmaceutically acceptable salts thereof.

[0075] In one embodiment, the present invention is R 9 This specification provides compounds of formula (I) described herein, wherein the compound is hydrogen, or pharmaceutically acceptable salts thereof.

[0076] In one embodiment, the present invention is R 10 However, amino, hydroxy, C1-C6-alkyl, amino-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, amino-C1-C6-alkyl-NH-C(O)-, amino-C1-C6-alkoxy-C1-C6-alkoxy-C(O)-, hydroxy-C1-C6-alkyl, and group [ka] The following compounds of formula (I) described herein, selected from the above, are provided, or pharmaceutically acceptable salts thereof.

[0077] In one embodiment, the present invention is R 11 The present invention provides compounds of formula (I) as described herein, selected from hydroxy, amino, and amino-C1-C6-alkyl compounds, or pharmaceutically acceptable salts thereof.

[0078] In one embodiment, the present invention provides that A is a 3-14 member heterocyclyl and C3-C 10- Provides compounds of formula (I) as described herein, selected from cycloalkyl groups, or pharmaceutically acceptable salts thereof.

[0079] In one embodiment, the present invention provides that B is a 3-14 member heterocyclyl and C3-C 10 - Provides compounds of formula (I) as described herein, selected from cycloalkyl groups, or pharmaceutically acceptable salts thereof.

[0080] In one embodiment, the present invention is L 1 The present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof, selected from covalent, C1-C6-alkyl, -C(O)-NH-C1-C6-alkyl-, and -NH-C(O)-NH-C1-C6-alkyl.

[0081] In a preferred embodiment, the present invention is L 2 The present invention provides compounds of formula (I) as described herein, selected from carbonyl, C1-C6-alkyl, -C(O)-NH-, and -NH-C(O)-, or pharmaceutically acceptable salts thereof.

[0082] In one embodiment, the present invention provides a compound of formula (I) described herein, wherein p is 1, or a pharmaceutically acceptable salt thereof.

[0083] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein q is selected from 0 and 1.

[0084] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein r is selected from 0 and 1.

[0085] In a preferred embodiment, the present invention is R 1 This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein is a halogen.

[0086] In a preferred embodiment, the present invention is R 2 This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein is a halogen.

[0087] In a preferred embodiment, the present invention is R 3 This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein is a halogen.

[0088] In a preferred embodiment, the present invention is R 4 The present invention provides compounds of formula (I) as described herein, selected from C1-C6-alkoxy and halo-C1-C6-alkoxy, or pharmaceutically acceptable salts thereof.

[0089] In a preferred embodiment, the present invention is R 6 This specification provides compounds of formula (I) described herein, wherein the compound is hydrogen, or pharmaceutically acceptable salts thereof.

[0090] In a preferred embodiment, the present invention is R 8 is the basis [ka] This specification provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0091] In a preferred embodiment, the present invention is R 10 However, amino-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, amino-C1-C6-alkoxy-C1-C6-alkoxy-C(O)-, and group [ka] The following compounds of formula (I) described herein, selected from the above, are provided, or pharmaceutically acceptable salts thereof.

[0092] In a preferred embodiment, the present invention is R 11The present invention provides compounds of formula (I) as described herein, selected from hydroxyl and amino compounds, or pharmaceutically acceptable salts thereof.

[0093] In a preferred embodiment, the present invention is L 1 The present invention provides compounds of formula (I) as described herein, selected from covalent bonds and C1-C6 alkyl groups, or pharmaceutically acceptable salts thereof.

[0094] In a preferred embodiment, the present invention is L 2 The present invention provides compounds of formula (I) as described herein, selected from carbonyl, -C(O)-NH-, and -NH-C(O)-, or pharmaceutically acceptable salts thereof.

[0095] In a preferred embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein q is 1.

[0096] In a particularly preferred embodiment, the present invention is R 1 This specification provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein the compound is chloro.

[0097] In a particularly preferred embodiment, the present invention is R 2 This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the compound is fluoro.

[0098] In a particularly preferred embodiment, the present invention is R 3 This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the compound is fluoro.

[0099] In a particularly preferred embodiment, the present invention is R 4 The present invention provides compounds of formula (I) as described herein, selected from methoxy and difluoromethoxy, or pharmaceutically acceptable salts thereof.

[0100] In a particularly preferred embodiment, the present invention is R 7This specification provides compounds of formula (I) described herein, wherein the compound is methyl, or pharmaceutically acceptable salts thereof.

[0101] In a particularly preferred embodiment, the present invention is R 10 However, 2-aminoacetyl, 2-aminopropanoyl, 2-(dimethylamino)acetyl, 3-(2-aminoethoxy)propanoyl, and the base [ka] The following compounds of formula (I) described herein, selected from the above, are provided, or pharmaceutically acceptable salts thereof.

[0102] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof, wherein A is selected from azetidinil, cyclobutyl, pyrrolidinil, and piperidil.

[0103] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof, wherein B is selected from cyclobutyl, pyrrolidinil, and piperidil.

[0104] In a particularly preferred embodiment, the present invention is L 1 This provides compounds of formula (I) described herein, selected from covalent bonds and -(CH2)2-, or pharmaceutically acceptable salts thereof.

[0105] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof. N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(2-piperazine-1-ylethylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(pyrroridine-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(4-piperidylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(4-piperidylmethylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-(6-aminohexylcarbamoyl)-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-(aminomethyl)cyclobutyl]methylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[(3-aminocyclobutyl)methylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chlorophenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(2-piperazine-1-ylethylcarbamoyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(3-piperazine-1-ylpropylcarbamoyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methyl-N-[3-methyl-4-(3-piperazine-1-ylpropylcarbamoyl)phenyl]imidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(difluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(3-fluoro-4-isopropoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(2-chloro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(2,6-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-(3-aminopropylcarbamoyl)-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(2-amino-2-oxoethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[1-(piperidine-4-carbonyl)pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[2-[[2-(dimethylamino)acetyl]amino]ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[5-(dimethylamino)pentylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(2-isopentyloxyethylcarbamoyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[2-(3-hydroxypyrrolidine-1-yl)ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[2-[3-(hydroxymethyl)pyrrolidine-1-yl]ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[3-[2-(dimethylamino)ethoxy]propylcarbamoyl]-3-ethylphenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[1-[3-(2-aminoethoxy)propanoyl]pyrrolidine-3-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-(piperidine-4-carbonyl)-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[1-[3-(2-aminoethoxy)propanoyl]-4-piperidyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-[[3-(aminomethyl)cyclobutanecarbonyl]amino]cyclobutyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[2-[1-(3-aminopropanoyl)azetidine-3-yl]ethylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[4-[3-(3-aminopropanoylamino)propylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]piperidine-4-carboxamide; N-[2-[[4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-methylbenzoyl]amino]ethyl]piperidine-4-carboxamide; N-[2-[[4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-methylbenzoyl]amino]ethyl]-4-hydroxypiperidine-4-carboxamide; N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]piperidine-4-carboxamide; N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-4-hydroxy-piperidine-4-carboxamide; N-[4-[[1-(2-aminoacetyl)azetidine-3-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[1-(2-aminoacetyl)azetidine-3-yl]methylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-(2-aminoethylcarbamoyl)cyclobutyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-(3-aminoazetidine-1-carbonyl)cyclobutyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-[(3-aminocyclobutyl)carbamoyl]cyclobutyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-(2-aminoethylcarbamoyl)cyclobutyl]carbamoyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[[1-(2-aminoacetyl)azetidine-3-yl]carbamoyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluorophenyl]-N-[4-[2-[[(2R,4R)-4-hydroxy-4-methylpyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluorophenyl]-N-[4-[2-[[(2R,4R)-4-ethyl-4-hydroxypyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[2-[[(2R,4R)-4-hydroxy-4-methylpyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[2-[[(2R,4R)-4-ethyl-4-hydroxypyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[2-[[(3R,4R)-4-hydroxypyrrolidine-3-yl]carbamoylamino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[2-[[(3S,4S)-4-hydroxypyrrolidine-3-yl]carbamoylamino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluorophenyl]-N-[4-[2-[[(3R,4R)-4-hydroxypyrrolidine-3-yl]carbamoylamino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluorophenyl]-N-[4-[2-[[(3S,4S)-4-hydroxypyrrolidine-3-yl]carbamoylamino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; (3R,4R)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxy-piperidine-4-carboxamide; (3S,4S)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxy-piperidine-4-carboxamide; (3S,4R)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxy-piperidine-4-carboxamide; (3R,4S)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxy-piperidine-4-carboxamide; N-[3-chloro-4-[2-[[(2R,4R)-4-hydroxy-4-methylpyrrolidine-2-carbonyl]amino]ethylcarbamoyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[2-[[(2R,4R)-4-ethyl-4-hydroxypyrrolidine-2-carbonyl]amino]ethylcarbamoyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[3-[[(4R)-4-hydroxypyrrolidine-2-carbonyl]amino]cyclobutyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]piperidine-4-carboxamide; N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-4-hydroxy-piperidine-4-carboxamide; (3R,4R)-N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-hydroxy-piperidine-4-carboxamide; (3S,4S)-N-[3-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-hydroxy-piperidine-4-carboxamide; N-[4-[2-[1-(azetidine-3-ylmethyl)azetidine-3-yl]ethylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]-1-(pyrrolidine-3-ylmethyl)piperidine-4-carboxamide; 1-(azetidine-3-ylmethyl)-N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]piperidine-4-carboxamide; N-[4-[[1-(azetidine-3-ylmethyl)-4-piperidyl]methylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; 5-(4-methoxyphenyl)-1-methyl-N-[3-methyl-4-(methylcarbamoyl)phenyl]imidazole-2-carboxamide; N-[3-chloro-4-[[(exo)-3-[(2S,4R)-4-hydroxyprolyl]-3-azabicyclo[3.1.0]hexane6-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; and (Exo)-6-[[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]-N-[(Trans)-4-hydroxypyrrolidine-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide Selected from.

[0106] In preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof. N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[1-[3-(2-aminoethoxy)propanoyl]pyrrolidine-3-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-(piperidine-4-carbonyl)-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[2-[1-(3-aminopropanoyl)azetidine-3-yl]ethylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[4-[[1-(2-aminoacetyl)azetidine-3-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-[(3-aminocyclobutyl)carbamoyl]cyclobutyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[3-[[(4R)-4-hydroxypyrrolidine-2-carbonyl]amino]cyclobutyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]piperidine-4-carboxamide; and (3S,4S)-N-[3-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-hydroxy-piperidine-4-carboxamide Selected from.

[0107] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof. Example A1 N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide Example A2 N-[3-chloro-4-(2-piperazine-1-ylethylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide Example A3 N-[3-chloro-4-(pyrrolidine-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example A4 N-[3-chloro-4-(4-piperidylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example A5 N-[3-chloro-4-(4-piperidylmethylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example A6 N-[4-(6-aminohexylcarbamoyl)-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide Example A7 N-[4-[[3-(aminomethyl)cyclobutyl]methylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example A8 N-[4-[(3-aminocyclobutyl)methylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazo-l-2-carboxamide; formic acid Example A9 N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chlorophenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; formic acid Example A10 N-[3-chloro-4-(2-piperazine-1-ylethylcarbamoyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid Example A11 N-[3-chloro-4-(3-piperazine-1-ylpropylcarbamoyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid Example A12 5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methyl-N-[3-methyl-4-(3-piperazine-1-ylpropylcarbamoyl)phenyl]imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid Example A13 N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; formic acid Example A14 N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(difluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; hydrochloride Example A15 N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(3-fluoro-4-isopropoxy-phenyl)-1-methyl-imidazole-2-carboxamide; hydrochloride Example A16 N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(2-chloro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; hydrochloride Example A17 N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; hydrochloride Example A18 N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(2,6-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; hydrochloride Example A19 N-[4-(3-Aminopropylcarbamoyl)-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide Example A20 N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; hydrochloride Example A21 N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(2-amino-2-oxo-ethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; hydrochloride Example A22 N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; hydrochloride Example B1 N-[3-Chloro-4-[[1-(piperidine-4-carbonyl)pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; formic acid Example A23 N-[3-Chloro-4-[[1-[2-(dimethylamino)acetyl]pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide Example A24 N-[3-Chloro-4-[2-[[2-(dimethylamino)acetyl]amino]ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid Example A25 N-[3-Chloro-4-[[1-[2-(dimethylamino)acetyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide Example A26 N-[3-Chloro-4-[5-(dimethylamino)pentylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide Example A27 N-[3-Chloro-4-(2-isopentyloxyethylcarbamoyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; formic acid Example A28 N-[3-chloro-4-[2-(3-hydroxypyrrolidine-1-yl)ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide Example A29 N-[3-chloro-4-[2-[3-(hydroxymethyl)pyrrolidine-1-yl]ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide Example A30 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[3-[2-(dimethylamino)ethoxy]propylcarbamoyl]-3-ethylphenyl]-1-methylimidazole-2-carboxamide Example B2 N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B3 N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B4 N-[4-[[1-[3-(2-aminoethoxy)propanoyl]pyrrolidine-3-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B5 N-[3-chloro-4-[[1-(piperidine-4-carbonyl)-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B6 N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B7 N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; Example B8 N-[4-[[1-[3-(2-aminoethoxy)propanoyl]-4-piperidyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B9 N-[4-[[3-[[3-(aminomethyl)cyclobutanecarbonyl]amino]cyclobutyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B10 N-[4-[2-[1-(3-aminopropanoyl)azetidine-3-yl]ethylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid Example B11 N-[4-[3-(3-aminopropanoylamino)propylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid Example B12 N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]piperidine-4-carboxamide; formic acid Example B13 N-[2-[[4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-methylbenzoyl]amino]ethyl]piperidine-4-carboxamide; formic acid Example B14 N-[2-[[4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-methylbenzoyl]amino]ethyl]-4-hydroxypiperidine-4-carboxamide; formic acid Example B15 N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]piperidine-4-carboxamide; 2,2,2-trifluoroacetic acid Example B16 N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-4-hydroxy-piperidine-4-carboxamide; 2,2,2-trifluoroacetic acid Example B17 N-[4-[[1-(2-aminoacetyl)azetidine-3-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B18 N-[4-[[1-(2-aminoacetyl)azetidine-3-yl]methylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B19 N-[4-[[3-(2-aminoethylcarbamoyl)cyclobutyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B20 N-[4-[[3-(3-Aminoazetidine-1-carbonyl)cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; formic acid Example B21 N-[4-[[3-[(3-Aminocyclobutyl)carbamoyl]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid Example B22 N-[4-[[3-(2-Aminoethylcarbamoyl)cyclobutyl]carbamoyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid Example B23 N-[4-[[1-(2-Aminoacetyl)azetidin-3-yl]carbamoyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; formic acid Example B24 5-[4-(Cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[2-[[(2R,4R)-4-Hydroxy-4-methyl-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; formic acid Example B25 5-[4-(Cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[2-[[(2R,4R)-4-Ethyl-4-hydroxy-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; formic acid Example B26 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[2-[[(2R,4R)-4-hydroxy-4-methylpyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; formic acid Example B27 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[2-[[(2R,4R)-4-ethyl-4-hydroxypyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; formic acid Example B28 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[2-[[(3R,4R)-4-hydroxypyrrolidine-3-yl]carbamoylamino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; formic acid Example B29 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[2-[[(3S,4S)-4-hydroxypyrrolidine-3-yl]carbamoylamino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; formic acid Example B30 5-[4-(cyanomethoxy)-2,3-difluorophenyl]-N-[4-[2-[[(3R,4R)-4-hydroxypyrrolidine-3-yl]carbamoylamino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; formic acid Example B31 5-[4-(cyanomethoxy)-2,3-difluorophenyl]-N-[4-[2-[[(3S,4S)-4-hydroxypyrrolidine-3-yl]carbamoylamino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; formic acid Example B32 (3R,4R)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxypiperidine-4-carboxamide; formic acid Example B33 (3S,4S)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxy-piperidine-4-carboxamide; formic acid Example B34 (3S,4R)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxypiperidine-4-carboxamide; formic acid Example B35 (3R,4S)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxypiperidine-4-carboxamide; formic acid Example B36 N-[3-chloro-4-[2-[[(2R,4R)-4-hydroxy-4-methylpyrrolidine-2-carbonyl]amino]ethylcarbamoyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; formic acid Example B37 N-[3-chloro-4-[2-[[(2R,4R)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; formic acid Example B38 N-[3-chloro-4-[[3-[[(4R)-4-hydroxypyrrolidine-2-carbonyl]amino]cyclobutyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B39 N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]piperidine-4-carboxamide; formic acid Example B40 N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-4-hydroxy-piperidine-4-carboxamide; formic acid Example B41 (3R,4R)-N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-hydroxy-piperidine-4-carboxamide; formic acid Example B42 (3S,4S)-N-[3-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-hydroxy-piperidine-4-carboxamide; formic acid Example C1 N-[4-[2-[1-(azetidine-3-ylmethyl)azetidine-3-yl]ethylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid Example C2 N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]-1-(pyrrolidine-3-ylmethyl)piperidine-4-carboxamide; formic acid Example C3 1-(azetidine-3-ylmethyl)-N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]piperidine-4-carboxamide; formic acid Example C4 N-[4-[[1-(azetidine-3-ylmethyl)-4-piperidyl]methylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid, and Example D1 5-(4-methoxyphenyl)-1-methyl-N-[3-methyl-4-(methylcarbamoyl)phenyl]imidazole-2-carboxamide Selected from.

[0108] In preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof. Example A25 N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide Example B2 N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B4 N-[4-[[1-[3-(2-aminoethoxy)propanoyl]pyrrolidine-3-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B5 N-[3-chloro-4-[[1-(piperidine-4-carbonyl)-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B7 N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; Example B10 N-[4-[2-[1-(3-aminopropanoyl)azetidine-3-yl]ethylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid Example B17 N-[4-[[1-(2-aminoacetyl)azetidine-3-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B21 N-[4-[[3-[(3-aminocyclobutyl)carbamoyl]cyclobutyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid Example B38 N-[3-chloro-4-[[3-[[(4R)-4-hydroxypyrrolidine-2-carbonyl]amino]cyclobutyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid Example B39 N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]piperidine-4-carboxamide; formic acid; and Example B42 (3S,4S)-N-[3-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-hydroxy-piperidine-4-carboxamide Selected from.

[0109] In one embodiment, the present invention provides pharmaceutically acceptable salts of the compounds of formula (I) described herein, particularly pharmaceutically acceptable salts selected from hydrochloride, fumarate, lactate (particularly derived from L-(+)-lactic acid), tartrate (particularly derived from L-(+)-tartaric acid), and trifluoroacetate. In further specific embodiments, the present invention provides the compounds of formula (I) described herein (i.e., as “free base” or “free acid,” respectively).

[0110] In some embodiments, compounds of formula (I) are isotope-labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers. Such isotope-labeled (i.e., radioactively labeled) 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, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36Cl, 123 I, and 125 Examples include, but are not limited to, formula (I). Certain isotope-labeled compounds of formula (I), for example, those incorporating radioactive isotopes, are useful for studying the tissue distribution of drugs and / or substrates. Radioactive isotope tritium, i.e., 3 H and carbon-14, that is, 14 C is particularly useful for this purpose, considering its ease of incorporation and immediate detection means. For example, the compound of formula (I) can be enriched at 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0111] Heavier isotopes, such as deuterium, 2 Substitution with H, etc., can improve metabolic stability, potentially leading to certain therapeutic benefits, such as a longer in vivo half-life or a reduced required dose. 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as 1N may be useful in positron emission tomography (PET) studies to examine the receptor occupancy of a substrate. Compounds of formula (I) labeled with isotope can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the examples below, using appropriate isotope-labeled reagents instead of previously used unlabeled reagents.

[0112] Manufacturing process The compounds of formula (I) of the present invention can be prepared by sequential or convergent synthetic routes. The synthesis of the compounds of the present invention is shown in the following scheme. The skills required to carry out the reactions and the purification of the resulting products are known to those skilled in the art. The substituents and indicators used in the following description of the process have the significance set forth herein unless otherwise noted. More specifically, the compounds of formula (I) can be prepared by the methods shown below, the methods shown in the examples, or similar methods. Appropriate reaction conditions for each reaction step are known to those skilled in the art. For reaction conditions described in the literature that may affect the reactions described, see, for example, the following: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition, Richard C. Larock, John Wiley & Sons, New York, NY. 2018). The inventors have found it convenient to carry out the reactions in or without a solvent. The properties of the solvent used are not particularly limited, as long as it does not adversely affect the reagents involved in the reaction and can dissolve the reagents to at least some extent. The described reactions can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. It is convenient to carry out the described reactions in a temperature range between -78°C and reflux temperature. The time required for the reaction can also vary considerably, depending on many factors, particularly the reaction temperature and the properties of the reagents. However, a period of 0.5 hours to several days will usually be sufficient to obtain the described intermediates and compounds. The reaction sequence is not limited to that shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivity. The starting materials can be commercially available or prepared by methods similar to those shown below, by methods described in the references or examples cited herein, or by methods known in the art.

[0113] All substituents, especially R 1 ~R 9Unless otherwise specified, these terms are defined above and in the claims. Furthermore, unless otherwise specified, all reactions, reaction conditions, abbreviations, and symbols have meanings familiar to those skilled in the art of organic chemistry.

[0114] [ka] In the formula, PG1 represents an alkyl group, such as Me, Et, or isobutyl, which is a suitable protecting group.

[0115] The compound of formula intermediate C can be prepared according to scheme 1. 5-bromo-1-methylimidazole can be reacted with isobutylcarbonochloride under basic conditions to obtain compound A. Acid B can be obtained by hydrolysis of A. Intermediate A can be obtained by coupling B and amine C in DMSO with a coupling agent such as HATU / DIPEA. Suzuki coupling of intermediate A with bronic acid or ester (intermediate B) can be achieved using a palladium catalyst and a phosphine ligand to obtain compound D. Hydrolysis compound D produces intermediate C.

[0116] [ka] In the formula, PG2 is a suitable amino protecting group such as Boc. In the formula, Y is a primary amine (intermediate D) or a secondary amine (Example A, compound E).

[0117] Intermediate D (Y=NH2) / Example A (Y=NHR 8 The compounds can be prepared according to routes 1 and 2 of Scheme 2. By coupling acid intermediate C with free amine Y or protected amine PG2-Y using a coupling agent such as HATU / DIPEA in DMSO, compound A of formula example (route 1) or compound E is obtained. By deprotecting compound E, intermediate D or Example A (route 2) is obtained.

[0118] [ka] In the formula, PG2 is a suitable amino protecting group such as Boc; Y is either a primary amine (intermediate D) or a secondary amine (Example A, compound E).

[0119] Intermediate D (Y=NH2) / Example A (Y=NHR 8 Compounds can also be prepared according to the route outlined in Scheme 3. Thus, compound G is obtained by coupling acid intermediate F with protected amine PG2-Y using a coupling agent such as HATU / DIPEA in DMSO. Compound H is obtained by further coupling B with amine G using a coupling agent such as HATU / DIPEA in DMSO. The Suzuki coupling of intermediate H with bronic acid or ester (intermediate B) can be achieved using a palladium catalyst and a phosphine ligand to obtain compound E. By deprotecting compound E, intermediate D or Example A is obtained, respectively.

[0120] [ka] In the formula, PG3 is a suitable amino protecting group such as Boc; Y is a primary amine (intermediate D) or a secondary amine (compound I, examples B and C); Z is an amine or the group RC(O)-NH-, and together Y and Z form the group R as defined herein. 8 It forms.

[0121] Compounds B and C can be prepared according to the route of Scheme 4. Compound I is obtained by coupling acid D with the protected amine PG3-Z using a coupling agent such as HATU / DIPEA in DMSO, and then B is obtained by deprotecting PG3 of Z. In some cases, compound I was prepared by reductively aminating intermediate D with aldehyde PG3-Z using NaBH3CN in a MeOH solution, and then deprotecting PG3 of Z to obtain B.

[0122] In one embodiment, the present invention provides a method for producing a compound of formula (I) described herein, wherein the method is one of any one of schemes 1 to 4 described above.

[0123] In a further embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, when prepared according to the process described herein.

[0124] Use of the compound of the present invention As shown in the experimental section, the compound of formula (I) and its pharmaceutically acceptable salts possess valuable pharmacological properties for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically by Acinetobacter species, and most specifically by Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0125] The compounds of formula (I) and their pharmaceutically acceptable salts are active as antibiotics, particularly as antibiotics against Acinetobacter species, more specifically as antibiotics against Acinetobacter baumanni, and most specifically as pathogen-specific antibiotics against Acinetobacter baumanni.

[0126] Compounds of formula (I) and their pharmaceutically acceptable salts may be used as antibiotics, i.e., as appropriate antimicrobial agents in the treatment and prevention of bacterial infections, particularly in the treatment and prevention of bacterial infections caused by Acinetobacter species, and more specifically in the treatment and prevention of bacterial infections caused by Acinetobacter baumannii.

[0127] The compounds of the present invention may be used alone or in combination with other drugs for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically by Acinetobacter species, most specifically by Acinetobacter baumanni, in particular bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0128] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

[0129] In a further embodiment, the present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, for use as antibiotics.

[0130] In a further embodiment, the present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of hospital-acquired infections and diseases resulting therefrom.

[0131] In certain embodiments, the hospital-acquired infection and the resulting illness are selected from bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, or a combination thereof.

[0132] In a further embodiment, the present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of infections caused by Gram-negative bacteria and diseases resulting therefrom.

[0133] In certain embodiments, the infections and resulting diseases caused by Gram-negative bacteria are selected from bacteremia, pneumonia, meningitis, urinary tract infections, wound infections, or a combination thereof.

[0134] In a further embodiment, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0135] In a further embodiment, the present invention provides a method for the treatment or prevention of infections and diseases resulting from Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, comprising administering a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof to a mammal.

[0136] In a further embodiment, the present invention provides for the use of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof as an antibiotic.

[0137] In a further embodiment, the present invention provides the use of compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0138] In a further embodiment, the present invention provides the use of compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for the preparation of pharmaceuticals useful for the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0139] In certain embodiments, the infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, are selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections or combinations thereof.

[0140] In a further embodiment, the present invention provides compounds of formula (I) defined above, or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically Acinetobacter species, most specifically Acinetobacter baumanni, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0141] In a further embodiment, the present invention provides a method for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically Acinetobacter species, most specifically Acinetobacter baumanni, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, comprising administering a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof to a mammal.

[0142] In a further embodiment, the present invention provides the use of compounds of formula (I) defined above, or pharmaceutically acceptable salts thereof, for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically Acinetobacter species, most specifically Acinetobacter baumanni, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0143] In a further embodiment, the present invention provides the use of compounds of formula (I) defined above, or pharmaceutically acceptable salts thereof, for the preparation of pharmaceuticals for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically Acinetobacter species, most specifically Acinetobacter baumanni, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections. Such pharmaceuticals comprise compounds of formula (I) defined above or pharmaceutically acceptable salts thereof.

[0144] Pharmaceutical composition and administration In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives. Exemplary pharmaceutical compositions are described in Examples 1 to 4.

[0145] In a further embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically Acinetobacter species, most specifically Acinetobacter baumanni, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0146] Compounds of formula (I) and their pharmaceutically acceptable salts may be used as pharmaceuticals (e.g., in the form of pharmaceutical formulations). Pharmaceutical formulations may be administered into the body orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration may be carried out parenterally, for example, intramuscularly or intravenously (e.g., in the form of injections or infusions).

[0147] Compounds of formula (I) and their pharmaceutically acceptable salts may be treated with pharmaceutically inert inorganic or organic additives for the manufacture of tablets, coated tablets, dragees, and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., may be used as such additives for tablets, dragees, and hard gelatin capsules, for example.

[0148] Suitable additives for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0149] Suitable additives for the production of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, and glucose.

[0150] Suitable additives for injection solutions include, for example, water, alcohol, polyols, glycerol, and vegetable oils.

[0151] Suitable additives for suppositories include, for example, natural oils or hydrogenated oils, waxes, fats, and semi-solid or liquid polyols.

[0152] Furthermore, pharmaceutical preparations may contain preservatives, solubilizers, viscosity enhancers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts to alter osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other therapeutically useful substances.

[0153] Dosages can vary widely and, of course, to suit the individual requirements of each specific case. Generally, for oral administration, a daily dose of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (e.g., about 300 mg / person), may be appropriately divided into 1 to 3 individual doses, each consisting of, for example, the same amount. However, it is clear that the upper limits given herein may be exceeded where indicated.

[0154] Co-administration of the compound of formula (I) with other drugs The compound of formula (I) or a salt thereof, or any compound disclosed herein or a pharmaceutically acceptable salt thereof, may be used alone or in combination with other agents for treatment. For example, the second agent in a combination pharmaceutical formulation or administration regimen may have complementary activity to the compound of formula (I) so as not to adversely affect each other. The compounds may be administered together or separately in a single pharmaceutical composition. In one embodiment, the compound or a pharmaceutically acceptable salt may be co-administered with an antibiotic, in particular an antibiotic for the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0155] The term "co-administration" refers to the simultaneous administration, or any separate, sequential administration, of one or more further active pharmaceutical ingredients, including the compound of formula (I) or a salt thereof, or the compounds disclosed herein or pharmaceutically acceptable salts thereof, as well as antibiotic preparations. If the administrations are not simultaneous, the compounds are administered at close intervals. Furthermore, it is not important whether the compounds are administered in the same dosage form; for example, one compound may be administered intravenously and another orally.

[0156] Typically, antimicrobial agents can be co-administered. Specific examples of such agents are carbapenems (meropenem), fluoroquinolones (ciprofloxacin), aminoglycosides (amikacin), tetracyclines (tigecycline), colistin, sulbactam, sulbactam + durlobactam, cefiderocol (fetroja), macrocyclic peptides, and macrolides (erythromycin), as illustrated in International Publication Nos. 2017072062, 2019185572, and 2019206853, respectively.

[0157] In one embodiment, the present invention provides a pharmaceutical composition according to this specification, further comprising a further therapeutic agent.

[0158] In one embodiment, the additional therapeutic agent is an antibiotic preparation. In one embodiment, the additional therapeutic agent is an antibiotic preparation useful for treating or preventing infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0159] In one embodiment, the additional therapeutic agent is an antibiotic preparation selected from carbapenems (meropenem), fluoroquinolones (ciprofloxacin), aminoglycosides (amikacin), tetracyclines (tigecycline), colistin, sulbactam, sulbactam + durlobactam, cefiderocol (fetroja), macrocyclic peptides, and macrolides (erythromycin), as exemplified in International Publication Nos. 2017072062, 2019185572, and 2019206853.

[0160] Examples The present invention will be better understood by referring to the following embodiments. However, the claims should not be construed as being limited to the scope of these embodiments.

[0161] If the preparation is obtained as a mixture of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0162] Unless otherwise specified, all reaction examples and intermediates were prepared under an argon atmosphere.

[0163] The abbreviations used in this specification are as follows: ACN or MeCN acetonitrile BINAP 2,2'-bis(diphenylphosphin)-1,1'-binaphthalene CFU Colony Formation Unit d day DCM Dichloromethane DIPEA N,N-diisopropylethylamine HCl or EA ethyl acetate FA Formic Acid h or hr time HATU:1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC: High-Performance Liquid Chromatography HPLC-UV: High-performance liquid chromatography with ultraviolet detector IC50 Maximum Half-Dose Inhibitory Concentration IC90 90% inhibitory concentration PE (Petroleum Ether) PdCl2(DPPF)[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd2(dba)3 Tris(dibenzylideneacetone) Dipalladium(0) PG protecting group Precat 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 weight X-PHOS 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0164] Intermediate A1 Methyl 4-[(5-bromo-1-methylimidazole-2-carbonyl)amino]-2-chlorobenzoate

[0165] Step 1: Isobutyl 5-bromo-1-methylimidazole-2-carboxylate

[0166] To a solution of 5-bromo-1-methylimidazole (20 g, 124 mmol) and DIPEA (32.1 g, 43.4 mL, 248 mmol) in DCM (140 mL), a solution of isobutylcarbonochloride (22.1 g, 161 mmol) in DCM (60 mL) was slowly added at -70°C. The addition time was approximately 30 minutes. The mixture was stirred at -70°C for 2 hours. Next, the mixture was slowly warmed to room temperature and stirred overnight. The solution was then washed with water and concentrated under reduced pressure. The unpurified product was then purified by flash column chromatography, yielding isobutyl 5-bromo-1-methyl-1H-imidazole-2-carboxylate (29 g) as a yellow oil. MS[M+H] + :261.2.

[0167] Step 2: 5-bromo-1-methylimidazole-2-carboxylic acid

[0168] A solution of isobutyl 5-bromo-1-methyl-1H-imidazole-2-carboxylate (29 g, 111 mmol) in MeOH (5 mL) and THF (120 mL) was mixed with a solution of lithium hydroxide monohydrate (9.32 g, 222 mmol) in water (60 mL). The mixture was stirred at room temperature for 3 hours. The organic solvent was removed under reduced pressure. A 12N HCl aqueous solution was added with stirring until the pH reached 4-5. The white solid was filtered, washed with MeOH, and dried over anhydrous Na2SO4 to obtain 5-bromo-1-methylimidazole-2-carboxylic acid (20.5 g) as a white solid. MS[M+H] + :204.8.

[0169] Step 3: Methyl 4-[(5-bromo-1-methylimidazole-2-carbonyl)amino]-2-chlorobenzoate

[0170] A mixture of 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid (13 g, 63.4 mmol), methyl 4-amino-2-chlorobenzoate (11.8 g, 63.4 mmol), HATU (24.1 g, 63.4 mmol), and DIPEA (24.6 g, 190 mmol) in DMF (50 mL) was stirred overnight at room temperature. The mixture was then poured into water. The aqueous phase was extracted with DCM. The combined organic phases were washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. A solid precipitated from the concentrated solution. The solid was collected, washed with MeOH, and dried to obtain methyl 4-[(5-bromo-1-methylimidazole-2-carbonyl)amino]-2-chlorobenzoate (18 g) as a pale yellow solid. MS[M+H] + :371.8.

[0171] Intermediate A2 tert-butyl 4-[(5-bromo-1-methylimidazole-2-carbonyl)amino]-2-chlorobenzoate

[0172] Step 1: tert-butyl 2-chloro-4-nitro-benzoate

[0173] A mixture of 2-chloro-4-nitrobenzoic acid (15.0 g, 74.42 mmol), N,N-dimethylpyridine-4-amine (2.73 g, 22.33 mmol), and N,N-diethylethaneamine (31.12 mL, 223.26 mmol) in THF (80 mL) was mixed with a solution of tert-butoxycarbonyl tert-butyl carbonate (24.36 g, 111.63 mmol) in THF (20 mL) at -10°C. The resulting mixture was heated to 25°C and stirred for a further 14 hours. The mixture was concentrated. The residue was treated with EA (50 mL) and H2O (50 mL). The mixture was extracted with EA. The combined organic layer was concentrated. Next, the unpurified product was purified by flash column chromatography to obtain tert-butyl 2-chloro-4-nitro-benzoate (18.8 g) as a colorless solid.

[0174] Step 2: tert-butyl 4-amino-2-chlorobenzoate

[0175] Iron (20.37 g, 364.81 mmol) was added to a mixture of tert-butyl 2-chloro-4-nitro-benzoate (18.8 g, 72.96 mmol) and ammonium chloride (19.51 g, 364.81 mmol) in ethanol (200 mL) and water (200 mL). The mixture was stirred at 25°C for 14 hours. The mixture was filtered through Celite. The filtrate was concentrated to remove ethanol. The mixture was extracted with EA. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to obtain tert-butyl 4-amino-2-chloro-benzoate (16.31 g) as a pale yellow solid. MS[M+H] + :228.1.

[0176] Step 3: tert-butyl 4-[(5-bromo-1-methylimidazole-2-carbonyl)amino]-2-chlorobenzoate

[0177] A mixture of 5-bromo-1-methylimidazole-2-carboxylate hydrochloride (7.0 g, 28.99 mmol), tert-butyl 4-amino-2-chlorobenzoate (6.0 g, 26.35 mmol), HATU (13.23 g, 34.79 mmol), and DIPEA (16.16 mL, 92.77 mmol) in DMF (15 mL) was stirred at 25°C for 3 hours. Water (10 mL) was added to the mixture and extracted with EA. The combined organic layer was concentrated. The unpurified product was purified by FCC to obtain tert-butyl 4-[(5-bromo-1-methylimidazole-2-carbonyl)amino]-2-chlorobenzoate (8 g, 19.29 mmol) as a white solid. MS[M+H] + :414.0.

[0178] The following intermediates were prepared in the same manner. [Table 1]

[0179] Intermediate B1 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0180] Step 1: 1-Bromo-4-(difluoromethoxy)-2,3-difluorobenzene

[0181] 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) were dissolved in DMF (250 mL) and water (57 mL). The reaction mixture was heated to 100 °C, stirred under N2 for 3.0 hours, and the reaction mixture was poured into 1.5 L of H2O and extracted with ELISA (3 × 250 mL). The organic layers were combined, washed with saturated NaCl (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The unpurified substance was purified by flash chromatography to obtain 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene (25.2 g).

[0182] Step 2: 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0183] In a 250 mL round-bottom flask, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (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) were added to 150 mL of dioxane. The vial was capped and heated under N2 at 80°C for 15 hours. The unpurified reaction mixture was concentrated under reduced pressure. The reaction mixture was poured into 50 mL of H2O and extracted with ELISA (50 mL x 3). The organic layers were combined, washed with saturated NaCl (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The unpurified substance was purified by flash chromatography to obtain 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25 g, 81.7 mmol, yield 84.6%).

[0184] The following intermediates were prepared in the same manner. [Table 2]

[0185] Intermediate C1 2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoic acid

[0186] Step 1: Methyl 2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoate

[0187] Under N2 protection, a mixture of methyl 4-[(5-bromo-1-methylimidazole-2-carbonyl)amino]-2-chlorobenzoate (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)ferrocenepalladium dichloride (350 mg, 537 μmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was irradiated under microwave at 100°C for 60 minutes. This reaction was repeated 8 times. The combined reaction solution was concentrated. Water (40 mL) was added, and the mixture was filtered. The aqueous phase was extracted by DCM. The combined organic phase was washed with water, dried over anhydrous Na2SO4, and concentrated. The concentrated organic phase was filtered, and the solid was dried to obtain unpurified methyl 2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoate (8.3 g) as a brown solid. MS[M+H] + :435.9.

[0188] Step 2: 2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoic acid

[0189] A solution of methyl 2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoate (8.3 g, 19 mmol) in MeOH (2 mL), THF (48 mL), and water (24 mL) was mixed with a solution of lithium hydroxide monohydrate (3.2 g, 76.2 mmol) in water (24 mL). The mixture was stirred overnight at room temperature. The mixture was then concentrated and acidified with 6N HCl while stirring until the pH reached 3-4. Several solids precipitated from the concentrated solution. The solids were filtered and dried to obtain 2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoic acid (7 g) as a brown solid. MS[M+H] + :422.3.

[0190] Intermediate C2 2-Chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoic acid

[0191] Step 1: tert-butyl 2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoate

[0192] In a 25 mL microwave vial, tert-butyl 4-(5-bromo-1-methyl-1H-imidazole-2-carboxamide)-2-chlorobenzoate (1 g, 2.41 mmol), 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (775 mg, 2.53 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (157 mg, 241 μmol), and Na2CO3 (767 mg, 7.23 mmol) were added to dioxane (18 mL) and water (1.8 mL) under N2 conditions. The reaction mixture was heated under N2 conditions at 100 °C for 15 hours. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified substance was purified by flash chromatography to obtain tert-butyl 2-chloro-4-(5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamide)benzoate (1.2 g, 2.34 mmol, yield 96.8%). MS[M+H] + :514.0.

[0193] Step 2: 2-Chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoic acid

[0194] In a 100 mL round-bottom flask, tert-butyl 2-chloro-4-(5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamide)benzoate (1.2 g, 2.34 mmol) was mixed with DCM (4 mL) to obtain a pale yellow solution. TFA (5.4 mL, 70.1 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified product was used directly in the next step to obtain 2-chloro-4-(5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamide)benzoic acid (1.07 g). MS[M+H] + :458.0.

[0195] The following intermediates were prepared in the same manner. [Table 3-1] [Table 3-2]

[0196] Intermediate D1 N-[3-chloro-4-(pyrrolidine-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide

[0197] Step 1: tert-butyl 3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]pyrrolidine-1-carboxylate

[0198] A mixture of tert-butyl 3-aminopyrrolidine-1-carboxylate (1.04 g, 5.6 mmol), 2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoic acid (1.97 g, 4.67 mmol), DIPEA (1.81 g, 14 mmol), and HATU (1.77 g, 4.67 mmol) in DMF (10 mL) was stirred at room temperature for 35 minutes. The mixture was then poured into water. The aqueous layer was extracted with DCM. The combined organic layer was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column to obtain tert-butyl 3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]pyrrolidine-1-carboxylate (2.3g) as a yellow oil. MS[M+H] + :590.0.

[0199] Step 2: N-[3-chloro-4-(pyrroridine-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide

[0200] A solution of tert-butyl 3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]pyrrolidine-1-carboxylate (2.3 g, 3.9 mmol) in TFA (10 mL) and DCM (10 mL) was stirred at room temperature for 30 minutes. The mixture was then filtered. Water (10 mL) was added. The aqueous layer was basicized with NH3.H2O and extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, and concentrated to obtain N-[3-chloro-4-(pyrrolidine-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide (1.8 g). MS[M+H] + :490.2.

[0201] The following intermediates were prepared in the same manner. [Table 4-1] [Table 4-2]

[0202] Intermediate D7 (Example A19) N-[4-(3-aminopropylcarbamoyl)-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide

[0203] Step 1: tert-butyl N-[3-[(4-amino-2-ethyl-benzoyl)amino]propyl]carbamate

[0204] To a solution of intermediate 4-amino-2-ethylbenzoic acid (825 mg, 5.0 mmol) and tert-butyl(3-aminopropyl) carbamate (1.30 g, 7.5 mmol) in anhydrous DMF (15 mL), DIPEA (1.30 g, 10 mmol) was added. The resulting mixture was then stirred at room temperature for 10 minutes, HATU (2.85 g, 7.5 mmol) was added to the mixture, and the mixture was stirred for a further 10 hours.

[0205] The mixture was poured into water (50 mL), and the aqueous solution was extracted with DCM (100 mL x 2). The organic layers were combined, washed with water and saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a red oily substance. This was purified by flash column to obtain tert-butyl N-[3-[(4-amino-2-ethyl-benzoyl)amino]propyl]carbamate (1.2 g) as a yellow oily substance. MS[M+H] + :322.2

[0206] Step 2: tert-butyl N-[3-[[4-[(5-bromo-1-methylimidazole-2-carbonyl)amino]-2-ethyl-benzoyl]amino]propyl]carbamate

[0207] To a solution of 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid (1.0 g, 5.0 mmol) and tert-butyl (3-(4-amino-2-ethylbenzamido)propyl) carbamate (1.6 g, 5.0 mmol) in anhydrous DMF (25 mL), DIPEA (1.3 g, 10 mmol) was added, and the resulting mixture was stirred at room temperature for 10 minutes. Then, HATU (3.8 g, 10 mmol) was added to the mixture, and it was stirred for a further 10 hours.

[0208] The mixture was poured into water (50 mL), and the aqueous solution was extracted with DCM (150 mL x 2). The organic layers were combined, washed with water and saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a red oily substance. This was purified by flash column to obtain tert-butyl N-[3-[[4-[(5-bromo-1-methylimidazole-2-carbonyl)amino]-2-ethyl-benzoyl]amino]propyl]carbamate (1.8 g) as a yellow solid. MS[M+H] + :508.3

[0209] Step 3: tert-butyl N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]carbamate

[0210] A mixture of tert-butyl(3-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamide)-2-ethylbenzamide)propyl) carbamate (1.73 g, 3.4 mmol), 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.56 g, 5.1 mmol), sodium carbonate (1.1 g, 10.2 mmol), and 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride (220 mg, 0.34 mmol) in 1,4-dioxane (25 ml) and water (2.5 ml) was stirred at 100°C for 4.0 hours. After cooling to room temperature, the mixture was poured into water (50 mL), and the aqueous solution was extracted with DCM (100 mL x 2). The organic layers were combined, washed with water and saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a red oily substance. This was purified by flash column chromatography, and the desired compound was supplied as a yellow oily substance to obtain tert-butyl N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]carbamate (1.2 g). MS[M+H] + :608.2

[0211] Step 4: N-[4-(3-aminopropylcarbamoyl)-3-ethyl-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide

[0212] To a solution of tert-butyl N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]carbamate (1.2 g, 2.0 mmol) in THF (15 ml), 3N HCl (5.0 mL) was added at room temperature. The resulting mixture was stirred for 5.0 hours, and then the pH was adjusted to 7-8 with aqueous ammonia. The mixture was poured into water (50 mL), then extracted with dichloromethane / isopropanol (100 / 10 mL), and the organic layer was concentrated to obtain a red oily substance. This was purified by flash column to obtain N-[4-(3-aminopropylcarbamoyl)-3-ethyl-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide (0.8 g) as a pale red oily substance. MS[M+H] + :508.2

[0213] The following intermediates were prepared in the same manner. [Table 5]

[0214] Intermediate E1 (2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-4-methylpyrrolidine-2-carboxylic acid

[0215] A solution of (2S)-1-tert-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (2 g, 8.72 mmol) in THF (20 mL) was added dropwise to a solution of methyllithium (8.72 mL, 13.09 mmol) under a nitrogen atmosphere at -20°C. The resulting mixture was stirred at the same temperature for 1 hour, then stirred further at 25°C for 11 hours. Under ice cooling, the reaction mixture was added to 1N hydrochloric acid aqueous solution (50 mL) and subsequently 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 unpurified product was purified by preparative HPLC (FA) to obtain the following two final compounds: P1,(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-4-methyl-pyrrolidine-2-carboxylic acid (50 mg) as a dark green solid, and the labeled compound P2,(2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-4-methyl-pyrrolidine-2-carboxylic acid (600 mg) as a grayish-white solid. MS[M+H] + :190.0.

[0216] The following intermediates were prepared in the same manner. [Table 6]

[0217] Example A1 N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide [ka]

[0218] Step 1: tert-butyl N-[2-[2-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]ethoxy]ethyl]carbamate

[0219] At room temperature, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosfinan 2,4,6-trioxide (226 mg, 711 μmol) was added to a mixture of 2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoic acid (150 mg, 356 μmol), tert-butyl N-[2-(2-aminoethoxy)ethyl]carbamate (72.6 mg, 356 μmol), and DIPEA (138 mg, 1.07 mmol) in DMF (2 mL). After stirring for 3 hours, the reaction was completed. The mixture was then poured into water. The aqueous layer was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to obtain the unpurified product tert-butylN-[2-[2-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]ethoxy]ethyl]carbamate (200 mg). The unpurified product was used in the next step of the reaction without further purification. MS[M+H] + :607.9.

[0220] Step 2: N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide

[0221] 200 mg, 329 μmol of tert-butyl N-[2-[2-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]ethoxy]ethyl]carbamate (200 mg, 329 μmol) in TFA (3 mL) and CH2Cl2 (3 mL) was stirred at room temperature for 1 hour. The mixture was then filtered. 5 mL of water was added. The solution was basicized to pH 8-9 with K2CO3. The aqueous phase was extracted by DCM. The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC to obtain N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide (31 mg) as a white powder. MS[M+H] + :508.2.

[0222] The following compounds were prepared in the same manner. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0223] Example B1 N-[3-chloro-4-[[1-(piperidine-4-carbonyl)pyrroridine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid [ka]

[0224] Step 1: tert-butyl 4-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]pyrrolidine-1-carbonyl]piperidine-1-carboxylate

[0225] A mixture of N-[3-chloro-4-(pyrroridine-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide (200 mg, 408 μmol), 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (187 mg, 816 μmol), HATU (233 mg, 612 μmol), and DIPEA (158 mg, 1.22 mmol) in DMF (5 mL) was stirred overnight. The mixture was then poured into water. The aqueous layer was extracted with DCM. The combined organic layers were washed with water, dried over anhydrous sodium 2SO4, and concentrated to obtain the unpurified product tert-butyl 4-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]pyrrolidine-1-carbonyl]piperidine-1-carboxylate (200 mg). The unpurified product was used directly in the reaction of the next step.

[0226] Step 2: N-[3-chloro-4-[[1-(piperidine-4-carbonyl)pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid

[0227] A solution of tert-butyl 4-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]pyrrolidine-1-carbonyl]piperidine-1-carboxylate (200 mg, 285 μmol) in TFA (5 mL) and DCM (5 mL) was stirred for 30 minutes. The mixture was then filtered. Water (5 mL) was added. The aqueous layer was basicized with NH3.H2O. The aqueous layer was extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC to obtain N-[3-chloro-4-[[1-(piperidine-4-carbonyl)pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; formic acid (85 mg). MS[M+H] + :601.4.

[0228] The following compounds were prepared in the same manner. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10] [Table 8-11]

[0229] Example C1 N-[4-[2-[1-(azetidine-3-ylmethyl)azetidine-3-yl]ethylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid [ka]

[0230] Step 1: tert-butyl 3-[[3-[2-[[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]ethyl]azetidine-1-yl]methyl]piperazine-1-carboxylate

[0231] In a 50 mL round-bottom flask, N-(4-((2-(azetidine-3-yl)ethyl)carbamoyl)-3-chlorophenyl)-5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamide (118 mg, 219 μmol), tert-butyl 3-formylazetidine-1-carboxylate (121 mg, 656 μmol), and NaBH3CN (68.7 mg, 1.09 mmol) were mixed with MeOH (6 mL) to obtain a pale yellow solution. The reaction mixture was heated to 45 °C and stirred for 3 hours. The unpurified reaction mixture was concentrated under reduced pressure. The reaction mixture was poured into 25 mL of saturated NaHCO3 and extracted with ELISA (25 mL x 3). Combine the organic layers, wash with saturated NaCl (25 mL), dry the organic layers over Na2SO4, concentrate under reduced pressure, and obtain tert-butyl 3-((3-(2-(2-chloro-4-(5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamide)benzamide)

[0232] Ethyl)azetidine-1-yl)methyl)azetidine-1-carboxylate (155 mg) was obtained. MS[M+H] + :709.1.

[0233] Step 2: N-[4-[2-[1-(azetidine-3-ylmethyl)azetidine-3-yl]ethylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

[0234] In a 50 mL round-bottom flask, tert-butyl 3-((3-(2-(2-chloro-4-(5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamide)benzamide)ethyl)azetidine-1-yl)methyl)azetidine-1-carboxylate (35 mg, 49.4 μmol) was mixed with DCM (3 mL) to obtain a light brown solution. 2,2,2-trifluoroacetic acid (1.13 g, 9.87 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified substance was purified by preparative HPLC to obtain N-(4-((2-(1-(azetidine-3-ylmethyl)azetidine-3-yl)ethyl)carbamoyl)-3-chlorophenyl)-5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamide bis(2,2,2-trifluoroacetate) (12 mg), MS[M+H] + :609.2.

[0235] The following compounds were prepared in the same manner. [Table 9]

[0236] Example A23 N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide [ka]

[0237] A mixture of N-[3-chloro-4-(pyrroridine-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide (300 mg, 612 μmol), 2-(dimethylamino)acetic acid (126 mg, 1.22 mmol), HATU (349 mg, 919 μmol), and DIPEA (237 mg, 1.84 mmol) in DMF (5 mL) was stirred overnight. The mixture was poured into water. The aqueous layer was extracted with DCM. The organic layer was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC to obtain 130 mg of N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide. MS[M+H] + :575.5.

[0238] The following compounds were prepared in the same manner. [Table 10-1] [Table 10-2]

[0239] Example D1 5-(4-methoxyphenyl)-1-methyl-N-[3-methyl-4-(methylcarbamoyl)phenyl]imidazole-2-carboxamide [ka]

[0240] Step 1) Ethyl 5-bromo-1-methylimidazole-2-carboxylate

[0241] To a stirred solution of ethyl chloroformate (2.38 mL, 24.84 mmol) and N,N-diisopropylethylamine (4.33 mL, 24.84 mmol) in ACN (50 mL), a solution of 5-bromo-1-methyl-1H-imidazole (2 g, 12.42 mmol) in ACN (20 mL) was slowly added at 0°C. The mixture was stirred at 10°C for 16 hours. The mixture was concentrated, the residue was treated with water (100 mL), and extracted with RINKAN (100 mL x 3). The combined extract was washed with saline solution, dried over MgSO4, filtered, concentrated, and purified by flash column chromatography (0-50% RINKAN in hexane) to obtain the marked compound (2.4 g) as a pale yellow oil. MS (ESI, m / z): 233.0 [M+H] + .

[0242] Step 2) Ethyl 5-(4-methoxyphenyl)-1-methylimidazole-2-carboxylate

[0243] A mixture of ethyl 5-bromo-1-methylimidazole-2-carboxylate (1 g, 4.29 mmol), 4-methoxyphenylboronic acid (717 mg, 4.72 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (314 mg, 0.430 mmol), and sodium carbonate (0.91 g, 8.58 mmol) in 1,4-dioxane (18 mL) / water (2 mL) was stirred under N2 at 90°C for 16 hours. The mixture was filtered and purified by silica column chromatography to obtain the marked compound (710 mg, 2.73 mmol) as a yellow solid. MS (ESI, m / z): 261.1 [M+H] + .

[0244] Step 3) 5-(4-methoxyphenyl)-1-methylimidazole-2-carboxylic acid

[0245] To a solution of ethyl 5-(4-methoxyphenyl)-1-methylimidazole-2-carboxylate (710 mg, 2.73 mmol) in THF (10 mL) / water (10 mL) / methanol (5 mL), lithium hydroxide (218.2 mg, 5.46 mmol) was added and the mixture was stirred at 5°C for 16 hours. The mixture was poured into water (50 mL) and extracted with  (30 mL × 2). The aqueous layer was then acidified to pH=3 with HCl solution (1 N) and extracted with  (50 mL × 2). The organic layer was concentrated to obtain the marked compound (205 mg) as a pale yellow solid. MS(ESI, m / z): 233.0[M+H] + .

[0246] Step 4) N,2-dimethyl-4-nitro-benzamide

[0247] A solution of methyl 2-methyl-4-nitro-benzoate (2.8 g, 14.4 mmol) in methylamine in ethanol (30 mL, 5.0 mmol) was stirred at 70°C for 3 hours. The solution was concentrated and washed with MTBE / DCM (100 mL, 50:1) to obtain the labeled compound (2.65 g, 13.65 mmol) as a grayish-white solid.

[0248] Step 5) 4-amino-N,2-dimethylbenzamide

[0249] A solution of palladium (0.14 mL, 1.36 mmol) and N,2-dimethyl-4-nitrobenzamide (2.65 g, 13.6 mmol) in methanol (30 mL) was stirred under H2 (2287 mmHg) at 5°C for 16 hours. The solution was concentrated and washed with MTBE (100 mL) to obtain the labeled compound (1.8 g) as a white solid. MS(ESI, m / z): 165.2[M+H] + .

[0250] Step 6) 5-(4-methoxyphenyl)-1-methyl-N-[3-methyl-4-(methylcarbamoyl)phenyl]imidazole-2-carboxamide

[0251] 5-(4-methoxyphenyl)-1-methylimidazole-2-carboxylic acid (100 mg, 0.43 mmol), triethylamine (0.18 mL, 1.3 mmol), and 4-amino-N,2-dimethylbenzamide (70.7 mg, 0.43 mmol) were stirred in THF (5 mL). 1-propanephosphonic anhydride in  (548 mg) was added, and the mixture was stirred at 10°C for 16 hours. The solution was poured into water (30 mL), extracted with  (30 mL), and concentrated to obtain the marked compound (55.1 mg) as a white solid. MS (ESI, m / z): 379.1 [M+H] + .

[0252] Intermediate D15 N-[4-[[(exo)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide.1:1 hydrogen chloride

[0253] Step 1: tert-butyl(exo)-6-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamide)-2-chlorobenzamide)-3-azabicyclo[3.1.0]hexane-3-carboxylate [ka]

[0254] At room temperature, a light brown suspension of 4-(5-bromo-1-methyl-1H-imidazole-2-carboxamide)-2-chlorobenzoic acid trifluoroacetate [2489205-90-3] (600 mg, 1.27 mmol, 1 equivalent) and tert-butyl(exo)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (378 mg, 1.9 mmol, 1.5 equivalents) in DMF (5 ml) was prepared by adding DIPEA (1.33 ml, 7.62 mmol, 6 equivalents), followed by HATU (724 mg, 1.9 mmol, 1.5 equivalents). The reaction mixture was stirred overnight at room temperature. Water was then added, the resulting suspension was filtered, washed with water, and the recovered solid was dried under reduced pressure to obtain the marked compound (885 mg, quantitative yield) as a light brown solid, which was used without further purification. MS:538.1[M+H]+ESI pos

[0255] Step 2: (Exo)-6-[[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester [ka]

[0256] (Exo)-6-[[4-[(5-bromo-1-methylimidazole-2-carbonyl)amino]-2-chlorobenzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (225 mg, 0.401 mmol, 1 equivalent) was dissolved in 1,4-dioxane (2.5 mL) and water (0.250 mL) at room temperature. (2,3-difluoro-4-methoxyphenyl)boronic acid (90 mg, 0.481 mmol, 1.2 equivalents), Na2CO3 (85 mg, 0.802 mmol, 2 equivalents), and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (26 mg, 0.040 mmol, 0.100 equivalents) were added. After degassing with Ar for 5 minutes, the mixture was stirred at 90°C for 4 hours. The reaction mixture was diluted with ethyl acetate, filtered through Celite, and concentrated. The residue was purified by silica gel column chromatography using toluene in heptane as the eluent, yielding the marked compound (151.1 mg, 58.23%) as a grayish-white solid. MS: 602.2[M+H]+,ESI pos.

[0257] Step 3: N-[4-[[(exo)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide.1:1 hydrogen chloride [ka]

[0258] (Exo)-6-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (151.1 mg, 0.233 mmol, 1 equivalent) was dissolved in dichloromethane (0.500 mL) in a light brown solution. 4M hydrogen chloride (583 μL, 2.33 mmol, 10 equivalents) in dioxane was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness, and the marked compound (149.1 mg, 92.55%) was obtained as a light brown solid. MS: 502.1[M+H]+,ESI pos.

[0259] Example B43 N-[3-chloro-4-[[(exo)-3-[(2S,4R)-4-hydroxyprolyl]-3-azabicyclo[3.1.0]hexane6-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide.1:1 hydrogen chloride [ka]

[0260] Step 1: (2S,4R)-2-[(exo)-6-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-4-hydroxy-pyrrolidine-1-carboxylate tert-butyl ester [ka]

[0261] To a light brown solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-proline (25 mg, 0.109 mmol, 1.5 equivalents) and N-[4-[[(exo)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide.1:1 hydrogen chloride (50 mg, 0.072 mmol, 1 equivalent) in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (63.1 uL, 0.362 mmol, 5 equivalents) and HATU (41 mg, 0.109 mmol, 1.5 equivalents) were added, and the reaction mixture was stirred at room temperature for 1.5 hours. Then, water was added, and the mixture was extracted with DCM. Next, the organic layer was washed twice with 5% LiCl solution and saline solution. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using DCM:MeOH as the eluent to obtain the marked compound (28.4 mg, 50.98%) as a white solid. MS: 715.2[M+H]+,ESI pos.

[0262] Step 2: N-[3-chloro-4-[[(exo)-3-[(2S,4R)-4-hydroxyprolyl]-3-azabicyclo[3.1.0]hexane6-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide.1:1 hydrogen chloride [ka]

[0263] (2S,4R)-2-[(exo)-6-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (28.4 mg, 0.037 mmol, 1 equivalent) was dissolved in 300 μL of dichloromethane. 46 μL of HCl (0.185 mmol, 5 equivalents) was added to this pale brown solution, and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to dryness, and the marked compound (31.7 mg, quantitative yield) was obtained as a grayish-white solid. MS: 615.2[M+H]+,ESI pos.

[0264] Example B44 (Exo)-6-[[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]-N-[(Trans)-4-hydroxypyrrolidine-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide.1:1 hydrogen chloride [ka]

[0265] Step 1: (Trans)-3-[[(Exo)-6-[[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylate tert-butyl ester [ka]

[0266] To a colorless solution of (trans)-3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (43.95 mg, 0.217 mmol, 3 equivalents) in N,N-dimethylformamide, triethylamine (50.5 uL, 0.362 mmol, 5 equivalents) and 1,1'-carbonyldiimidazole (29.37 mg, 0.181 mmol, 2.5 equivalents) were added, and the reaction mixture was stirred at room temperature for 20 minutes. Then, N-[4-[[(exo)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide 1:1 hydrogen chloride (50 mg, 0.072 mmol, 1 equivalent) was added, and stirring was continued at room temperature for 1.5 hours. Next, water was added, and the mixture was extracted with DCM. The organic layer was then washed twice with 5% LiCl solution and saline solution. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using DCM:MeOH as the eluent, and the marked compound (51.1 mg, 87.91%) was obtained as a white solid. MS:730.3[M+H]+,ESI pos.

[0267] Step 2: (Exo)-6-[[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(Trans)-4-hydroxypyrrolidine-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide.1:1 hydrogen chloride [ka]

[0268] (Trans)-3-[[(Exo)-6-[[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (51.1 mg, 0.064 mmol, 1 equivalent) was dissolved in dichloromethane (500 μL) and 4M HCl (79.6 μL, 0.318 mmol, 5 equivalents) in dioxane was added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to dryness, and the marked compound (30.6 mg, 65.6%) was obtained as a grayish-white solid. MS:630.2[M+H]+,ESI pos

[0269] Assay procedure Antimicrobial susceptibility testing: Determination of the 90% growth inhibitory concentration (IC90) The in vitro antimicrobial activity of the compound was determined according to the following procedure:

[0270] The assay quantitatively measured the in vitro activity of the compound against Acinetobacter baumanni ATCC17978 or ATCC 17961 using 10-point Iso-Sensitest broth medium.

[0271] Stock DMSO compounds were serially diluted 2-fold in a 384-well microtiter plate (e.g., in the range of final concentrations from 50 to 0.097 μM), 49 μl of bacterial suspension was seeded into Iso-Sensitest medium, and the final cell concentration was ~5x10⁶ at a final volume of 50 μl / well. (5) The concentration was set to CFU / ml. Microtiter plates were incubated at 35±2°C.

[0272] Bacterial cell growth was determined by measuring optical density at λ=600nm every 20 minutes over a 16-hour time course. Growth inhibition was calculated during the logarithmic growth of bacterial cells, and the concentrations that inhibited growth by 50% (IC50) and 90% (IC90) were determined.

[0273] Table 1 shows the 90% growth inhibitory concentration (IC90) of the compound of the present invention obtained in micromoles per liter against the Acinetobacter baumanni ATCC17978 strain.

[0274] Table 2 provides the 90% growth inhibitory concentration (IC90) of the compound of the present invention obtained in micromoles per liter against the Acinetobacter baumanni ATCC17961 strain.

[0275] The specific compounds of the present invention exhibit an IC90 of 25 μmol / l or less (Acinetobacter baumannii ATCC17978 and / or ATCC17961).

[0276] More specific compounds of the present invention exhibit an IC90 of 5 μmol / l or less (Acinetobacter baumannii ATCC17978 and / or ATCC17961).

[0277] The most specific compounds of the present invention exhibit an IC90 of 1 μmol / l or less (Acinetobacter baumannii ATCC17978 and / or ATCC17961). [Table 11] [Table 12]

[0278] Example 1 The compound of formula (I) can be used in a manner known to itself as an active ingredient to manufacture tablets of the following composition.

[0279] per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropyl methylcellulose 20 mg 425mg

[0280] Example 2 The compound of formula (I) can be used as an active ingredient in a manner known to itself to produce capsules of the following composition:

[0281] per capsule Active ingredient: 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5mg Magnesium stearate 0.5 mg 220.0 mg

[0282] Example 3 The compound of formula (I) can be used in known ways as an active ingredient for the preparation of injection solutions of the following compositions.

[0283] Active ingredient 100mg Lactic acid 90% 100mg Add an appropriate amount of NaOH or HCl to adjust the pH to 4.0. To adjust the osmotic pressure to 290 mOsm / kg, add an appropriate amount of sodium chloride or glucose. Add 100ml of water for injection (WFI)

[0284] Example 4 The compound of formula (I) can be used in known ways as an active ingredient for the preparation of injection solutions of the following compositions.

[0285] Active ingredient 100mg Hydroxypropyl-β-cyclodextrin 10g Add an appropriate amount of NaOH or HCl to adjust the pH to 7.4. To adjust the osmotic pressure to 290 mOsm / kg, add an appropriate amount of sodium chloride or glucose. Add 100ml of water for injection (WFI)

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, R １ is chloro or C1-C6-alkyl; R ２ , R ３ , R ５ and R ６ These are independently selected from hydrogen and halogen; R4 is selected from C1-C6-alkoxy, amide-C1-C6-alkyl, cyano-C1-C6-alkoxy, and fluoro-C1-C6-alkoxy; R ７ It is a C1-C6-alkyl group; R ８ is C １ -C ６ -alkyl, amino-C １ -C ６ -alkyl, amino-C １ -C ６ -alkyl-C(O)-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl, C １ -C ６ -alkyl-NH-C １ -C ６ -alkyl-, amino-C １ -C ６ -alkoxy-C １ -C ６ -alkyl-, C<00000​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ ６ -Alkyl-, C １ -C ６ -Alkyl-NH-C １ -C ６ -Alkyl-C(O)-NH-C １ -C ６ -Alkyl-, (C １ -C ６ -Alkyl) ２ N-C １ -C ６ -Alkyl-C(O)-NH-C １ -C ６ -Alkyl-, and group 【Chemistry 2】 Selected from; R ９ is hydrogen and C １ -C ６ - Selected from alkyl groups; R １０ is halogen, cyano, amino, hydroxy, C １ -C ６ -alkyl, C １ -C ６ -alkoxy, halo-C １ -C ６ -alkyl, halo-C １ -C ６ -alkoxy, amino-C １ -C ６ -alkyl-, C １ -C ６ -alkyl-NH-C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-, amino-C １ -C ６ -alkyl-C(O)-, C １ -C ６ -alkyl-NH-C １ -C ６ -alkyl-C(O)-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-C(O)-, amino-C １ -C ６ -alkyl-NH-C(O)-, amino-C １ -C ６ -alkoxy-C １ -C ６ -alkyl-C(O)-, hydroxy-C １ [[ID=7,6]]-C ６ -alkyl and the group 【Transformation 3】 Selected from; R １１ These are halogen, cyano, amino, hydroxy, and C. １ -C ６ - Alkyl, C １ -C ６ - Alkoxy, Halo-C １ -C ６ -Alkyl, Halo-C １ -C ６ -alkoxy, amino-C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-NH-C １ -C ６ -Alkyl-, (C １ -C ６ -Alkyl) ２ N-C １ -C ６ -Alkyl-, Amino-C １ -C ６ -Alkyl-C(O)-, C １ -C ６ -Alkyl-NH-C １ -C ６ -Alkyl-C(O)-, (C １ -C ６ -Alkyl) ２ N-C １ -C ６ -Alkyl-C(O)-, Amino-C １ -C ６ -Alkyl-NH-C(O)-,amino-C １ -C ６ -Alkoxy-C １ -C ６ -Alkyl-C(O)- and hydroxy-C １ -C ６ - Selected from alkyl groups; A and B are independently selected from 3- to 14-membered heterocyclyls and C3-C10-cycloalkyls, respectively; L １ This is a covalent bond, carbonyl, -NH-C(O)-, C １ -C ６ -Alkyl, -C(O)-NH-C １ -C ６ -Alkyl-, -C １ -C ６ -alkyl-NH-C(O)- and -NH-C(O)-NH-C １ -C ６ Selected from -alkyl-; L ２ Covalent bond, carbonyl, -NH-C(O)-, -C(O)-NH-, C １ -C ６ -Alkyl, -C(O)-NH-C １ -C ６ -Alkyl-, -C １ -C ６ -alkyl-NH-C(O)- and -NH-C(O)-NH-C １ -C ６ Selected from -alkyl-; p is 1; (q and r are independently selected from 0, 1, 2, and 3.) Compounds of or pharmaceutically acceptable salts thereof.

2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is chloro.

3. A compound of formula (I) according to claim 1 or 2, wherein both R2 and R3 are halogens, or a pharmaceutically acceptable salt thereof.

4. A compound of formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein both R2 and R3 are fluoro.

5. A compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R7 is methyl.

6. R ８ However, C １ -C ６ -Alkyl, amino-C １ -C ６ - Alkyl, (C １ -C ６ -Alkyl) ２ N-C １ -C ６ -Alkyl-, Amino-C １ -C ６ -Alkoxy-C １ -C ６ -Alkyl-, (C １ -C ６ -Alkyl) ２ N-C １ -C ６ -Alkoxy-C １ -C ６ -Alkyl-, Amino-C １ -C ６ -Alkyl-C(O)-NH-C １ -C ６ -Alkyl-, (C １ -C ６ -Alkyl) ２ N-C １ -C ６ -Alkyl-C(O)-NH-C １ -C ６ -Alkyl- and group 【Chemistry 4】 Selected from; R ９ is hydrogen; R １０ However, amino, hydroxy, C １ -C ６ -Alkyl, amino-C １ -C ６ -Alkyl-C(O)-, (C １ -C ６ -Alkyl) ２ N-C １ -C ６ -Alkyl-C(O)-, Amino-C １ -C ６ -Alkyl-NH-C(O)-,amino-C １ -C ６ -Alkoxy-C １ -C ６ -Alkyl-C(O)-,Hydroxy-C １ -C ６ - Alkyl and group 【Transformation 5】 Selected from; R １１ However, hydroxy, amino and amino-C １ -C ６ - Selected from alkyl groups; L １ is a covalent bond, C １ -C ６ -Alkyl, -C(O)-NH-C １ -C ６ -Alkyl- and -NH-C(O)-NH-C １ -C ６ Selected from -alkyl-; L ２ However, carbonyl, C １ -C ６ Selected from -alkyl, -C(O)-NH- and -NH-C(O)-; A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein q and r are each independently selected from 0 and 1.

7. R ８ is the basis 【Transformation 6】 And; R ９ is hydrogen; R １０ However, Amino-C １ -C ６ -Alkyl-C(O)-, (C １ -C ６ -Alkyl) ２ N-C １ -C ６ -Alkyl-C(O)-, Amino-C １ -C ６ -Alkoxy-C １ -C ６ -Alkyl-C(O)- and groups 【Transformation 7】 Selected from; R １１ However, selected from hydroxyl and amino; L １ However, covalent bonds and C １ -C ６ - Selected from alkyl groups; L ２ However, it is selected from carbonyl, -C(O)-NH- and -NH-C(O)-; q is 1; A compound of formula (I) according to claim 6 or a pharmaceutically acceptable salt thereof, wherein r is selected from 0 and 1.

8. R ８ is the basis 【Transformation 8】 And; R ９ is hydrogen; R １０ However, 2-aminoacetyl, 2-aminopropanoyl, 2-(dimethylamino)acetyl, 3-(2-aminoethoxy)propanoyl and the group 【Chemistry 9】 Selected from; R １１ However, selected from hydroxyl and amino; A is selected from azetidinil, cyclobutyl, pyrrolidinil, and piperidil; B is selected from cyclobutyl, pyrrolidinil, and piperidil; L １ However, covalent bonds and -(CH ２ ) ２ - Selected from; L ２ However, it is selected from carbonyl, -C(O)-NH- and -NH-C(O)-; q is 1; A compound of formula (I) according to claim 7 or a pharmaceutically acceptable salt thereof, wherein r is selected from 0 and 1.

9. N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(2-piperazine-1-ylethylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(pyrrolidine-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(4-piperidylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(4-piperidylmethylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-(6-aminohexylcarbamoyl)-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-(aminomethyl)cyclobutyl]methylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[(3-aminocyclobutyl)methylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chlorophenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(2-piperazine-1-ylethylcarbamoyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(3-piperazine-1-ylpropylcarbamoyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methyl-N-[3-methyl-4-(3-piperazine-1-ylpropylcarbamoyl)phenyl]imidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethylphenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(difluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(3-fluoro-4-isopropoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethylphenyl]-5-(2-chloro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethylphenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethylphenyl]-5-(2,6-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-(3-aminopropylcarbamoyl)-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethylphenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethylphenyl]-5-[4-(2-amino-2-oxoethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[1-(piperidine-4-carbonyl)pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[2-[[2-(dimethylamino)acetyl]amino]ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[5-(dimethylamino)pentylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(2-isopentyloxyethylcarbamoyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[2-(3-hydroxypyrrolidine-1-yl)ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[2-[3-(hydroxymethyl)pyrrolidine-1-yl]ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[3-[2-(dimethylamino)ethoxy]propylcarbamoyl]-3-ethylphenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[1-[3-(2-aminoethoxy)propanoyl]pyrrolidine-3-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-(piperidine-4-carbonyl)-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[1-[3-(2-aminoethoxy)propanoyl]-4-piperidyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-[[3-(aminomethyl)cyclobutanecarbonyl]amino]cyclobutyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[2-[1-(3-aminopropanoyl)azetidine-3-yl]ethylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[4-[3-(3-aminopropanoylamino)propylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]piperidine-4-carboxamide; N-[2-[[4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-methylbenzoyl]amino]ethyl]piperidine-4-carboxamide; N-[2-[[4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-methylbenzoyl]amino]ethyl]-4-hydroxypiperidine-4-carboxamide; N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]piperidine-4-carboxamide; N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-4-hydroxypiperidine-4-carboxamide; N-[4-[[1-(2-aminoacetyl)azetidine-3-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[1-(2-aminoacetyl)azetidine-3-yl]methylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-(2-aminoethylcarbamoyl)cyclobutyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-(3-aminoazetidine-1-carbonyl)cyclobutyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-[(3-aminocyclobutyl)carbamoyl]cyclobutyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-(2-aminoethylcarbamoyl)cyclobutyl]carbamoyl]-3-ethylphenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[1-(2-aminoacetyl)azetidine-3-yl]carbamoyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluorophenyl]-N-[4-[2-[[(2R,4R)-4-hydroxy-4-methylpyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluorophenyl]-N-[4-[2-[[(2R,4R)-4-ethyl-4-hydroxypyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[2-[[(2R,4R)-4-hydroxy-4-methylpyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[2-[[(2R,4R)-4-ethyl-4-hydroxypyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[2-[[(3R,4R)-4-hydroxypyrrolidine-3-yl]carbamoylamino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-(2,3-difluoro-4-methoxyphenyl)-N-[4-[2-[[(3S,4S)-4-hydroxypyrrolidine-3-yl]carbamoylamino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluorophenyl]-N-[4-[2-[[(3R,4R)-4-hydroxypyrrolidine-3-yl]carbamoylamino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluorophenyl]-N-[4-[2-[[(3S,4S)-4-hydroxypyrrolidine-3-yl]carbamoylamino]ethylcarbamoyl]-3-methylphenyl]-1-methylimidazole-2-carboxamide; (3R,4R)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxypiperidine-4-carboxamide; (3S,4S)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxypiperidine-4-carboxamide; (3S,4R)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxypiperidine-4-carboxamide; (3R,4S)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxypiperidine-4-carboxamide; N-[3-chloro-4-[2-[[(2R,4R)-4-hydroxy-4-methylpyrrolidine-2-carbonyl]amino]ethylcarbamoyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[2-[[(2R,4R)-4-ethyl-4-hydroxypyrrolidine-2-carbonyl]amino]ethylcarbamoyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[3-[[(4R)-4-hydroxypyrrolidine-2-carbonyl]amino]cyclobutyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]piperidine-4-carboxamide; N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-4-hydroxypiperidine-4-carboxamide; (3R,4R)-N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-hydroxy-piperidine-4-carboxamide; (3S,4S)-N-[3-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-hydroxy-piperidine-4-carboxamide; N-[4-[2-[1-(azetidine-3-ylmethyl)azetidine-3-yl]ethylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]-1-(pyrrolidine-3-ylmethyl)piperidine-4-carboxamide; 1-(azetidine-3-ylmethyl)-N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]piperidine-4-carboxamide; N-[4-[[1-(azetidine-3-ylmethyl)-4-piperidyl]methylcarbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; 5-(4-methoxyphenyl)-1-methyl-N-[3-methyl-4-(methylcarbamoyl)phenyl]imidazole-2-carboxamide; N-[3-chloro-4-[[(exo)-3-[(2S,4R)-4-hydroxyprolyl]-3-azabicyclo[3.1.0]hexane6-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; (Exo)-6-[[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoyl]amino]-N-[(Trans)-4-hydroxypyrrolidine-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide A compound selected from, or a pharmaceutically acceptable salt thereof.

10. N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[1-[3-(2-aminoethoxy)propanoyl]pyrrolidine-3-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-(piperidine-4-carbonyl)-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[2-[1-(3-aminopropanoyl)azetidine-3-yl]ethylcarbamoyl]-3-chlorophenyl]-5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methylimidazole-2-carboxamide; N-[4-[[1-(2-aminoacetyl)azetidine-3-yl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[4-[[3-[(3-aminocyclobutyl)carbamoyl]cyclobutyl]carbamoyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[[3-[[(4R)-4-hydroxypyrrolidine-2-carbonyl]amino]cyclobutyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide; N-[3-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]piperidine-4-carboxamide; and (3S,4S)-N-[3-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-hydroxy-piperidine-4-carboxamide A compound selected from or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a therapeutically inactive carrier.

12. The pharmaceutical composition according to claim 11 for use as an antibiotic.

13. A pharmaceutical composition according to claim 11 or 12 for use in the treatment or prevention of hospital-acquired infections and diseases resulting therefrom.

14. A pharmaceutical composition according to any one of claims 11 to 13, for use in the treatment or prevention of infections caused by Gram-negative bacteria and diseases resulting therefrom.

15. The pharmaceutical composition according to claim 14, wherein the Gram-negative bacteria are selected from Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli.

16. The pharmaceutical composition according to claim 15, wherein the Gram-negative bacterium is Acinetobacter baumanni.

17. A pharmaceutical composition according to any one of claims 11 to 14, for use in the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

18. A method for treating or preventing infections and diseases caused by Enterococcus faecium, Staphylococcus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 10 to a mammal other than a human.

19. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for the preparation of a medicament useful for the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

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