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HK40078454A - Novel heterocyclic compounds - Google Patents

Novel heterocyclic compounds Download PDF

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Publication number
HK40078454A
HK40078454A HK62023067104.7A HK62023067104A HK40078454A HK 40078454 A HK40078454 A HK 40078454A HK 62023067104 A HK62023067104 A HK 62023067104A HK 40078454 A HK40078454 A HK 40078454A
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HK
Hong Kong
Prior art keywords
phenyl
carbonyl
methyl
chloro
imidazole
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Application number
HK62023067104.7A
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Chinese (zh)
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HK40078454B (en
Inventor
Cheng Zhanling
Han Xingchun
Kramer Christian
Lerner Christian
Liu Yongqiang
Nettekoven Matthias
Pflieger Philippe
Puellmann Bernd
Wang Jianhua
Wang Lisha
Wang Min
Wang Yongguang
Yang Song
Zhou Chengang
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F. Hoffmann-La Roche Ag
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Publication of HK40078454A publication Critical patent/HK40078454A/en
Publication of HK40078454B publication Critical patent/HK40078454B/en

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Description

Novel heterocyclic compound
Technical Field
The present invention relates to novel heterocyclic compounds that exhibit antibacterial properties. The invention also relates to methods of using the compounds to treat or prevent bacterial infections and diseases caused thereby, in particular, Acinetobacter baumannii (Acinetobacter baumannii) infections and diseases caused thereby.
Background
Acinetobacter baumannii is a gram-negative, aerobic, non-fermenting bacterium that has been considered an emerging pathogen with very limited therapeutic options in the past few decades.
Acinetobacter baumannii (a. baumannii) is considered a serious threat by the american centers for disease control and prevention and belongs to the so-called "ESKAPE" pathogens (Enterococcus faecalis), Staphylococcus aureus (Staphylococcus aureus), Klebsiella pneumoniae (Klebsiella pneumoniae), Acinetobacter baumannii (Acinetobacter baumannii), Pseudomonas aeruginosa (Pseudomonas aeruginosa) and Enterobacter species (Enterobacter species) and escherichia coli (e.coli)), which currently cause most nosocomial infections and effectively "escape" the activity of antimicrobials.
Acinetobacter baumannii is most commonly encountered in intensive care units and surgical units where the widespread use of antibiotics has enabled acinetobacter baumannii to select for resistance to all known antimicrobial agents, and where it causes infections including bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.
Acinetobacter baumannii has excellent ability to up-regulate and acquire determinants of drug resistance, and exhibits environmental persistence that allows it to survive and spread in hospital environments, making this organism a common cause of outbreaks of infection and endemic pathogens associated with health care.
Due to the increased antibiotic resistance to most, if not all, available treatment regimens, multi-drug resistant (MDR) acinetobacter baumannii infections, particularly infections caused by carbapenem-resistant acinetobacter baumannii, are difficult or even impossible to treat, have high mortality rates, and have increased morbidity and prolonged hospital stays in intensive care units.
Acinetobacter baumannii was defined according to the antimicrobial benefit assessment group (AATF) of the american society for Infectious Diseases (IDSA), which is still the "best illustration of the mismatch between unmet medical needs and current antimicrobial development approaches". Therefore, there is an urgent need and demand for the identification of compounds suitable for the treatment of diseases and infections caused by acinetobacter baumannii.
The present invention provides novel compounds that exhibit activity against drug sensitive and resistant strains of acinetobacter baumannii.
Disclosure of Invention
In a first aspect, the present invention provides a compound of formula (I)
Or a pharmaceutically acceptable salt thereof, wherein R 1 To R 4 M, n and p are as described herein.
In one aspect, the present invention provides a process for the preparation of a compound of formula (I) as described herein, wherein the process is as described in any one of schemes 1 to 5 herein.
In another aspect, the present invention provides a compound of formula (I) as described herein, prepared according to the process described herein.
In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein and a therapeutically inert carrier.
In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as an antibiotic.
In another aspect, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of nosocomial infections and diseases caused thereby.
In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, for use in the treatment or prevention of infections and diseases caused thereby by gram-negative bacteria.
In another aspect, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of infection by and disease caused by enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli, or a combination thereof.
In another aspect, the present invention provides a method for the treatment or prophylaxis of infection by and disease caused by enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli, or a combination thereof, which comprises administering to a mammal a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein as an antibiotic.
In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for the treatment or prophylaxis of infections and diseases caused by enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli, or combinations thereof.
In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, for the manufacture of a medicament for the treatment or prevention of infection by and disease resulting from enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli, or a combination thereof.
Detailed Description
Definition of
Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.
The term "alkyl" refers to 1 to 6 carbon atoms ("C 1 -C 6 -alkyl ") (e.g. 1,2,3, 4,5 or 6 carbon atoms) of a monovalent or polyvalent (e.g. monovalent or divalent) straight or branched chain saturated hydrocarbon group. In some embodiments, the alkyl group contains 1 to 3 carbon atoms, for example 1,2, or 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2, 2-dimethylpropyl. A particularly preferred but non-limiting example of an alkyl group is methyl.
The term "alkynyl" denotes a monovalent straight or branched chain hydrocarbon radical of 2 to 6 carbon atoms having at least one carbon-carbon triple bond ("C 2 -C 6 -alkynyl "). In particular embodiments, the alkynyl group has 2 to 4 carbon atoms and at least one triple bond. Examples of alkynyl include ethynyl, propynyl, n-butynyl or isobutynyl. The preferred alkynyl group is propynyl.
The term "alkoxy" means an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Unless otherwise indicated, alkoxy groups contain 1 to 6 carbon atoms ("C) 1 -C 6 -alkoxy "). In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred but non-limiting example of an alkoxy group is methoxy.
The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Preferably, the term "halogen" or "halo" refers to fluorine (F), chlorine (Cl) or bromine (Br). Particularly preferred but non-limiting examples of "halogen" or "halo" are fluorine (F) and chlorine (Cl).
The term "cycloalkyl" as used herein refers to 3 to 10 ring carbon atoms ("C) 3 -C 10 -cycloalkyl ") groups, saturated or partially unsaturated monocyclic or bicyclic hydrocarbon groups. In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. "bicyclic cycloalkyl" refers to cycloalkyl moieties consisting of two saturated carbocyclic rings having two common carbon atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) as well as spirocyclic moieties (i.e., the two rings are connected via one common ring atom). Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms (e.g., 3,4, 5, or 6 carbon atoms). Some non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and spiro [2.3 ]]Hexane-5-yl.
The term "aminoalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced with an amino group. Preferably, "aminoalkoxy" refers to an alkoxy group in which 1,2, or 3 hydrogen atoms of the alkoxy group have been substituted with an amino group. Preferred but non-limiting examples of aminoalkoxy are aminomethoxy and 1-aminoethoxy.
The term "aminoalkoxyalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced with an aminoalkoxy group. Preferably, "aminoalkoxyalkoxy" refers to an alkoxy group in which 1,2, or 3 hydrogen atoms of the alkoxy group have been replaced with an aminoalkoxy group. Most preferably, "aminoalkoxyalkoxy" refers to an alkoxy group in which 1 hydrogen atom of the alkoxy group has been replaced with an aminoalkoxy group.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, system having 3 to 10 ring atoms, preferably 3 to 8 ring atoms, wherein 1,2 or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, the remaining ring atoms being carbon. "bicyclic heterocyclyl" refers to a heterocyclic moiety consisting of two rings having two common ring atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) as well as a spiro moiety (i.e., the two rings are connected via one common ring atom). Some non-limiting examples of heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxopyrrolidin-1-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, 5-oxopyrrolidin-3-yl, 2-oxo-1-piperidinyl, 2-oxo-3-piperidinyl, 2-oxo-4-piperidinyl, 6-oxo-2-piperidinyl, 6-oxo-3-piperidinyl, 1-piperidinyl, 2-piperidinyl, piperidinyl, 3-piperidinyl, 4-piperidinyl, morpholino, morpholin-2-yl, morpholin-3-yl, pyrrolidinyl (e.g., pyrrolidin-3-yl), 3-azabicyclo [3.1.0] hex-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,4,6,6 a-hexahydro-1H-pyrrolo [3,4-c ] pyrrol-5-yl.
The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system ("C") having a total of 6 to 10 ring members 6 -C 10 -aryl ") and wherein at least one ring in the ring system is aromatic. A particularly preferred but non-limiting example of an aryl group is phenyl.
The term "heteroaryl" refers to a monovalent or polyvalent monocyclic or bicyclic, preferably bicyclic, ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, and more preferably 5 to 10 ring members, wherein at least one ring in the ring system is aromatic and at least one ring in the ring system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5-10 membered heteroaryl group containing 1,2,3 or 4 heteroatoms independently selected from O, S and N. Most preferably, "heteroaryl" refers to a 5-10 membered heteroaryl group containing 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl groups include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1, 2-benzoxazol-3-yl, 1, 2-benzoxazol-4-yl, 1, 2-benzoxazol-5-yl, 1, 2-benzoxazol-6-yl, 1, 2-benzooxazol-7-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-4-yl and 1,2, 4-oxadiazol-3-yl. Most preferably, "heteroaryl" refers to pyridinyl and pyrimidinyl.
The term "heteroaryloxy" refers to a heteroaryl group, as previously defined, appended to the parent molecular moiety through an oxygen atom.
The term "hydroxy" refers to an-OH group.
The term "amino" refers to the group-NH 2 A group.
The term "cyano" refers to the group — CN (nitrile).
The term "oxo" refers to a double bond oxygen (═ O).
The term "carbamoyl" refers to-C (O) NH 2 A group.
The term "carbamimidoyl" refers to a groupOr
The term "carboxy" refers to a-C (O) OH group (i.e., a carboxylic acid moiety).
The term "carbonyl" refers to a carbon radical (C ═ O) shared by two of the four covalent bonds and an oxygen atom.
The term "haloalkyl" refers to an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by a halogen atom, preferably fluorine. Preferably, "haloalkyl" refers to an alkyl group wherein 1,2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluorine. Non-limiting examples of haloalkyl groups are fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, 2-fluoroethyl and 2, 2-difluoroethyl. A particularly preferred but non-limiting example of haloalkyl is trifluoromethyl.
The term "cyanoalkyl" refers to an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a cyano group. Preferably, "cyanoalkyl" refers to an alkyl group wherein 1,2 or 3 hydrogen atoms of the alkyl group have been substituted with a cyano group. Most preferably, "cyanoalkyl" refers to an alkyl group wherein 1 hydrogen atom of the alkyl group has been replaced by a cyano group.
The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by a halogen atom, preferably fluorine. Preferably, "haloalkoxy" refers to an alkoxy group in which 1,2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluorine. A particularly preferred, but non-limiting example of haloalkoxy is Fluoromethoxy (FCH) 2 O-), difluoromethoxy (F) 2 CHO-), and trifluoromethoxy (F) 3 CO-)。
The term "cyanoalkoxy" refers to an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a cyano group. Preferably, "cyanoalkoxy" refers to an alkoxy group in which 1,2 or 3 hydrogen atoms of the alkoxy group have been replaced by a cyano group. Most preferably, "cyanoalkoxy" refers to an alkoxy group in which 1 hydrogen atom of the alkoxy group has been replaced by a cyano group.
The term "carbamoylalkoxy" refers to an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a carbamoyl group. Preferably, "carbamoylalkoxy" refers to an alkoxy group wherein 1,2 or 3 hydrogen atoms of the alkoxy group have been replaced by a carbamoyl group. Most preferably, "carbamoylalkoxy" refers to an alkoxy group wherein 1 hydrogen atom of the alkoxy group has been replaced by a carbamoyl group.
The term "alkoxyalkoxy" refers to an alkoxy group wherein at least one hydrogen atom of the alkoxy group has been replaced by an alkoxy group, preferably methoxy. Preferably, "alkoxyalkoxy" refers to an alkoxy group in which 1,2 or 3 hydrogen atoms of the alkoxy group have been replaced by an alkoxy group (preferably methoxy). A preferred but non-limiting example of an alkoxyalkoxy group is 2-methoxyethoxy.
The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a hydroxyl group. Preferably, "hydroxyalkyl" refers to an alkyl group wherein 1,2 or 3 hydrogen atoms (most preferably 1 hydrogen atom) of the alkyl group have been replaced by a hydroxyl group. Preferred, but non-limiting examples of hydroxyalkyl groups are hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), and 3-hydroxy-3-methyl-butyl.
The term "aminoalkyl" refers to an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced with an amino group. Preferably, "aminoalkyl" refers to an alkyl group wherein 1,2, or 3 hydrogen atoms (most preferably 1 hydrogen atom) of the alkyl group have been replaced with an amino group. Preferred but non-limiting examples of aminoalkyl groups are aminomethyl, aminoethyl (e.g., 2-aminoethyl), and 3-amino-3-methyl-butyl.
The term "carboxyalkyl" refers to an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by a carboxy group. Preferably, "carboxyalkyl" refers to an alkyl group wherein 1,2 or 3 hydrogen atoms (most preferably 1 hydrogen atom) of the alkyl group have been replaced by a carboxyl group. Preferred, but non-limiting, examples of carboxyalkyl groups are carboxymethyl, carboxyethyl (e.g., 2-carboxyethyl), and 3-carboxy-3-methyl-butyl.
The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effects and properties of the free base or free acid, which are not biologically or otherwise undesirable. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, 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, N-acetylcysteine and the like. In addition, these salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, and the like). Specific pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride, fumarate, lactate (especially derived from L- (+) -lactic acid), tartrate (especially derived from L- (+) -tartaric acid) and trifluoroacetate salts.
The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers (e.g., racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.
According to the Cahn-Ingold-Prelog convention, asymmetric carbon atoms may be in either the "R" or "S" configuration.
The term "treating" as used herein includes: (1) inhibiting the state, disorder or condition of at least one clinical or subclinical symptom of the disease (e.g., arresting, reducing, or delaying the progression of the disease or its recurrence in the context of maintenance therapy); and/or (2) remission (i.e., resolution of the state, disorder or condition of the disease or at least one clinical or subclinical symptom). The benefit to the patient to be treated is statistically significant or at least perceptible to the patient or physician. However, it is understood that when a drug is administered to a patient to treat a disease, the results may not always be an effective treatment.
The term "control" as used herein includes: preventing or delaying the onset of clinical symptoms of a state, disorder or condition that develops in a mammal, particularly a human, that may be afflicted with or susceptible to the state, disorder or condition but that has not yet experienced or exhibited clinical or subclinical symptoms of the state, disorder or condition.
The term "mammal" as used herein includes humans and non-humans, and includes, but is not limited to, humans, non-human primates, dogs, cats, mice, cows, horses, and pigs. In a particularly preferred embodiment, the term "mammal" refers to a human.
The term "nosocomial infection" refers to a hospital-acquired infection (HAI), which is an infection acquired in a hospital or other health care facility. To emphasize the hospital and non-hospital environment, it is sometimes also referred to as health care related infection (HAI or HCAI). Such infections may be obtained in hospitals, nursing homes, rehabilitation facilities, outpatient clinics, or other clinical settings.
Compounds of the invention
In a first aspect, the present invention provides a compound of formula (I)
Or a pharmaceutically acceptable salt thereof, wherein:
R 1 independently at each occurrence, selected from hydroxy, halogen, cyano, amino, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, amino-C 1 -C 6 -alkoxy-, radicalAnd a group C 1 -C 6 -alkyl-L 2 -; wherein C is 1 -C 6 -alkyl is optionally substituted with 1-3 substituents selected from: hydroxy, amino, halogen, cyano, C 1 -C 6 -alkyl-NH-, (C) 1 -C 6 -alkyl groups) 2 N-, amino-C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-, carbamoyl-C 1 -C 6 -alkoxy-, amidino, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkoxy-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-C (O) -NH-C 1 -C 6 -alkoxy-, C 2 -C 6 -alkynyl-NH-, carboxy and C 1 -C 6 -an alkoxy group;
R 2 independently at each occurrence, selected from halogen, cyano, C 1 -C 6 Alkyl radical, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl and halo-C 1 -C 6 -an alkoxy group;
R 3 selected from hydrogen, C 1 -C 6 -alkyl and halo-C 1 -C 6 -an alkyl group;
R 4 independently at each occurrence selected from halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 -alkoxy, cyano, halo-C 1 -C 6 -alkyl, cyano-C 1 -C 6 Alkyl radicals, (C) 1 -C 6 -alkyl groups) 2 N-, halo-C 1 -C 6 -alkoxy, cyano-C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-, (C) 1 -C 6 -alkyl groups) 2 N-C (O) -and 5-to 14-membered heteroaryloxy; and is provided with
R 5 Independently at each occurrence, selected from amino, hydroxy, C 1 -C 6 Alkyl, amino-C 1 -C 6 -alkyl-, hydroxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, (C) 1 -C 6 -alkyl groups) 2 N-、(C 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 alkyl-C (O) -, oxo, carbamoyl-C 1 -C 6 -alkyl, carboxyRadical, carboxy-C 1 -C 6 Alkyl, halogen (fluoro), cyano, C 1 -C 6 aminoalkyl-S (O) 2 -and group
R 6 Independently at each occurrence, selected from amino, hydroxy, C 1 -C 6 Alkyl, amino-C 1 -C 6 -alkyl-, hydroxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, (C) 1 -C 6 -alkyl groups) 2 N–、(C 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 alkyl-C (O) -, oxo, carbamoyl-C 1 -C 6 Alkyl, carboxyl-C 1 -C 6 Alkyl, halogen, cyano and C 1 -C 6 aminoalkyl-S (O) 2 –；
A is a 3-to 14-membered heterocyclyl;
b and C are independently selected from 3-to 14-membered heterocyclyl, C 3 -C 10 -cycloalkyl, 5-to 14-membered heteroaryl and C 6 -C 10 -an aryl group;
L 1 and L 3 Independently selected from covalent bonds, -O-, -NH-, -N (C) 1 -C 6 -alkyl) -, -CH 2 O–、–OCH 2 –、–(CH 2 ) s C(O)–、–CH 2 NHC(O)–、–CH 2 C(O)NH–、–CH 2 –、–NHC(O)–、–S(O) 2 –、–S(O) 2 NH–、–C(O)NH(CH 2 ) 2 -and-NH-nhc (o) -;
L 2 selected from the group consisting of covalent bonds, carbonyl, -S (O) 2 -, -NHC (O) -, -C (O) NH-and-S (O) 2 NH–；
m is 1,2,3 or 4;
n is 0, 1,2,3 or 4;
p is 0, 1,2,3, 4 or 5;
q is 0, 1 or 2;
r is 0 or 1; and is
s is 0, 1,2,3 or 4.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein m is 1.
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is 1 Selected from amino, amino-C 1 -C 6 -alkoxy, radicalAnd a group C 1 -C 6 -alkyl-L 2 -; wherein:
C 1 -C 6 -alkyl is substituted with 1-2 substituents selected from: hydroxy, amino, cyano, C 1 -C 6 -alkyl-NH-, (C) 1 -C 6 -alkyl groups) 2 N-, amino-C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-, carbamoyl-C 1 -C 6 -alkoxy-, amidino, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkoxy-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-C (O) -NH-C 1 -C 6 -alkoxy-, C 2 -C 6 -alkynyl-NH-, carboxy and C 1 -C 6 -an alkoxy group; and
wherein R is 5 、q、B、L 1 And L 2 As defined herein.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is 1 Is a groupWherein R is 5 、q、B、L 1 And L 2 As used hereinAnd (4) defining.
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L 1 Is selected from-CH 2 O–、–(CH 2 ) s C(O)–、–CH 2 NHC(O)–、–CH 2 C(O)NH–、–CH 2 –、–NHC(O)–、–S(O) 2 –、–S(O) 2 NH–、–C(O)NH(CH 2 ) 2 -and-NH-NHC (O) -.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L 1 Selected from carbonyl, -CH 2 C(O)–、–CH 2 NHC (O) -and NHC (O) -.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L 2 Selected from the group consisting of covalent bonds, carbonyl, -S (O) 2 -, -NHC (O) -, -C (O) NH-and-S (O) 2 NH–。
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1 or 2.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein s is 0, 1 or 4.
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from 3-to 14-membered heterocyclyl, C 3 -C 10 -cycloalkyl and 5-to 14-membered heteroaryl.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is a 3-to 14-membered heterocyclyl.
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein B is selected from azetidinyl, pyrrolidinyl, 3-azabicyclo [3.1.0] hexanyl and piperidinyl.
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently at each occurrence, selected from amino, hydroxy, C 1 -C 6 Alkyl, amino-C 1 -C 6 -alkyl-, hydroxy-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl groups) 2 N-、(C 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 alkyl-C (O) -, oxo, carbamoyl-C 1 -C 6 Alkyl, carboxyl-C 1 -C 6 Alkyl, halogen, aminoalkyl-S (O) 2 -and groupWherein R is 6 R, C and L 3 As defined herein.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently at each occurrence, selected from amino, hydroxy and hydroxy-C 1 -C 6 -alkyl-.
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is 5 Independently at each occurrence, is selected from the group consisting of amino, hydroxy, and hydroxymethyl.
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L 3 Is a covalent bond or a carbonyl group.
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1.
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein C is C 3 -C 10 -cycloalkyl or 3-to 14-membered heterocyclyl.
In one embodiment, the inventionThe invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 6 Is a hydroxyl group.
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
m is 1; and is
R 1 Selected from amino, amino-C 1 -C 6 -alkoxy-, radicalAnd a group C 1 -C 6 -alkyl-L 2 -; wherein:
C 1 -C 6 -alkyl is substituted with 1-2 substituents selected from: hydroxy, amino, cyano, C 1 -C 6 -alkyl-NH-, (C) 1 -C 6 -alkyl groups) 2 N-, amino-C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-, carbamoyl-C 1 -C 6 -alkoxy-, amidino, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkoxy-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-C (O) -NH-C 1 -C 6 -alkoxy-, C 2 -C 6 -alkynyl-NH-, carboxy and C 1 -C 6 -an alkoxy group;
L 1 is selected from-CH 2 O–、–(CH 2 ) s C(O)–、–CH 2 NHC(O)–、–CH 2 C(O)NH–、–CH 2 –、–NHC(O)–、–S(O) 2 –、–S(O) 2 NH–、–C(O)NH(CH 2 ) 2 -and-NH-nhc (o) -;
L 2 selected from the group consisting of covalent bond, carbonyl, -S (O) 2 -, -NHC (O) -, -C (O) NH-and-S (O) 2 NH–；
q is 0, 1 or 2;
s is 0, 1 or 4;
b is selected from 3-to 14-membered heterocyclic group, C 3 -C 10 -cycloalkanesA 5-to 14-membered heteroaryl; and is
R 5 Independently at each occurrence, selected from amino, hydroxy, C 1 -C 6 Alkyl, amino-C 1 -C 6 -alkyl-, hydroxy-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl groups) 2 N–、(C 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 alkyl-C (O) -, oxo, carbamoyl-C 1 -C 6 Alkyl, carboxyl-C 1 -C 6 Alkyl, halogen, aminoalkyl-S (O) 2 -and groupWherein:
L 3 is a covalent bond or a carbonyl group;
r is 0 or 1;
c is C 3 -C 10 -cycloalkyl or 3-to 14-membered heterocyclyl; and is
R 6 Is a hydroxyl group.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
m is 1; and is provided with
R 1 Is a groupWherein:
L 1 selected from carbonyl, -CH 2 C(O)–、–CH 2 NHC (O) -and NHC (O) -;
q is 0 or 1;
b is a 3-to 14-membered heterocyclyl; and is
R 5 Selected from amino, hydroxy and hydroxy-C 1 -C 6 -alkyl-.
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
m is 1; and is provided with
R 1 Is a groupWherein:
L 1 selected from carbonyl, -CH 2 C(O)–、–CH 2 NHC (O) -and NHC (O) -;
q is 0 or 1;
b is selected from azetidinyl, pyrrolidinyl, 3-azabicyclo [3.1.0] hexanyl, and piperidinyl; and is
R 5 Selected from amino, hydroxy and hydroxymethyl-.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein n is 1 and R is 2 Selected from halogen and C 1 -C 6 -an alkyl group.
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein n is 1 and R is 2 Selected from chlorine and methyl.
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (II):
wherein R is 1 、R 2 、R 3 And R 4 M and p are as defined herein.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 Is C 1 -C 6 -an alkyl group.
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 Is methyl.
In one embodiment, the present invention provides a method as described hereinA compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein p is 1,2,3 or 4, and R 4 Independently at each occurrence, selected from halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 -alkoxy, cyano, halo-C 1 -C 6 -alkyl, cyano-C 1 -C 6 Alkyl radicals, (C) 1 -C 6 -alkyl groups) 2 N-, halo-C 1 -C 6 -alkoxy, cyano-C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-, (C) 1 -C 6 -alkyl groups) 2 N-C (O) -and heteroaryloxy.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 2 or 3 and R is 4 Independently at each occurrence is selected from C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy and cyano-C 1 -C 6 -alkoxy groups.
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 2 or 3 and R is 4 Independently at each occurrence, is selected from the group consisting of fluorine, chlorine, methoxy, FCH 2 O–,F 2 CHO-and CNCH 2 O–。
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (III):
wherein:
R 4a selected from hydrogen, halogen, C 1 -C 6 -alkyl, cyano and halo-C 1 -C 6 -an alkyl group;
R 4b selected from hydrogen, halogen, cyano and C 1 -C 6 -an alkoxy group;
R 4c selected from halogen, C 1 -C 6 -alkoxy, cyano-C 1 -C 6 -alkyl, cyano-C 1 -C 6 -alkoxy, (C) 1 -C 6 -alkyl groups) 2 N-, halo-C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, (C) 1 -C 6 -alkyl groups) 2 N-C (O) -and heteroaryloxy;
R 4d selected from hydrogen and halogen; and is
Wherein R is 1 、R 2 、R 3 M and n are as defined herein.
In a preferred embodiment, the present invention provides a compound of formula (III) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
R 4a is halogen;
R 4b selected from hydrogen and halogen;
R 4c is selected from C 1 -C 6 -alkoxy, cyano-C 1 -C 6 -alkoxy and halo-C 1 -C 6 -an alkoxy group; and is
R 4d Is hydrogen.
In a particularly preferred embodiment, the present invention provides a compound of formula (III) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
R 4a selected from fluorine and chlorine;
R 4b selected from hydrogen, fluorine and chlorine;
R 4c selected from methoxy, FCH 2 O–、F 2 CHO-and CNCH 2 O-; and is provided with
R 4d Is hydrogen.
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
m is 1; and is
R 1 Selected from amino, amino-C 1 -C 6 -alkoxy-, radicalAnd a group C 1 -C 6 -alkanesradical-L 2 -; wherein:
C 1 -C 6 -alkyl is substituted with 1-2 substituents selected from: hydroxy, amino, cyano, C 1 -C 6 -alkyl-NH-, (C) 1 -C 6 -alkyl groups) 2 N-, amino-C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-, carbamoyl-C 1 -C 6 -alkoxy-, amidino, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkoxy-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-C (O) -NH-C 1 -C 6 -alkoxy-, C 2 -C 6 -alkynyl-NH-, carboxy and C 1 -C 6 -an alkoxy group;
L 1 is selected from-CH 2 O–、–(CH 2 ) s C(O)–、–CH 2 NHC(O)–、–CH 2 C(O)NH–、–CH 2 –、–NHC(O)–、–S(O) 2 –、–S(O) 2 NH–、–C(O)NH(CH 2 ) 2 -and-NH-nhc (o) -;
L 2 selected from the group consisting of covalent bonds, carbonyl, -S (O) 2 -, -NHC (O) -, -C (O) NH-and-S (O) 2 NH–；
q is 0, 1 or 2;
s is 0, 1 or 4;
b is selected from 3-to 14-membered heterocyclic group, C 3 -C 10 -cycloalkyl and 5-to 14-membered heteroaryl; and is
R 5 Independently at each occurrence, selected from amino, hydroxy, C 1 -C 6 Alkyl, amino-C 1 -C 6 -alkyl-, hydroxy-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl groups) 2 N–、(C 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 alkyl-C (O) -, oxo, carbamoyl-C 1 -C 6 -an alkyl group,Carboxy, carboxy-C 1 -C 6 Alkyl, halogen, aminoalkyl-S (O) 2 -and groupWherein:
L 3 is a covalent bond or a carbonyl group;
r is 0 or 1;
c is C 3 -C 10 -cycloalkyl or 3-to 14-membered heterocyclyl;
R 6 is a hydroxyl group;
n is 1;
R 2 selected from halogen and C 1 -C 6 -an alkyl group;
R 3 is C 1 -C 6 -an alkyl group;
p is 1,2,3 or 4; and is
R 4 Independently at each occurrence, selected from halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 -alkoxy, cyano, halo-C 1 -C 6 -alkyl, cyano-C 1 -C 6 Alkyl radicals, (C) 1 -C 6 -alkyl groups) 2 N-, halo-C 1 -C 6 -alkoxy, cyano-C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-, (C) 1 -C 6 -alkyl groups) 2 N-C (O) -and heteroaryloxy.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
m is 1; and is
R 1 Is a groupWherein:
L 1 selected from carbonyl, -CH 2 C(O)–、–CH 2 NHC (O) -and NHC (O) -;
q is 0 or 1;
b is a 3-to 14-membered heterocyclyl; and is provided with
R 5 Selected from amino, hydroxy and hydroxy-C 1 -C 6 -alkyl-
n is 1;
R 2 selected from halogen and C 1 -C 6 -an alkyl group;
R 3 is C 1 -C 6 -an alkyl group;
p is 2 or 3; and is
R 4 Independently at each occurrence, selected from halogen, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy and cyano-C 1 -C 6 -an alkoxy group.
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
m is 1; and is provided with
R 1 Is a groupWherein:
L 1 selected from carbonyl, -CH 2 C(O)–、–CH 2 NHC (O) -and NHC (O) -;
q is 0 or 1;
b is selected from azetidinyl, pyrrolidinyl, 3-azabicyclo [3.1.0] hexanyl, and piperidinyl; and is
R 5 Selected from amino, hydroxy and hydroxymethyl-;
n is 1;
R 2 selected from chlorine and methyl;
R 3 is methyl;
p is 2 or 3; and is
R 4 Independently at each occurrence, is selected from the group consisting of fluorine, chlorine, methoxy, FCH 2 O–、F 2 CHO-and CNCH 2 O–。
In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from:
n- [ 3-chloro-4- [4- [ (3R) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4S) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,3S) -3-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [3- (dimethylamino) propyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [2- (methylamino) ethyl ] piperidine-4-carboxamide;
n- [4- [4- [ (3R) -3-aminopyrrolidine-1-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- (aminomethyl) morpholine-4-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3R) -3- (hydroxymethyl) piperazine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (2S,4S) -4-aminopyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S) -pyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S) -piperidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S) -piperidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (2-aminoethyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (methylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2R) -pyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (3-amino-2-hydroxy-propyl) -1- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-N- [ 3-methyl-4- [4- [ (3R) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S) -3- (hydroxymethyl) piperazine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (1, 1-dioxo-1, 4-thiazinane-4-carbonyl) piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-N- [ 3-methyl-4- [4- [2- (methylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (morpholine-4-carbonyl) piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-N- [ 3-methyl-4- [4- (morpholine-4-carbonyl) piperidine-1-carbonyl ] phenyl ] imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (2, 6-diazaspiro [3.3] heptane-2-carbonyl) piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -N- [4- [4- (1, 1-dioxo-1, 4-thiazinan-4-carbonyl) piperidine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (2R) -2- (aminomethyl) morpholine-4-carbonyl ] piperidine-1-carbonyl ] -3-methyl-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (thiomorpholine-4-carbonyl) piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-aminoazetidine-1-carbonyl) piperidine-1-carbonyl ] -3-methyl-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (aminomethyl) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (5-hydroxypiperidine-3-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (2-aminoethyl) -4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperazine-1-carboxamide;
n- [ 3-chloro-4- (4-piperazin-1-ylsulfonylpiperidine-1-carbonyl) phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ [ (2S) -pyrrolidine-2-carbonyl ] amino ] ethyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (2S) -2- (aminomethyl) morpholine-4-carbonyl ] piperidine-1-carbonyl ] -3-methyl-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-piperidinylsulfonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- [ (2-amino-2-oxo-ethyl) amino ] ethyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
(3R) -1- [2- [4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperazin-1-yl ] -2-oxo-ethyl ] pyrrolidine-3-carboxylic acid;
1- [2- [4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperazin-1-yl ] -2-oxo-ethyl ] azetidine-3-carboxylic acid;
5- [ 3-chloro-4- (cyanomethoxy) -2-fluoro-phenyl ] -N- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -5- (3-fluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ rac- (1R,5S) -3-azabicyclo [3.1.0] hexane-6-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (2-aminoethyl) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3R) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-aminocyclobutanecarbonyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-aminocyclobutanecarbonyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (3-hydroxypyrrolidine-3-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -3-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- (azetidin-3-yl) acetyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-3-fluoro-4- (fluoromethoxy) phenyl ] -N- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [ 2-chloro-3-fluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
5- [ 2-chloro-4- (difluoromethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-hydroxypyrrolidine-3-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ [ (3R) -pyrrolidin-3-yl ] methyl ] piperidine-4-carboxamide;
n- [4- [4- (2-aminoacetyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (2S) -azetidine-2-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (2-pyrrolidin-1-ylacetyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (2-pyrrolidin-3-ylacetyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2R) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3R) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2S) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3R) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ [ (3R) -pyrrolidin-3-yl ] methyl ] piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ [ (3S) -pyrrolidin-3-yl ] methyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- (3-hydroxypyrrolidin-1-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3-hydroxyazetidin-3-yl) methyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2S) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2S) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (3-hydroxyazetidin-3-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [1- (2-aminoethyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (azetidine-3-carbonyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (pyrrolidin-3-ylmethyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S) -pyrrolidin-3-yl ] piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ rac- (1S,5R) -3-azabicyclo [3.1.0] hex-6-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (dimethylamino) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-5- (2,3, 5-trifluoro-4-methoxy-phenyl) imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ rac- (1S,5R) -3-azabicyclo [3.1.0] hex-6-yl ] piperidine-4-carboxamide;
n- [4- [3- (2-aminoethoxy) azetidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [ 2-chloro-3-fluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ [ (3R) -pyrrolidin-3-yl ] methyl ] piperidine-4-carboxamide;
5- [ 2-chloro-4- (difluoromethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (4-ethoxy-2, 3-difluoro-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (5-hydroxypiperidine-3-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-4- (difluoromethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-3-fluoro-4- (fluoromethoxy) phenyl ] -N- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [1- (azetidine-3-carbonyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -3-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (azetidin-2-ylmethyl) -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- (3-hydroxyazetidin-3-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- (azetidin-3-yl) acetyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [1- (4-hydroxypiperidine-4-carbonyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2S) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -3-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R) -pyrrolidin-3-yl ] piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- [ 2-chloro-3-fluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S) -pyrrolidin-3-yl ] piperidine-4-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (4-ethoxy-2, 3-difluoro-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [3- [3- (aminomethyl) azetidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
3- [ [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carbonyl ] amino ] propanoic acid;
4- [ [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carbonyl ] amino ] butanoic acid;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (dimethylcarbamoyl) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ rac- (1R,5S) -3-azabicyclo [3.1.0] hexane-6-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [3- (aminomethyl) cyclobutanecarbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (2-amino-2-oxo-ethyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [ rac- (3aR,6aS) -5- (piperidine-4-carbonyl) -1,3,3a,4,6,6 a-hexahydropyrrolo [3,4-c ] pyrrole-2-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (3-hydroxyazetidin-1-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] azetidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [3- (piperazine-1-carbonyl) azetidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [ rac- (3aR,6aS) -5- [ rac- (3R) -pyrrolidine-3-carbonyl ] -1,3,3a,4,6,6 a-hexahydropyrrolo [3,4-c ] pyrrole-2-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [3- [ [2- (dimethylamino) acetyl ] amino ] azetidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [3- [ rac- (3aR,6aS) -2,3,3a,4,6,6 a-hexahydro-1H-pyrrolo [3,4-c ] pyrrole-5-carbonyl ] azetidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [ rac- (3aS,6aR) -2- [2- (dimethylamino) acetyl ] -1,3,3a,4,6,6 a-hexahydropyrrolo [3,4-c ] pyrrole-5-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-5- (2,3, 4-trifluorophenyl) imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (3-cyano-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [3- [ rac- (3aR,6aR) -2,3,3a,4,6,6 a-hexahydro-1H-pyrrolo [3,4-c ] pyrrole-5-carbonyl ] pyrrolidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (3-cyano-2, 4-difluoro-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [ [2- (dimethylamino) acetyl ] amino ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] -2-ethyl-benzoyl ] -N- [3- (prop-2-ynylamino) propyl ] piperidine-4-carboxamide;
5- (2, 3-difluoro-4-methoxy-phenyl) -N- [4- [4- [4- [3- (dimethylamino) propyl ] piperazine-1-carbonyl ] piperidine-1-carbonyl ] -3-ethyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (2-aminoethyl) -1- [4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] -2-ethyl-benzoyl ] piperidine-4-carboxamide;
1- [4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] -2-ethyl-benzoyl ] -N- [2- [2- (dimethylamino) ethoxy ] ethyl ] piperidine-4-carboxamide;
5- [4- (difluoromethoxy) phenyl ] -N- [4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] -3-ethyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- (2-chloro-4-methoxy-phenyl) -N- [4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] -3-ethyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] -3-ethyl-phenyl ] -5- (3-fluoro-4-isopropoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (3-cyclobutyl-1, 2, 4-oxadiazol-5-yl) methyl ] piperidine-1-carbonyl ] -3-ethyl-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
n- [ 3-chloro-4- [4- [ (3S,4S) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4S) -4-hydroxy-4-methyl-pyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S,4R) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
4- [4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] -2-methyl-benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4S) -4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -N- [4- [4- [ (2S,4S) -4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -N- [4- [4- [ (2S,4S) -4-hydroxy-4-methyl-pyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3R,4S) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- (2, 3-difluoro-4-methoxy-phenyl) -N- [4- [4- [ (3R,4R) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3R,4R) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
n- [ 3-chloro-4- (piperazine-1-carbonyl) phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S,4R) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-guanidinobutyryl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-aminopropionyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (5-aminopentanoyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
3-chloro-4- [4- (3-cyanopropionyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-aminopropionylamino) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-yl) -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [4- [4- [ (1S,3R) -3-aminocyclopentanecarbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (2-aminoethylsulfonylamino) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- (4-piperidinyl) piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- (4-pyridylmethyl) piperidine-4-carboxamide;
5- [ 2-chloro-4- (cyanomethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- [ (3R) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-4- (cyanomethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- [ (3S) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4R) -4-fluoropyrrolidin-3-yl ] piperidine-4-carboxamide;
5- [ 3-chloro-2-fluoro-4- (fluoromethoxy) phenyl ] -N- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4R) -4-fluoropyrrolidin-3-yl ] piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ [ (3S) -pyrrolidin-3-yl ] methyl ] piperidine-4-carboxamide;
n- [4- [4- (2-aminoethoxy) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (azetidin-3-ylmethoxy) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (4-aminobutyryl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ (2S) -2-aminopropyl ] -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [4- [4- [1- (2-aminoethyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [1- [2- (dimethylamino) acetyl ] piperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (4-aminopiperidine-1-carbonyl) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [2- (difluoromethyl) -3-fluoro-4-methoxy-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (pyrrolidin-3-ylsulfonylamino) piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (3S) -3-aminopyrrolidine-1-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-4- (cyanomethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (3R) -3-aminopyrrolidine-1-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ [ (3R) -pyrrolidin-3-yl ] methyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- (4-piperidinylsulfonylamino) piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [3- (dimethylamino) azetidine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-4- (cyanomethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-carbamoylpyrrolidine-1-carbonyl) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [4- [4- [1- (2-amino-2-oxo-ethyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [1- (2-aminoethylsulfonyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4S) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- (4-methylsulfonylpiperazine-1-carbonyl) phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (methylsulfonylamino) piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (2-aminoethylsulfonyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (2-oxoimidazolidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [3- (2-aminoethyl) azetidine-1-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2-pyrrolidin-3-ylacetyl) amino ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [ 3-fluoro-4- (fluoromethoxy) -2-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 3-chloro-2-fluoro-4- (fluoromethoxy) phenyl ] -N- [4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (3S,4S) -3-amino-4-fluoro-pyrrolidine-1-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- (4-pyrrolidin-3-ylsulfonylpiperazine-1-carbonyl) phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-aminobicyclo [1.1.1] pentane-1-carbonyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ [ (1-methyl-4-piperidinyl) amino ] carbamoyl ] piperidine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2-cyano-3-fluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (5-oxopyrrolidin-3-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [3- (dimethylamino) propionylamino ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-4- (cyanomethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 3-chloro-4- (cyanomethoxy) phenyl ] -N- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- (4-piperidinylmethyl) piperidine-4-carboxamide;
n- [4- [4- [3- (aminomethyl) azetidine-1-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (methylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-aminoazetidine-1-carbonyl) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] amino ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [3- [2- (2-aminoethoxy) ethoxy ] propionyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (5-oxopyrrolidin-2-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (5-oxopyrrolidine-2-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [ 3-chloro-4- [4- [ (2S,4S) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- (4-aminopiperidine-1-carbonyl) -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (methylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (6-oxopiperidine-3-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (2-azaspiro [3.3] heptane-6-carbonyl) piperazine-1-carbonyl ] -3-methyl-phenyl ] -5- (2-chloro-3-fluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [ 3-chloro-4- [4- [ (3R) -3- (hydroxymethyl) piperazine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [ 3-chloro-4- [4- [ (2R,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [6- [ (3R) -3- (hydroxymethyl) piperazine-1-carbonyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [3- [2- [ [2- (dimethylamino) acetyl ] amino ] ethoxy ] propionyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -1-methyl-N- [ 3-methyl-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] imidazole-2-carboxamide;
n- [ 3-chloro-4- [3- [ [ rac- (3R) -pyrrolidine-3-carbonyl ] amino ] pyrrolidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- (2, 6-diazaspiro [3.3] heptane-2-carbonyl) phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ (1S) -2-amino-1-methyl-ethyl ] -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [ (3R) -3- (hydroxymethyl) piperazine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] pyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [ (3S) -3- (hydroxymethyl) piperazine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [2- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] -2, 6-diazaspiro [3.3] heptane-6-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2-fluoro-3, 4-dimethoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [5- [ (3aS,4S,6aR) -2-oxo-1, 3,3a,4,6,6 a-hexahydrothieno [3,4-d ] imidazol-4-yl ] pentanoyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (2, 5-dioxoimidazolidin-4-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [3- [3- (2-aminoethoxy) propionylamino ] pyrrolidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
2- [4- [4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperazine-1-carbonyl ] -1-piperidinyl ] acetic acid;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (2-methoxyethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (2-pyridinyloxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (4-pyridinyloxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (3, 4-difluoro-5-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-pyrimidin-2-yloxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethyl) -2-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl]-3-methyl-phenyl]-9-methoxy-6, 7-dihydro-5H-imidazo [5,1-a [ ]][2]Benzazepine compounds-3-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [3- (2-aminoethoxy) propionyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [1- (2-amino-2-oxo-ethyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (3R) -3-aminopyrrolidine-1-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S) -pyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2S) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [ 2-fluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (2-aminoethyl) -1- [ 2-chloro-4- [ [5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- (2-aminoethyl) -1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- (4-piperidinyl) piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R) -pyrrolidin-3-yl ] piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- (4-piperidinyl) piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [ 2-fluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R) -pyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [4- [3- [ [3- (aminomethyl) cyclobutanecarbonyl ] amino ] azetidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [3- [ (2-aminoacetyl) amino ] azetidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-carbamoylcyclobutanecarbonyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (3-hydroxycyclobutanecarbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (3-methoxypropionyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [3- (3-amino-3-oxo-propoxy) propionyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide; and
n- [4- [4- (5-amino-5-oxo-pentanoyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from:
n- [ 3-chloro-4- [4- [ rac- (1R,5S) -3-azabicyclo [3.1.0] hexane-6-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- [ 3-chloro-2-fluoro-4- (fluoromethoxy) phenyl ] -N- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- (2-pyrrolidin-3-ylacetyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- (azetidin-3-yl) acetyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- [ 3-chloro-2-fluoro-4- (fluoromethoxy) phenyl ] -N- [4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4S) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,3S) -3-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
n- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- (azetidin-3-yl) acetyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2S) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3R) -3- (hydroxymethyl) piperazine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
n- [4- [4- [ (2S,4S) -4-aminopyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
n- [ 3-chloro-4- [4- [ (3S,4R) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S,4R) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
4- [4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] -2-methyl-benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide; and
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide.
In one embodiment, the present invention provides pharmaceutically acceptable salts of compounds of formula (I) as described herein, especially pharmaceutically acceptable salts selected from the hydrochloride, fumarate, lactate (especially derived from L- (+) -lactic acid), tartrate (especially derived from L- (+) -tartaric acid) and trifluoroacetate salts. In yet another particular embodiment, the present invention provides a compound according to formula (I) as described herein (i.e. as "free base" or "free acid", respectively).
In some embodiments, the compounds of formula (I) are isotopically labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, respectively, such as but not limited to 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 36 Cl、 123 I and 125 I. certain isotopically-labeled compounds of formula (I) (e.g., those containing a radioisotope) are useful in drug and/or matrix tissue distribution studies. Radioisotope tritium (i.e. tritium 3 H) And carbon-14 (i.e. 14 C) This is particularly useful because they are easily incorporated and detection means are readily available. For example, the compound of formula (I) may be enriched in 1,2, 5, 10, 25, 50, 75, 90, 95 or 99% of a given isotope.
With heavier isotopes such as deuterium, i.e. 2 H) Substitution may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
Use justElectron emitting isotopes (such as 11 C、 18 F、 15 O and 13 n) substitutions can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the examples set forth below using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously used.
Preparation process
The preparation of the compounds of formula (I) according to the invention can be carried out by continuous or convergent synthetic routes. The synthesis of the compounds of the invention is shown in the following scheme. The skills required to carry out the reaction and purification of the resulting product are known to those skilled in the art. Unless stated to the contrary, the substituents and indices used in the description of the procedures below have the meanings given herein before. In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples, or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. Also, see, for example, the literature for reported reaction conditions that affect the reaction: comprehensive Organic Transformations A Guide to Functional Group Preparations,3rd Edition, Richard C.Larock. John Wiley & Sons, New York, N.Y. 2018. We have found it convenient to carry out the reaction in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent used, as long as it has no adverse effect on the reaction or the reagents involved and can dissolve the reagents, at least to some extent. The reaction described can occur over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reaction in a temperature range between-78 ℃ and reflux temperature. The time required for the reaction can also vary widely, depending on a number of factors, in particular the reaction temperature and the nature of the reagents. However, a time of 0.5 hours to several days is generally sufficient to produce the described intermediates and compounds. The reaction sequence is not limited to the reaction sequence shown in the scheme, however, the order of the reaction steps may be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods analogous to those given below, by methods described in the specification or in the references cited in the examples or by methods known in the art.
Unless otherwise indicated, all substituents, in particular R 2 To R 4 As defined hereinabove and in the claims. In addition, unless otherwise expressly stated, all reactions, reaction conditions, abbreviations and symbols have the meaning well known to those of ordinary skill in the art of organic chemistry.
Scheme 1
Wherein Ra is alkyl, in particular Me, Et or isobutyl.
Form I intermediates may be prepared according to scheme 1. 5-bromo-1-methyl-imidazole can be acylated with isobutyl chloroformate under basic conditions (such as DIPEA in DCM) to give Ia (step a). The acid Ib may be prepared by using a suitable base and a suitable solvent (e.g.K) at room temperature 2 CO 3 EtOH/water solution) of Ia (step b). Ib and amine Ic with condensing agents (such as CDI, DCC, HATU, HBTU, T) 3 P) in a suitable solvent (such as DMF, DMA or dioxane), optionally in a base (e.g. NEt) 3 Amide coupling in the presence of DIPEA or DMAP) to give intermediate form I (step c).
Scheme 2
Wherein Ra is alkyl, in particular Me, Et or isobutyl.
Wherein "building block X" is a cyclic amine with or without PG, wherein "PG" represents a suitable protecting group, such as a Cbz or Boc protecting group
Intermediate form VI or example form I can be prepared according to scheme 1 in scheme 2. Form I of intermediate is hydrolyzed at room temperature using a suitable base and a suitable solvent (e.g., LiOH or NaOH in EtOH/water) to give form II of intermediate (step 1 a). Amide coupling of this intermediate with building block X and building block Y (intermediate type XIII) using for example the method described in scheme 3 step 3b, then deprotecting PG of Y (if necessary) to give intermediate type IX or example type II, (step 2 a).
In scheme 3, an acid compound (intermediate form IV) can be amide-coupled with the building block X-Y (intermediate form VII) using methods known in the art, e.g. as described in step C of scheme 1. deprotection of PG from X-Y (if desired) affords compounds of formula intermediate form IX or example form II, using methods known in the art and as described in step 1C of scheme 2, (step 3a)
The compounds of formula (example type III) can be prepared according to the three routes outlined in scheme 3.
Scheme 3
Wherein X is a cyclic amine with or without PG, wherein "PG" represents a suitable protecting group, such as a Cbz or Boc protecting group
Wherein the structural unit Q is an amine with or without PG, wherein "PG" represents a suitable protecting group, such as a Cbz or Boc protecting group
Wherein the building block Y-Q in scheme 2 is an acid (Y) -amine (Q) compound with or without PG, wherein "PG" represents a suitable protecting group, e.g. a Cbz or Boc protecting group.
Wherein the building block X-Y-Q in scheme 3 is a haloalkane (Y) compound with or without PG attached to two amines (X-cyclic amine and Q), wherein "PG" represents a suitable protecting group, e.g., a Cbz or Boc protecting group.
In scheme 1, removal of the protecting group (if necessary) from intermediate form IX can be achieved by applying methods known in the art and e.g. as described in scheme 2, step 1C. Amide coupling with building block q (ig) is then carried out using, for example, the method described in scheme 3, step 3b, to give example form III (step 1 a).
In scheme 2, removal of the protecting group (if necessary) from intermediate form VI can be achieved by applying methods known in the art and, for example, the methods described in scheme 2, step 1C. Amide coupling with building blocks Y-Q (intermediate X form) is then carried out using, for example, the method described in scheme 3, step 3b, to afford example form III (step 2 a).
In scheme 3, amide coupling between the acid compound (intermediate form IV) and the building block X-Y-Q (intermediate form VIII) can be achieved by using, for example, the method described in scheme 3, step 3 b. The protecting group is then removed (if necessary) to give form III, using methods known in the art and methods such as those described in scheme 2, step 1C.
In one aspect, the present invention provides a process for preparing a compound of formula (I) as described herein, wherein the process is as described in any one of schemes 1 to 5 above.
In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, manufactured according to the process disclosed herein.
Using the compounds of the invention
As shown in the experimental part, the compounds of formula (I) and their pharmaceutically acceptable salts have valuable pharmacological properties for the treatment or prevention of infections caused by pathogens, in particular by bacteria, more in particular by acinetobacter species, most in particular by acinetobacter baumannii, and diseases caused thereby, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.
The compounds of formula (I) and their pharmaceutically acceptable salts exhibit activity as antibiotics, in particular as antibiotics against acinetobacter species, more in particular as antibiotics against acinetobacter baumannii, most in particular as pathogen-specific antibiotics against acinetobacter baumannii.
The compounds of formula (I) and their pharmaceutically acceptable salts can be used as antibiotics, i.e. as antibacterial pharmaceutical ingredients suitable for the treatment and prevention of bacterial infections, in particular of bacterial infections caused by acinetobacter baumannii species, more in particular of bacterial infections caused by acinetobacter baumannii.
The compounds of the invention can be used alone or in combination with other drugs for the treatment or prevention of infections and diseases caused thereby, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, caused by pathogens, in particular by bacteria, more in particular by acinetobacter species, most in particular by acinetobacter baumannii.
In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.
In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as an antibiotic.
In another aspect, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of nosocomial infections and diseases caused thereby.
In particular embodiments, the nosocomial infection and the resulting disease is selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections or combinations thereof.
In another aspect, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of infections and diseases caused thereby by gram-negative bacteria.
In a particular embodiment, the infection by gram-negative bacteria and the disease caused thereby are selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections or combinations thereof.
In another aspect, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of infection by and disease caused by enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli, or a combination thereof.
In another aspect, the present invention provides a method for the treatment or prophylaxis of infection by and disease caused by enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli, or a combination thereof, which comprises administering to a mammal a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein as an antibiotic.
In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for the treatment or prophylaxis of infections and diseases caused by enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli, or combinations thereof.
In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, for the manufacture of a medicament for the treatment or prevention of infection by and disease resulting from enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli, or a combination thereof.
In a particular embodiment, the infection and resulting disease caused by enterococcus faecium, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli or a combination thereof is selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections or a combination thereof.
In a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for use in the treatment or prevention of infections and diseases caused thereby, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, caused by pathogens, in particular by bacteria, more in particular by acinetobacter sp.
In a further aspect, the present invention provides a method for the treatment or prophylaxis of infections caused by pathogens, in particular by bacteria, more in particular by acinetobacter species, most in particular by acinetobacter baumannii, and diseases caused thereby, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, which method comprises administering to a mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above.
In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for the treatment or prevention of infections and diseases caused thereby, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, caused by pathogens, in particular by bacteria, more in particular by acinetobacter species, most in particular by acinetobacter baumannii.
In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for the manufacture of a medicament for the treatment or prevention of infections caused by pathogens, in particular by bacteria, more in particular by acinetobacter sp. Such medicaments comprise a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.
Pharmaceutical compositions and administration
In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above, and one or more pharmaceutically acceptable excipients. Exemplary pharmaceutical compositions are described in examples a through D.
In a further aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and one or more pharmaceutically acceptable excipients for use in the treatment or prevention of infections and diseases caused thereby, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, caused by pathogens, in particular by bacteria, more in particular by acinetobacter sp.
The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical formulations may be administered internally, such as orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), intranasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration can also be carried out parenterally, such as intramuscularly or intravenously (e.g., in the form of an injection solution or infusion solution).
The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic excipients to produce tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as excipients for tablets, dragees and hard gelatine capsules.
Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, liquid polyols and the like.
Suitable excipients for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.
Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.
Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.
In addition, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffer masks or antioxidants. They may also contain other therapeutically valuable substances.
The dosage may vary within wide limits and will, of course, be fitted to the requirements in each particular case. In general, a daily dose of about 0.1mg to 20mg per kg body weight, preferably about 0.5mg to 4mg per kg body weight (e.g. about 300mg per person) for oral administration should be suitable, which is preferably divided into 1-3 separate doses (which may consist of e.g. the same amount). It will be apparent, however, that the upper limit given herein can be exceeded when shown as labeled.
A compound of formula (I) andco-administration of other agents
Compounds of formula (I) or salts thereof, or compounds disclosed herein or pharmaceutically acceptable salts thereof, may be used alone or in combination with other agents for use in therapy. For example, the second agent of a pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound of formula (I) such that they do not adversely affect each other. The compounds may be administered together or separately in a single pharmaceutical composition. In one embodiment, the compound or pharmaceutically acceptable salt may be co-administered with an antibiotic, particularly an antibiotic for the treatment or prevention of infection and diseases caused by enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli, or combinations thereof.
The term "co-administration" refers to the simultaneous administration or separate sequential administration in any manner of a compound of formula (I) or a salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof, and other active pharmaceutical ingredient(s), including antibiotics. If the administration is not simultaneous, the compounds should be administered within close time proximity to each other. Furthermore, it is immaterial whether the compounds are administered in the same dosage form, for example one compound may be administered intravenously and the other compound may be administered orally.
Generally, any agent having antimicrobial activity can be co-administered. Specific examples of such agents are carbapenems (meropenem), fluoroquinolones (ciprofloxacin), aminoglycosides (amikacin), tetracyclines (tigecycline), colistin, sulbactam + durobactam, cefditorel (Fetroja), macrocyclic peptides (as exemplified in WO 2017072062 a1, WO 2019185572 a1 and WO 2019206853 a 1), and macrocyclic lactones (erythromycin).
In one aspect, the invention provides a pharmaceutical composition described herein, further comprising an additional therapeutic agent.
In one embodiment, the additional therapeutic agent is an antibiotic.
In one embodiment, the additional therapeutic agent is an antibiotic for treating or preventing infection and disease resulting therefrom caused by enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli, or a combination thereof.
In one embodiment, the additional therapeutic agent is an antibiotic selected from the group consisting of carbapenems (meropenem), fluoroquinolones (ciprofloxacin), aminoglycosides (amikacin), tetracyclines (tigecycline), colistin, sulbactam + Durlobactam, cedarja (Fetroja), macrocyclic peptides (as exemplified in WO 2017072062 a1, WO 2019185572 a1, and WO 2019206853 a 1), and macrocyclic lactones (erythromycin).
Examples of the invention
The invention will be more fully understood by reference to the following examples. However, the claims should not be construed as limited to the scope of the embodiments.
Where the preparative examples are obtained as mixtures of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.
All reaction examples and intermediates were prepared under argon atmosphere if not otherwise stated.
Abbreviations used herein are as follows:
ACN or MeCN acetonitrile
BINAP 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl
CFU colony Forming Unit
d days
DCM dichloromethane
DIPEA N, N-diisopropylethylamine
EtOAc or EA ethyl acetate
FA formic acid
h(s) or hr(s) hours
HATU 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide hexafluorophosphate
HPLC: high performance liquid chromatography
HPLC-UV: high performance liquid chromatograph with ultraviolet detector
Half maximal inhibitory concentration of IC50
IC 9090% inhibitory concentration
PE Petroleum Ether
PdCl 2 (DPPF) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (II)
Pd 2 (dba) 3 Tris (dibenzylideneacetone) dipalladium (0)
PG protecting group
Precat precatalyst
prep-HPLC preparative high performance liquid chromatography
RBF round flask
rt Room temperature
sat saturation
SEM 2-methoxyethyl (trimethyl) silane
FA formic acid
TFA trifluoroacetic acid
wt. wt
X-PHOS 2-dicyclohexylphosphino-2 ',4',6' -triisopropylbiphenyl
Intermediate form I: 308
4- [ (5-bromo-1-methyl-imidazole-2-carbonyl) amino ] -2-chloro-benzoic acid methyl ester
Step 1: 5-bromo-1-methyl-imidazole-2-carboxylic acid isobutyl ester
To 5-bromo-1-methyl-imidazole (20g, 124 mmo) at-70 deg.Cl) and DIPEA (32.1g, 43.4mL, 248mmol) in DCM (140mL) a solution of isobutyl chloroformate (22.1g, 161mmol) in DCM (60mL) was slowly added dropwise over 30 minutes. The reaction was stirred at-70 ℃ for 2 hours, then slowly warmed to room temperature and stirred overnight. The solution was then washed with water and concentrated in vacuo. The crude product was then purified by flash column chromatography to give 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid isobutyl ester as a yellow oil (29g, 89.4% yield). MS (ESI, m/z): 261.2[ M + H] +
Step 2: 5-bromo-1-methyl-imidazole-2-carboxylic acid
To a solution of isobutyl 5-bromo-1-methyl-1H-imidazole-2-carboxylate (29g, 111mmol) in MeOH (5mL) and THF (120mL) was added a solution of lithium hydroxide monohydrate (9.32g, 222mmol) in water (60 mL). The mixture was stirred at room temperature for 3 hours. The organic solvent was removed under reduced pressure. 12N aqueous HCl was added with stirring until pH 4-5. The white solid was filtered, washed with MeOH and dried to give 5-bromo-1-methyl-imidazole-2-carboxylic acid (20.5g, 90% yield) as a white solid. MS (ESI, m/z): 204.8[ M + H] +
And step 3: 4- [ (5-bromo-1-methyl-imidazole-2-carbonyl) amino ] -2-chloro-benzoic acid methyl ester
A mixture of 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid (13g, 63.4mmol), methyl 2-chloro-4- (methylamino) benzoate (11.8g, 63.4mmol), HATU (24.1g, 63.4mmol), and DIPEA (24.6g, 33.2mL) in DMF (30mL) was stirred at room temperature overnight. The mixture was then poured into water. The aqueous phase was extracted with DCM (3X50 mL). The combined organic phases were washed with water and over anhydrous Na 2 SO 4 Dried and concentrated in vacuo. A solid precipitated from the concentrated solution. The solid was collected, washed with MeOH and dried to give 4- [ (5-bromo-1-methyl-imidazole-2-carbonyl) amino group as a light yellow solid]-2-chloro-benzoic acid methyl ester (18g, 76% yield). MS (ESI, m/z): 371.8[ M + H] +
The following intermediates of form I were prepared analogously to intermediate 308
Intermediate type II: 313
4- [ (5-bromo-1-methyl-imidazole-2-carbonyl) amino ] -2-chloro-benzoic acid
To 4- [ (5-bromo-1-methyl-imidazole-2-carbonyl) amino]To a solution of methyl-2-chloro-benzoate (7.6g, 20.4mmol) in MeOH (2mL) and THF (48mL) was added a solution of lithium hydroxide monohydrate (2.57g, 61.2mmol) in water (24 mL). The mixture was stirred at room temperature overnight. The mixture was then concentrated and the aqueous layer was acidified with 6N aqueous HCl. A solid precipitated from the concentrated solution. The solid was collected, washed with water and dried to give 4- [ (5-bromo-1-methyl-imidazole-2-carbonyl) amino) as a white solid]-2-chloro-benzoic acid (6g, 82% yield). MS (ESI, m/z): 358.0[ M + H] +
The following type II intermediates were prepared analogously to intermediate 313
Intermediate form III: 315
2- (4- (difluoromethoxy) -2, 3-difluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan
Step 1: 1-bromo-4- (difluoromethoxy) -2, 3-difluorobenzene
4-bromo-2, 3-difluorophenol (25g, 120mmol), sodium 2-chloro-2, 2-difluoroacetate (36.5g, 239mmol) and K 2 CO 3 (19.8g, 144mmol) of DMF (250mL) and water (57mL) in N 2 The mixture was stirred at 100 ℃ for 3.0 hours. The reaction mixture was poured into 1.5L H 2 O combined with EtOAc (3X250 m)L) extracting. The organic layers were combined, washed with saturated NaCl (1X200mL) and the organic layer was washed with Na 2 SO 4 Dried and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120g, 0% to 20% DCM in PE) to give 1-bromo-4- (difluoromethoxy) -2, 3-difluorobenzene (25.2g, 97.3mmol, 81.3% yield)
Step 2:2- (4- (difluoromethoxy) -2, 3-difluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan
To 250mL of RBF were added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolan) (24.5g, 96.5mmol), 1-bromo-4- (difluoromethoxy) -2, 3-difluorobenzene (25g, 96.5mmol), PdCl 2 (DPPF)-CH 2 Cl 2 Adduct (3.53g, 4.83mmol) and potassium acetate (18.9g, 193mmol) in dioxane (150 mL). The mixture was heated at 80 ℃ under N 2 Stirring was continued for 15 hours. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 50mL of H 2 O and extracted with EtOAc (3 × 50 mL). The organic layers were combined and washed with saturated NaCl (1 × 50 mL). The organic layer was washed with Na 2 SO 4 Dried and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 330g, 0% to 20% DCM in PE) to give 2- (4- (difluoromethoxy) -2, 3-difluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (25g, 81.7mmol, 84.6% yield).
The following form III intermediates were prepared analogously to intermediate 315
Intermediate form III: 319
2- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan
Step 1: 1-bromo-2, 3-difluoro-4- (fluoromethoxy) benzene
To a 5mL microwave vial was added 4-bromo-2, 3-difluorophenol (150mg, 718. mu. mol, eq: 1), fluoromethyl 4-methylbenzenesulfonate (176mg, 861. mu. mol), and Cs 2 CO 3 (351mg, 1.08mmol) in DMF (3 mL). The vial was capped and heated in a microwave at 90 ℃ overnight. The reaction mixture was poured into 50mL of H 2 O and extracted with EtOAc (3 × 25 mL). The organic layers were combined, washed with saturated NaCl (1X50mL) and then Na 2 SO 4 Dried and concentrated in vacuo to give 1-bromo-2, 3-difluoro-4- (fluoromethoxy) benzene (153mg, 635 μmol, 88.4% yield).
Step 2:
2- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan
To a 5mL microwave vial was added bis (pinacol) diboron (161mg, 635. mu. mol), 1-bromo-2, 3-difluoro-4- (fluoromethoxy) benzene (153mg, 635. mu. mol), PdCl 2 (DPPF)-CH 2 Cl 2 Adduct (46.5mg, 63.5 μmol) and potassium acetate (125mg, 1.27mmol) in dioxane (3 mL). The vial was placed under nitrogen, capped and heated by microwave at 80 ℃ overnight. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 25mL of H 2 O and extracted with EtOAc (3 × 25 mL). The organic layers were combined, washed with saturated NaCl (1 × 25mL), then Na 2 SO 4 Drying and vacuum concentrating to obtain 2- [2, 3-difluoro-4- (fluoromethoxy) phenyl]4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (180mg, 625. mu. mol, 98.4% yield).
The following type III intermediates were prepared analogously to intermediate 319
Intermediate form III: 322
4,4,5, 5-tetramethyl-2- (2,3, 5-trifluoro-4-methoxy-phenyl) -1,3, 2-dioxaborolan
Step 1: 4-bromo-2, 3, 6-trifluorophenol
In a 100mL round-bottom flask, 2,3, 6-trifluorophenol (215mg, 1.45mmol) was reacted with CHCl 3 (10mL) were mixed to provide a colorless solution. NBS (284mg, 1.6mmol) was added at 0 ℃. The reaction was allowed to warm to room temperature while stirring for 2 hours. The crude reaction mixture was concentrated in vacuo to give 4-bromo-2, 3, 6-trifluorophenol (330mg, 1.45mmol, 100% yield), which was used directly in the next step. (ESI, m/z): 227.0[ M-H]-。
And 2, step: 1-bromo-2, 3, 5-trifluoro-4-methoxybenzene
In a 100mL round-bottom flask, 4-bromo-2, 3, 6-trifluorophenol (330mg, 1.45mmol), MeI (413mg, 182. mu.l, 2.91mmol), and K 2 CO 3 (301mg, 2.18mmol) was mixed with acetonitrile (10mL) to give a pale yellow solution. The reaction mixture was heated to 50 ℃ and stirred for 2 hours. The reaction mixture was filtered through glass fiber paper. The crude material was purified by flash chromatography to give 1-bromo-2, 3, 5-trifluoro-4-methoxybenzene (220mg, 913 μmol, 62.8% yield).
And step 3: 4,4,5, 5-tetramethyl-2- (2,3, 5-trifluoro-4-methoxy-phenyl) -1,3, 2-dioxaborolan
To a 100mL microwave vial was added 1-bromo-2, 3, 5-trifluoro-4-methoxybenzene (220mg, 913. mu. mol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolan) (255mg, 1mmol), Pd 2 (dba) 3 (83.6mg, 91.3. mu. mol), X-PHOS (87mg, 183. mu. mol) and potassium acetate (269mg, 171. mu.l, 2.74mmol) in dioxane (10 mL). Place vial in N 2 Next, the lid was closed and heated by microwave at 100 ℃ for 2 hours. The reaction mixture was used in the next step without further purification.
Intermediate form III: 323
2, 3-difluoro-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline
Step 1: 4-bromo-2, 3-difluoro-N, N-dimethylaniline
In a 100mL round bottom flask, 4-bromo-2, 3-difluoroaniline (300mg, 1.44mmol), formaldehyde (433mg, 397. mu.L, 14.4mmol) and formic acid (6.64g, 5.53mL, 144mmol) were combined to give a light red solution. The reaction mixture was heated to 50 ℃ and stirred for 3 hours. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 50mL of saturated NaHCO 3 Neutralized and extracted with EtOAc (3 × 25 mL). The organic layers were combined, washed with saturated NaCl (1 × 25mL) and over Na 2 SO 4 Dried and concentrated in vacuo. The crude material was purified by flash chromatography to give 4-bromo-2, 3-difluoro-N, N-dimethylaniline (270mg, 1.14mmol, 79.3% yield). (ESI, m/z): 238.0[ M + H]+。
Step 2:2, 3-difluoro-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline
In a 100mL round bottom flask, 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolan) (70.5mg, 277. mu. mol), 4-bromo-2, 3-difluoro-N, N-dimethylaniline (65.5mg, 277. mu. mol), PdCl 2 (DPPF)-CH 2 Cl 2 Adduct (20.3mg, 27.7 μmol) and potassium acetate (81.7mg, 832 μmol) were mixed with dioxane (12mL) in N 2 This gave a light brown solution. The reaction mixture was heated to 100 ℃ and stirred for 5 hours. The reaction mixture was used directly in the next step.
Intermediate form III: 324
2, 3-difluoro-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide
Step 1: 4-bromo-2, 3-difluoro-N, N-dimethylbenzamide
In a 100mL round bottom flask, 4-bromo-2, 3-difluorobenzoic acid (300mg, 1.27mmol), dimethylamine (in THF) (1.9mL, 3.8 mmol)) And DIEA (327mg, 442. mu.l, 2.53mmol) was mixed with DMF (5mL) to give a colorless solution. HATU (578mg, 1.52mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into 100mL of H 2 O and extracted with EtOAc (3 × 25 mL). The organic layers were combined, washed with saturated NaCl (1 × 25mL), then Na 2 SO 4 Dried and concentrated in vacuo to give 4-bromo-2, 3-difluoro-N, N-dimethylbenzamide (334mg, 1.26mmol, 99.9% yield). (ESI, m/z): 264.0[ M + H]+。
Step 2:2, 3-difluoro-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide
To a 25mL microwave vial was added bis (pinacol) diboron (70.7mg, 278. mu. mol), 4-bromo-2, 3-difluoro-N, N-dimethylbenzamide (70mg, 265. mu. mol), Pd 2 (dba) 3 (24.3mg, 26.5. mu. mol), X-PHOS (25.3mg, 53. mu. mol) and potassium acetate (78mg, 795. mu. mol) in dioxane (6 mL). The vials were capped and microwaved in N 2 The mixture was heated at 100 ℃ for 3 hours. The reaction mixture was used directly in the next step.
Intermediate form III: 325
2- [ 2-chloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy ] acetonitrile
Step 1: 2- (4-bromo-2-chloro-phenoxy) acetonitrile
4-bromo-2-chlorophenol (3g, 14.5mmol), 2-bromoacetonitrile (2.08g, 17.4mmol) and K 2 CO 3 A mixture of (3g, 21.7mmol) in acetone (30mL) was stirred at 60 ℃ for 3 hours and then filtered. The solid was washed with EtOAc. The organic phase was washed with water, dried and concentrated to give the title compound as a yellow oil (3.5g, 98.2% yield).
And 2, step: 2- [ 2-chloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy ] acetonitrile
A mixture of 2- (4-bromo-2-chlorophenoxy) acetonitrile (3.5g, 14.2mmol), 4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (3.61g, 14.2mmol), potassium acetate (2.79g, 28.4mmol) and 1,1' -bis (diphenylphosphine) ferrocene-palladium (II) dichloride dichloromethane complex (1.74g, 2.13mmol) in 1, 4-dioxane (30mL) was stirred at 80 ℃ overnight. The mixture was then concentrated. Water (10mL) was added. The aqueous layer was extracted with DCM. The organic layer was concentrated and the residue was purified by flash column chromatography to give the title compound (2.8g, 67.2% yield). MS (ESI, m/z): 293.7[ M + H ] +
The following type III intermediates were prepared analogously to intermediate 325:
intermediate form IV: 341
2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoic acid
Step 1: 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoic acid methyl ester (intermediate form V)
Reacting 4- [ (5-bromo-1-methyl-imidazole-2-carbonyl) amino]-methyl 2-chloro-benzoate (intermediate 308, 1g, 2.68mmol), (2, 3-difluoro-4-methoxyphenyl) boronic acid (504mg, 2.68mmol), Na 2 CO 3 A mixture of (853mg, 8.05mmol) and 1,1' -bis (di-tert-butylphosphino) ferrocene palladium dichloride (350mg, 537 μmol) in 1, 4-dioxane solution (15mL) and water (1.5mL) was irradiated under microwave at 100 ℃ for 60 minutes. The process is totallyThis was done 8 times. The reaction mixtures were combined and concentrated in vacuo. Water (40mL) was added. The aqueous phase was extracted with DCM. The combined organic phases were washed with water and over anhydrous Na 2 SO 4 Dried and concentrated, and the solid was dried to give the title compound (8.3mg) as a brown solid. MS (ESI, m/z): 435.9[ M + H] +
Step 2: 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoic acid
To 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl]Amino group]To a solution of methyl benzoate (8.3g, 19mmol) in MeOH (2mL), THF (48mL) and water (24mL) was added a solution of lithium hydroxide monohydrate (3.2g, 76.2mmol) in water (24 mL). The mixture was stirred at room temperature overnight. The mixture was then concentrated and acidified with 6N HCl with stirring until pH 3-4. Some solids precipitated from the concentrated solution. The solid was filtered and dried to give the title compound as a brown solid (7g, 87%). MS (ESI, m/z): 422.3[ M + H] +
The following intermediates of form IV were prepared analogously to intermediate 341
Intermediate form VI: 362
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxylic acid
Step 1: 1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxylic acid methyl ester
2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] group]Amino group]A mixture of benzoic acid (intermediate 341, 3g, 7.11mmol), piperidine-4-carboxylic acid methyl ester (1.22g, 8.54mmol), DIPEA (2.76g, 3.73mL, 21.3mmol) and 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphospha-cyclohexane 2,4, 6-trioxide (3.39g, 10.7mmol) in DMF (10mL) was stirred at 25 ℃ overnight. The mixture was then poured into water. The aqueous phase was extracted with DCM. The combined organic phases were washed with anhydrous Na 2 SO 4 Dried and concentrated to give the title compound as a black oil (3g, 77.1%). MS (ESI, m/z): 547.47[ M + H] +
Step 2: 1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxylic acid
A mixture of methyl 1- (2-chloro-4- (5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamido) benzoyl) piperidine-4-carboxylate (3.5g, 6.4mmol) and lithium hydroxide monohydrate (1.07g, 25.6mmol) in THF (12mL), water (6mL) and MeOH (0.5mL) was stirred at room temperature overnight. The mixture was then acidified with 6N HCl with stirring until pH 2-3. The mixture was concentrated and the aqueous phase was extracted with DCM. The combined organic phases were washed with water, dried and concentrated to give the title compound as a black solid (2.8g, 82% yield). MS (ESI, m/z): 533.60[ M + H] +
The following type VI intermediates were prepared analogously to intermediate 362:
intermediate form VI: 373
N- [4- (4-aminopiperidine-1-carbonyl) -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide
Step 1: n- [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -4-piperidinyl ] carbamic acid tert-butyl ester
Piperidin-4-ylcarbamic acid tert-butyl ester (684mg, 3.41mmol), 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl]Amino group]A mixture of benzoic acid (intermediate 341, 1.2g, 2.85mmol), HATU (1.3g, 3.41mmol) and DIPEA (1.1g, 1.49mL, 8.54mmol) in DMF (10mL) was stirred at room temperature for 2 h. The mixture was then poured into water. The solid was collected and dried to give the title compound as a brown solid (1.5g, 87.3% yield). MS (ESI, m/z): 604.3[ M + H] +
Step 2: n- [4- (4-aminopiperidine-1-carbonyl) -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide
N- [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] at room temperature]Amino group]Benzoyl radical]-4-piperidinyl group]A solution of tert-butyl carbamate (1.5g, 2.48mmol) in DCM (10mL) and TFA (10mL) was stirred for 1 h. Under ice-cooling, the solution was treated with NH 3 .H 2 Basification until pH 8-9. The aqueous layer was extracted with DCM. The organic layer was passed over anhydrous Na 2 SO 4 Drying and concentrating to obtain black solidThe title compound (900mg, 66%). MS (ESI, m/z): 504.2[ M + H] +
The following form VI intermediates were prepared analogously to intermediate 373:
intermediate form VI: 392
N- (3-chloro-4- (piperazine-1-carbonyl) phenyl) -5- (2, 3-difluoro-4- (fluoromethoxy) phenyl) -1-methyl-1H-imidazole-2-carboxamide
Step 1
4- (2-chloro-4- (5- (2, 3-difluoro-4- (fluoromethoxy) phenyl) -1-methyl-1H-imidazole-2-carboxamido) benzoyl) piperazine-1-carboxylic acid tert-butyl ester
To a 25mL microwave vial was added tert-butyl 4- (4- (5-bromo-1-methyl-1H-imidazole-2-carboxamido) -2-chlorobenzoyl) piperazine-1-carboxylate (1g, 1.9mmol), 2- (2, 3-difluoro-4- (fluoromethoxy) phenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (602mg, 2.09mmol), 1' -bis (di-tert-butylphosphino) ferrocene palladium dichloride (124mg, 190. mu. mol), and Na 2 CO 3 (604mg, 5.69mmol) of dioxane (18 mL)/water (3 mL). The vials were capped and microwaved in N 2 The mixture was heated at 100 ℃ for 2 hours. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography to give tert-butyl 4- (2-chloro-4- (5- (2, 3-difluoro-4- (fluoromethoxy) phenyl) -1-methyl-1H-imidazole-2-carboxamido) benzoyl) piperazine-1-carboxylate (759mg, 1.25mmol, 65.8% yield). MS (ESI, m/z): 608.2[ M + H] +
Step 2
Intermediate 392
N- (3-chloro-4- (piperazine-1-carbonyl) phenyl) -5- (2, 3-difluoro-4- (fluoromethoxy) phenyl) -1-methyl-1H-imidazole-2-carboxamide
Tert-butyl 4- (2-chloro-4- (5- (2, 3-difluoro-4- (fluoromethoxy) phenyl) -1-methyl-1H-imidazole-2-carboxamido) benzoyl) piperazine-1-carboxylate (759mg, 1.25mmol) was mixed with THF (8mL) in a 100mL round bottom flask to give a dark brown solution. HCl (4.16mL, 49.9mmol) was added. The reaction was stirred at room temperature for 10 min. The crude reaction mixture was concentrated in vacuo to give N- (3-chloro-4- (piperazine-1-carbonyl) phenyl) -5- (2, 3-difluoro-4- (fluoromethoxy) phenyl) -1-methyl-1H-imidazole-2-carboxamide (634mg, 80% yield) which was used directly in the next step. MS (ESI, m/z): 508.2[ M + H ]] +
The following type VI intermediates were prepared analogously to intermediate 392:
intermediate form VII: 402
N- [2- (4-Piperidinyloxy) ethyl ] carbamic acid tert-butyl ester
Step 1: 4- [2- (tert-Butoxycarbonylamino) ethoxy ] piperidine-1-carboxylic acid benzyl ester
To a solution of benzyl 4-hydroxypiperidine-1-carboxylate (500mg, 2.13mmol) in DMF (10mL) at 0 deg.C was added sodium hydride (170mg, 4.25mmol) in portions. The reaction mixture was stirred for 30min, then 1,2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (474mg, 2.13mmol) was added. The reaction was slowly warmed to room temperature and stirred overnight. The reaction mixture was washed with brine and extracted with DCM. The organic layer was passed over anhydrous Na 2 SO 4 Dried and concentrated in vacuo to give benzyl 4- (2- ((tert-butoxycarbonyl) amino) ethoxy) piperidine-1-carboxylate (760mg, 94.5% yield). MS (ESI, m/z): 379.2[ M + H] + 。
Step 2: n- [2- (4-Piperidinyloxy) ethyl ] carbamic acid tert-butyl ester
To a solution of benzyl 4- (2- ((tert-butoxycarbonyl) amino) ethoxy) piperidine-1-carboxylate (760mg, 2.01mmol) in EtOH (20mL) was added Pd (OH) 2 (300mg), the reaction was stirred under a hydrogen atmosphere at room temperature for 6 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl (2- (piperidin-4-yloxy) ethyl) carbamate (320mg, 65.2% yield). MS (ESI, m/z): 245.1[ M + H] + 。
Intermediate form VII: 403
3- (4-Piperidyloxymethyl) azetidine-1-carboxylic acid tert-butyl ester
Step 1: 3- (4-Piperidyloxymethyl) azetidine-1-carboxylic acid tert-butyl ester
To a solution of tert-butyl 3- (hydroxymethyl) azetidine-1-carboxylate (500mg, 2.67mmol) in DMF (10mL) at 0 deg.C was added sodium hydride (320mg, 8.01mmol) portionwise and the reaction mixture stirred for 30min before 4-fluoropyridine hydrochloride (357mg, 2.67mmol) was added. The reaction mixture was slowly warmed to 60 ℃ and stirred for 1 hour. The reaction was quenched with water and extracted with EtOAc. The organic layer was passed over anhydrous Na 2 SO 4 Drying and curingConcentrated in vacuo to give tert-butyl 3- ((pyridin-4-yloxy) methyl) azetidine-1-carboxylate (600mg, 85% yield). MS (ESI, m/z): 265.1[ M + H] + 。
Step 2: 3- [ (1-phenylpyridin-1-ium-4-yl) oxymethyl ] azetidine-1-carboxylic acid tert-butyl; chloride compound
To a solution of tert-butyl 3- ((pyridin-4-yloxy) methyl) azetidine-1-carboxylate (600mg, 2.27mmol) in MeCN (10mL) was added (chloromethyl) benzene (287mg, 2.27 mmol). The reaction was stirred at 70 ℃ for 15 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give 1-benzyl-4- ((1- (tert-butoxycarbonyl) azetidin-3-yl) methoxy) pyridin-1-ium chloride (882mg, 99.4% yield). MS (ESI, m/z): 355.2[ M] + 。
And step 3: 3- [ (1-benzyl-3, 6-dihydro-2H-pyridin-4-yl) oxymethyl ] azetidine-1-carboxylic acid tert-butyl ester
To a solution of 1-benzyl-4- ((1- (tert-butoxycarbonyl) azetidin-3-yl) methoxy) pyridin-1-ium chloride (800mg, 2.05mmol) in MeOH (15mL) cooled in an ice bath was added sodium borohydride (387mg, 10.2mmol) in portions and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with ammonium chloride and washed with brine. The mixture was extracted with EtOAc and the organic layer was over anhydrous Na 2 SO 4 Dried and concentrated in vacuo to give tert-butyl 3- (((1-benzyl-1, 2,3, 6-tetrahydropyridin-4-yl) oxy) methyl) azetidine-1-carboxylate (700mg, 95.4% yield). MS (ESI, m/z): 359.2[ M + H] + 。
And 4, step 4: 3- (4-Piperidyloxymethyl) azetidine-1-carboxylic acid tert-butyl ester
To a solution of 3- (((1-benzyl-1, 2,3, 6-tetrahydropyridin-4-yl) oxy) methyl) azetidine-1-carboxylic acid tert-butyl ester (700mg, 1.95mmol) in EtOH (20mL) was added Pd (OH) 2 (350mg), the reaction was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl 3- ((piperidin-4-yloxy) methyl) azetidine-1-carboxylate (430mg, 81.4% yield). MS (ESI, m/z): 271.2[ M + H ]] + 。
Intermediate form VII: 404
(2- (azetidin-3-yloxy) ethyl) carbamic acid tert-butyl ester
Step 1: 3- (2- ((tert-Butoxycarbonyl) amino) ethoxy) azetidine-1-carboxylic acid benzyl ester
In a 100mL round-bottom flask, NaH (255mg, 6.37mmol) was mixed with DMF (15mL) to give a colorless solution. Benzyl 3-hydroxyazetidine-1-carboxylate (1.1g, 5.31mmol) was added at 0 ℃. The reaction was stirred at 0 ℃ for 30 minutes, then at room temperature for 30 minutes. 1,2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (1.42g, 6.37mmol) was then added at 0 ℃. The reaction was stirred at room temperature overnight. The reaction mixture was poured into 50mL of H 2 O and extracted with EtOAc (3 × 50 mL). The organic layers were combined and washed with saturated NaCl (1 × 50 mL). The organic layer was washed with Na 2 SO 4 Dried and concentrated in vacuo to afford benzyl 3- (2- ((tert-butoxycarbonyl) amino) ethoxy) azetidine-1-carboxylate (1.86g, 100% yield).
Step 2: (2- (azetidin-3-yloxy) ethyl) carbamic acid tert-butyl ester
In a 100mL round bottom flask, benzyl 3- (2- ((tert-butoxycarbonyl) amino) ethoxy) azetidine-1-carboxylate (350mg, 999 μmol) was mixed with MeOH (30mL) to give a colorless solution. Pd-C (21.3mg, 200. mu. mol) was added. The reaction was purged 3 times with hydrogen and then stirred at room temperature for 1 hour. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to give tert-butyl (2- (azetidin-3-yloxy) ethyl) carbamate (122mg, 56.5% yield). (ESI, m/z): 217.3[ M + H ] +.
Intermediate form VII: 405
(R) - (1- (piperazine-1-carbonyl) pyrrolidin-3-yl) carbamic acid tert-butyl ester
Step 1: (R) -4- (3- ((tert-butoxycarbonyl) amino) pyrrolidine-1-carbonyl) piperazine-1-carboxylic acid benzyl ester
A mixture of (R) -3- (Boc-amino) pyrrolidine (0.5g, 2.68mmol), 1-Cbz-piperazine (0.59g, 2.68mmol), triphosgene (0.48g, 0.810mmol) and triethylamine (0.93mL, 6.71mmol) in DMF (15mL) was stirred at 25 ℃ for 16 h. The mixture was added to water (50mL) and extracted with ethyl acetate (20 mL. times.3). The combined organic layers were washed with anhydrous Na 2 SO 4 Dried and concentrated under reduced pressure. The residue was then purified by flash column chromatography to give the title compound (178mg) as a white solid. MS (ESI, m/z): 433.2[ M + H] + 。
Step 2: (R) - (1- (piperazine-1-carbonyl) pyrrolidin-3-yl) carbamic acid tert-butyl ester
Reacting 4- [3- (tert-butoxycarbonylamino) pyrrolidine-1-carbonyl]A solution of piperazine-1-carboxylic acid benzyl ester (148.0mg, 0.340mmol) and Pd/C (20.0mg, 15% w/w) in methanol (10mL) was stirred under a hydrogen atmosphere at 25 ℃ for 6 hours. After filtration through celite, the filtrate was concentrated under reduced pressure to give the title compound (100mg) as a white solid, which was used in the next step without any purification. MS (ESI, m/z): 299.2[ M + H] + 。
Intermediate form VII: 406
4- (4-Piperidinylsulfonyl) piperazine-1-carboxylic acid tert-butyl ester
Step 1: 4- [ (1-benzyloxycarbonyl-4-piperidinyl) sulfonyl ] piperazine-1-carboxylic acid tert-butyl ester
A mixture of N, N-diisopropylethylamine (0.69mL, 3.93mmol), 1-Boc-piperazine (439.56mg, 2.36mmol), benzyl 4-chlorosulfonylpiperidine-1-carboxylate (0.5g, 1.57mmol) in DCM (10mL) was stirred under nitrogen at 25 ℃ for 3 hours. Water (5mL) was added to the mixture and extracted with DCM (10 mL. times.3). The combined organic layers were concentrated under reduced pressure. The residue was then purified by flash column to give the title compound (570mg) as a white solid. MS (ESI, m/z): 490.2[ M + H] + 。
Step 2: 4- (4-Piperidinylsulfonyl) piperazine-1-carboxylic acid tert-butyl ester
Pd/C (100.0mg, 18% w/w) and 4- [ (1-benzyloxycarbonyl-4-piperidinyl) sulfonyl]A solution of piperazine-1-carboxylic acid tert-butyl ester (570mg, 1.22mmol) in methanol (20mL) was stirred under a hydrogen atmosphere at 25 ℃ for 12 hours. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (455mg) as a colorless oil. MS (ESI, m/z): 334.2[ M + H ]] + 。
In analogy to 406, the following form VII intermediates were prepared:
intermediate form VII: 409
Methyl 3- (3-oxo-3-piperazin-1-yl-propoxy) propionate (409) and 3-methoxy-1- (piperazin-1-yl) propan-1-one (409a)
Step 1: 4- (3-Hydroxypropionyl) piperazine-1-carboxylic acid benzyl ester
A mixture of 1-Cbz-piperazine (5.0g, 22.7mmol), 3-hydroxypropionic acid (3.07g, 34.05mmol), 1-propylphosphonic anhydride solution, 50 wt% ethyl acetate (28.89g, 45.4mmol), and N, N-diisopropylethylamine (9.88mL, 56.75mmol) in DCM (113.5mL) was stirred at 25 ℃ for 16 hours. The mixture was added to water (20mL) and extracted with ethyl acetate (20 mL. times.3). The combined organic layers were concentrated under reduced pressure. The residue was purified by column to give the title compound (2.91g) as a brown oil. MS (ESI, m/z): 293.1[ M + H] + 。
Step 2: 4- [3- (3-methoxy-3-oxo-propoxy) propionyl ] piperazine-1-carboxylic acid benzyl ester and 4- (3-methoxypropionyl) piperazine-1-carboxylic acid benzyl ester
To a mixture of benzyl 4- (3-hydroxypropionyl) piperazine-1-carboxylate (2.5g, 8.55mmol) and sodium methoxide (1386.01mg, 25.66mmol) in THF (42.76mL) was added methyl acrylate (0.93mL, 10.26 mmol). The mixture was stirred at 25 ℃ for 12 hours. The mixture was quenched with water (10mL) and extracted with ethyl acetate (10mL × 3). The combined organic layers were concentrated under reduced pressure. The crude product was then purified by flash column chromatography to give a mixture of the title compound as a yellow oil (732 mg).
And step 3: 3- (3-oxo-3-piperazin-1-yl-propoxy) propionic acid methyl ester and 3-methoxy-1- (piperazin-1-yl) propan-1-one
A mixture of benzyl 4- [3- (3-methoxy-3-oxo-propoxy) propionyl ] piperazine-1-carboxylate and benzyl 4- (3-methoxypropionyl) piperazine-1-carboxylate (732mg) and Pd/C (73mg, 10% w/w) in methanol (20mL) was stirred under a hydrogen atmosphere for 48 hours. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give a mixture of the title compound as a brown gum (476 mg).
Intermediate form VII: 410
3-cyclobutyl-5- (piperidin-4-ylmethyl) -1,2, 4-oxadiazole
Step 1: 4- ((3-cyclobutyl-1, 2, 4-oxadiazol-5-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester
To a solution of (Z) -N' -hydroxycyclobutanecarboxamidine (4.68g, 41mmol, eq: 0.99) in DMF (70mL) and pyridine (6.85g, 7mL, 86.5mmol, eq: 2.09) at 50 deg.C was added dropwise a solution of 2- (1- (tert-butoxycarbonyl) piperidin-4-yl) acetic acid (isopropylcarbonic acid) anhydride (13.64g, 41.4mmol) in DMF (7mL) over 30 minutes. The mixture was stirred at the same temperature for 1 hour. The pale yellow clear solution was then heated to 100 ℃ and stirred overnight. The mixture is evaporated and usedThe HM-N column was absorbed, dried and purified by flash chromatography to give tert-butyl 4- ((3-cyclobutyl-1, 2, 4-oxadiazol-5-yl) methyl) piperidine-1-carboxylate (8.866g, 27.5mmol, 66.6% yield) as a colourless oil. MS (ESI, m/z): 266.2[ M-tBu + H] + 。
Step 2: 3-cyclobutyl-5- (piperidin-4-ylmethyl) -1,2, 4-oxadiazoles
To a solution of tert-butyl 4- ((3-cyclobutyl-1, 2, 4-oxadiazol-5-yl) methyl) piperidine-1-carboxylate (27.55g, 85.7mmol, eq: 1) in dichloromethane (240mL) was added dropwise a solution of 4M HCl in dioxane (85mL, 340mmol) over 1.5 hours, and the mixture was stirred at room temperature for 2.5 hours and then evaporated. As the product started to crystallize, the evaporation was stopped, 300mL of diethyl ether was added and the mixture was stirred at room temperature for 30 minutes. The white crystals were filtered off, washed twice with 100mL of diethyl ether and dried under reduced pressure to give 3-cyclobutyl-5- (piperidin-4-ylmethyl) -1,2, 4-oxadiazole (21.618g, 83.9mmol, 97.8% yield) as white crystals. MS (ESI, m/z): 222.2[ M + H] + 。
Intermediate form VIII: 411
(2-amino-2-oxoethyl) (2- (piperazin-1-yl) ethyl) carbamic acid tert-butyl ester
Step 1: 4- (2- (1, 3-dioxoisoindolin-2-yl) ethyl) piperazine-1-carboxylic acid benzyl ester
A mixture of N- (2-bromoethyl) phthalimide (5.0g, 19.68mmol), 1-Cbz-piperazine (5.2g, 23.61mmol) and triethylamine (4.11mL, 29.52mmol) in THF (30mL) was stirred at 70 ℃ for 14 hours. Adding H to the mixture 2 O (100mL), and extracted with ethyl acetate (50 mL. times.3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography to give the title compound (4.29g) as a brown oil. MS (ESI, m/z): 394.2[ M + H] + 。
Step 2: 4- (2-aminoethyl) piperazine-1-carboxylic acid benzyl ester
Reacting 4- [2- (1, 3-dioxo-isoindolin-2-yl) ethyl]A mixture of benzyl piperazine-1-carboxylate (4.26g, 10.83mmol) and hydrazine hydrate (1.28g, 21.7mmol) in ethanol (50mL) was stirred at 80 ℃ for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.78g) as a white solid, which was used in the next step without further purification.MS(ESI,m/z)：264.2[M+H] + 。
And step 3: 4- (2- ((2-amino-2-oxoethyl) (tert-butoxycarbonyl) amino) ethyl) piperazine-1-carboxylic acid benzyl trifluoroacetate
To a mixture of benzyl 4- (2-aminoethyl) piperazine-1-carboxylate (1.5g, 5.7mmol) and N, N-diisopropylethylamine (4.96mL, 28.48mmol) in tetrahydrofuran (20mL) was added 2-bromoacetamide (0.79g, 5.7 mmol). The mixture was stirred at 25 ℃ for 14 hours. To the mixture was added di-tert-butyl dicarbonate (2.49g, 11.39 mmol). The mixture was stirred at 25 ℃ for 14 hours. Water (30mL) was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL. times.3). The combined organic layers were washed with saturated NaHCO 3 The aqueous solution (20mL) was washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Kromasil-C18100x21.2mm 5 um; 5% -95% ACN in H 2 O solution, 0.1% TFA as eluent) to give the title compound (237mg) as a white solid. MS (ESI, m/z): 421.2[ M + H] + 。
And 4, step 4: (2-amino-2-oxoethyl) (2- (piperazin-1-yl) ethyl) carbamic acid tert-butyl ester
Reacting 4- [2- [ (2-amino-2-oxo-ethyl) -tert-butoxycarbonyl-amino]Ethyl radical]A mixture of benzyl trifluoroacetate (237.0mg, 0.560mmol) and Pd/C (47.4mg, 20% w/w) in methanol (10mL) of piperazine-1-carboxylic acid was stirred at 25 ℃ for 14 h. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound as a brown gum (122 mg). MS (ESI, m/z): 287.2[ M + H] + 。
In analogy to 411, the following type VIII intermediates were prepared:
intermediate form IX: 413
N- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide
In analogy to example 11, steps 1-2, from N- [ 3-chloro-4- (piperazine-1-carbonyl) phenyl]-5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide (intermediate 374) and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid gave the title compound. MS (ESI, m/z): 601.3[ M + H] +
Intermediate form X: 415
2- (3-tert-Butoxycarbonylethetidin-1-yl) acetic acid
Step 1: 1- (2-benzyloxy-2-oxo-ethyl) azetidine-3-carboxylic acid tert-butyl ester
To a solution of azetidine-3-carboxylic acid tert-butyl ester hydrochloride (910mg, 4.7mmol) and N, N-diisopropylethylamine (2.05mL, 11.75mmol) in DCM (15mL) was added benzyl 2-bromoacetate (1.4g, 6.11 mmol). The mixture was stirred at 25 ℃ for 5 hours. After removal of the solvent in vacuo, the crude product was purified by column chromatography to give the title compound (980mg) as a colorless oil. MS (ESI, m/z): 306.2[ M + H] + 。
Step 2:2- (3-tert-Butoxycarbonylethetidin-1-yl) acetic acid
To a solution of tert-butyl 1- (2-benzyloxy-2-oxo-ethyl) azetidine-3-carboxylate (900mg, 2.95mmol) in methanol (5mL) under a nitrogen atmosphere was added Pd/C (50.0mg, 6% w/w). The mixture was stirred under a hydrogen atmosphere at 25 ℃ for 18 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo to give the title compound as a white solid (660 mg). MS (ESI, m/z): 216.2[ M + H] + 。
The following form X intermediates were prepared analogously to intermediate 415:
intermediate form XI: 394
4- (4- (5-bromo-1-methyl-1H-imidazole-2-carboxamido) -2-chlorobenzoyl) piperazine-1-carboxylic acid tert-butyl ester
4- [ (5-bromo-1-methyl-imidazole-2-carbonyl) amino group at room temperature]A mixture of-2-chloro-benzoic acid (intermediate 313, 5.2g, 14.5mmol), piperazine-1-carboxylic acid tert-butyl ester (3.24g, 17.4mmol), HATU (6.62g, 17.4mmol) and DIPEA (5.62g, 7.6mL, 43.5mmol) in DMF (5mL) was stirred for 2 h. The mixture was then poured into water. The aqueous layer was extracted with DCM. The organic layer was washed with water, dried and concentrated to give the title compound as a solid (6.5g, 85.1% yield). MS (ESI, m/z): 526.1[ M + H] +
The following intermediates of type XI were prepared analogously to intermediate 394
Intermediate form XI: 418
5-bromo-N- [ 3-chloro-4- (piperazine-1-carbonyl) phenyl ] -1-methyl-imidazole-2-carboxamide
To 4- [4- [ (5-bromo-1-methyl-imidazole-2-carbonyl) amino at room temperature]-2-chloro-benzoyl]To a suspension of piperazine-1-carboxylic acid tert-butyl ester (intermediate 394, 6.5g, 12.3mmol) in THF (50mL) was added 12N HCl (10 mL). After stirring for 1 hour, the solution was taken up in NH 3 .H 2 And (4) alkalizing. The aqueous phase was extracted with DCM. The organic layer was washed with water, dried and concentrated to give the title compound as a yellow solid (5g, 95% yield). MS (ESI, m/z): 426.2[ M + H] +
The following intermediates of type XI were prepared analogously to intermediate 418
Intermediate form XI: 420
1- [4- [ (5-bromo-1-methyl-imidazole-2-carbonyl) amino ] -2-chloro-benzoyl ] piperidine-4-carboxylic acid
Step 1: 1- [4- [ (5-bromo-1-methyl-imidazole-2-carbonyl) amino ] -2-chloro-benzoyl ] piperidine-4-carboxylic acid methyl ester
A mixture of 4- (5-bromo-1-methyl-1H-imidazole-2-carboxamido) -2-chlorobenzoic acid (intermediate 313, 2.8g, 7.81mmol), piperidine-4-carboxylic acid methyl ester (1.34g, 9.37mmol) and HATU (3.86g, 10.2mmol), DIPEA (5.05g, 6.82mL, 39mmol) in DMF (15mL) was stirred at 25 ℃ overnight. The mixture was then poured into water. The aqueous phase was extracted with DCM. The organic phase was dried and concentrated to give the crude product (1.9g, 50.3% yield). MS (ESI, m/z): 483.1[ M + H] +
Step 2: 1- [4- [ (5-bromo-1-methyl-imidazole-2-carbonyl) amino ] -2-chloro-benzoyl ] piperidine-4-carboxylic acid
A solution of methyl 1- (4- (5-bromo-1-methyl-1H-imidazole-2-carboxamido) -2-chlorobenzoyl) piperidine-4-carboxylate (1.9g, 3.93mmol) and lithium hydroxide monohydrate (824mg, 19.6mmol) in THF (24mL) and water (12mL), MeOH (1mL) was stirred for 3H. The solution was then concentrated and the aqueous layer was washed with CH 3 And (4) acidifying COOH. The aqueous layer was extracted with DCM. The organic layer was washed with water, dried and concentrated to give the title compound as a yellow oil (1.6g, 86.7% yield). MS (ESI, m/z): 469.2[ M + H] +
Intermediate form XII: 421
3- [ [ [1- [4- [ (5-bromo-1-methyl-imidazole-2-carbonyl) amino ] -2-chloro-benzoyl ] piperidine-4-carbonyl ] amino ] methyl ] azetidine-1-carboxylic acid tert-butyl ester
A mixture of 1- (4- (5-bromo-1-methyl-1H-imidazole-2-carboxamido) -2-chlorobenzoyl) piperidine-4-carboxylic acid (intermediate 420, 1.6g, 3.41mmol), 3- (aminomethyl) azetidine-1-carboxylic acid tert-butyl ester (1.9g, 10.2mmol), DIPEA (1.32g, 1.78mL, 10.2mmol) and HATU (1.94g, 5.11mmol) in DMF (15mL) was stirred at room temperature for 1 hour. The mixture was then poured into water and the aqueous phase was extracted with DCM. The organic phase was washed with water, dried, and concentrated. The residue was purified by flash column to give the title compound as yellow oil (1.8g, 82.8% yield). MS (ESI, m/z): 637.2[ M + H] +
The following form XII intermediates were prepared analogously to intermediate 421:
intermediate form XII: 431
5-bromo-N- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide
Route 1:
to a mixture of 4- (5-bromo-1-methyl-1H-imidazole-2-carboxamido) -2-chlorobenzoic acid (intermediate 313, 4.1g, 11.4mmol), N-dimethyl-2- (piperazin-1-yl) ethan-1-amine (2.7g, 17.2mmol) and DIPEA (4.43g, 5.99mL, 34.3mmol) in DMF (10mL) was added 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphane 2,4, 6-trioxide (7.28g, 22.9mmol) at room temperature. After stirring for 20 minutes, the reaction was complete. The mixture was poured into water. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried, and concentrated. The residue was dried by a lyophilizer to give the title compound as a white solid (5.2g,91.4% yield). MS (ESI, m/z): 496.8[ M + H] +
Route 2:
step 1: (4-amino-2-chloro-phenyl) - [4- [2- (dimethylamino) ethyl ] piperazin-1-yl ] methanone
(intermediate 433)
To a solution of 1- (2-dimethylaminoethyl) piperazine (0.35g, 2.24mmol), 4-amino-2-chlorobenzoic acid (0.35g, 2.04mmol) and N, N-diisopropylethylamine (0.71mL, 4.08mmol) in DMF (10mL) was added O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.93g, 2.45 mmol). The mixture was stirred at 30 ℃ for 3 hours. The mixture was diluted with water (60mL) and extracted with EtOAc (75mL × 2). The organic layer was washed with brine (50mL × 2), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a light brown oil (600mg, 1.93mmol, 94.63% yield). MS (ESI, m/z): 311.1[ M + H] + 。
Step 2: 5-bromo-N- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide
(intermediate 432)
To (4-amino-2-chloro-phenyl) - [4- [2- (dimethylamino) ethyl]Piperazin-1-yl]To a solution of methanone (295.64mg, 0.950mmol), 5-bromo-1-methyl-imidazole-2-carboxylic acid (150mg, 0.730mmol) and N, N-diisopropylethylamine (0.23mL, 1.33mmol) in DMF (3mL) was added O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (303.49mg, 0.800 mmol). The mixture was stirred at 30 ℃ for 3 hours. The mixture was diluted with water (60mL) and extracted with EtOAc (75mL × 2). The organic layer was washed with brine (50mL × 2), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a light brown solid (70mg, 0.140mmol, 19.22% yield). MS (ESI, m/z): 499.0[ M + H] + 。
Intermediate form XIII: 434
(2S,4R) -1-tert-butoxycarbonyl-4-hydroxy-4-methyl-pyrrolidine-2-carboxylic acid and (2S,4S) -1-tert-butoxycarbonyl-4-hydroxy-4-methyl-pyrrolidine-2-carboxylic acid
(2S) -1-tert-butoxycarbonyl-4-oxo-pyrrolidine-2-carboxylic acid (2g, 8.72mmol) in THF (20mL) was added dropwise to a 1.5M solution of methyllithium in diethyl ether (8.72mL, 13.09mmol) at-20 ℃ under a nitrogen atmosphere. The resulting mixture was stirred at the same temperature for 1 hour, and then further stirred at 25 ℃ for 11 hours. The reaction mixture was added to a 1N aqueous hydrochloric acid solution (50mL) under ice-cooling, followed by extraction with ethyl acetate (50mL × 3). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was purified by preparative hplc (fa) to give 2 final compounds: p1, (2S,4R) -1-tert-butoxycarbonyl-4-hydroxy-4-methyl-pyrrolidine-2-carboxylic acid (50mg, 0.200mmol, 2.34% yield), MS (ESI, m/z): 190.0[ M + H-56 ]] + And compound P2 (2S,4S) -1-tert-butoxycarbonyl-4-hydroxy-4-methyl-pyrrolidine-2-carboxylic acid (600mg, 2.45mmol, 28.04% yield) as an off-white solid. MS (ESI, m/z): 190.0[ M + H-56 ]] + 。
Intermediate form XIII: 436
(2S,4S) -1-tert-butoxycarbonyl-4-hydroxy-4-ethyl-pyrrolidine-2-carboxylic acid and (2S,4R) -1-tert-butoxycarbonyl-4-ethyl-4-hydroxy-pyrrolidine-2-carboxylic acid
Ethyl magnesium bromide (7.27mL, 21.81mmol, 3M in ether) was added dropwise to a solution of (2S) -1-tert-butoxycarbonyl-4-oxo-pyrrolidine-2-carboxylic acid (2g, 8.72mmol) in THF (50mL) at-20 ℃ under a nitrogen atmosphere. The resulting mixture was stirred at the same temperature for 1 hour, and then further stirred at 25 ℃ for 10 hours. The reaction mixture was added to a 1N aqueous hydrochloric acid solution (100mL) under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was purified by preparative hplc (fa) to give 2 final compounds: the title compound P1(2S,4S) -1-tert-butoxycarbonyl-4-Ethyl-4-hydroxy-pyrrolidine-2-carboxylic acid (0.8g, 3.09mmol, 35.36% yield), MS (ESI, m/z): 282.0[ M + Na ]]+, and the title compound P2, (2S,4R) -1-tert-butoxycarbonyl-4-ethyl-4-hydroxy-pyrrolidine-2-carboxylic acid (0.2g, 0.770mmol, 8.84% yield) as an off-white solid. MS (ESI, m/z): 282.0[ M + Na ]] + 。
Intermediate form XIII: 12
(3S,4R) -1-tert-butoxycarbonyl-3-hydroxy-pyrrolidine-4-carboxylic acid
Step 1: (3S,4R) -1-tert-butoxycarbonyl-3-hydroxy-pyrrolidine-4-carboxylic acid (12)
To a solution of (3S,4R) -3-hydroxypiperidine-1, 4-dicarboxylic acid 1- (tert-butyl ester) 4-ethyl ester (2.1g, 7.68mmol) in methanol (20mL)/THF (20 mL)/water (20mL) was added lithium hydroxide (0.46g, 19.21mmol) and the reaction mixture was stirred at 30 ℃ for 12 hours. The crude product was adjusted to pH 7 with 1N aqueous HCl and the solution was lyophilized to give the title compound as an off-white solid (2.4g, 9.79mmol, 76.42% yield). The crude product was used without further purification. MS (ESI, m/z): 190.0[ M + H-56 ]] + 。
Intermediate 437
(3S,4S) -1-tert-butoxycarbonyl-3-hydroxy-pyrrolidine-4-carboxylic acid
(3S,4S) -1-tert-butoxycarbonyl-3-hydroxy-pyrrolidine-4-carboxylic acid may be prepared using CAS [2166250-53-7], in analogy to intermediate 12.
Example type I: 13
N- [4- (4-aminopiperidine-1-carbonyl) -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide formate salt
N- [4- (4-aminopiperidine-1-carbonyl) -3-chloro-phenyl]Crude (E) -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide(intermediate 373, 200mg) was purified by preparative HPLC to give the title compound (50 mg). MS (ESI, m/z): 504.2[ M + H] +
The following example form I was prepared analogously to example 13
Example type I: 17
N- [4- [4- (2-aminoethyl) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide formate salt
Step 1
N- [ 3-chloro-4- [4- [2- (methylamino) ethyl ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide
In a 100mL round bottom flask, 2-chloro-4- (5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamido) benzoic acid (200mg, 474. mu. mol), (tert-butyl 2- (piperidin-4-yl) ethyl) carbamate (141mg, 616. mu. mol), and DIPEA (184mg, 248. mu.l, 1.42mmol) were mixed with DMF to give a light brown solution. 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphane 2,4, 6-trioxide (603mg, 948. mu. mol) was added. The reaction was stirred at rt overnight. The reaction mixture was poured into 50mL of H 2 O and extracted with EtOAc (3 × 25 mL). The organic layers were combined and washed with saturated NaCl (3 × 25 mL). The organic layer was washed with Na 2 SO 4 Dried and concentrated in vacuo to give tert-butyl (2- (1- (2-chloro-4- (5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamido) benzoyl) piperidin-4-yl) ethyl) carbamate (295mg, 98.4% yield). MS (ESI, m/z): 632.1[ M + H]+。
Step 2
N- [4- [4- (2-aminoethyl) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide formate salt
Tert-butyl (2- (1- (2-chloro-4- (5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamido) benzoyl) piperidin-4-yl) ethyl) carbamate (295mg, 467 μmol) was mixed with THF (3mL) in a 100mL round bottom flask to give a light yellow solution. 4M HCl (3.5mL, 14mmol) in dioxane was added. The reaction was stirred at room temperature for 20 minutes. The crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to give N- (4- (4- (2-aminoethyl) piperidine-1-carbonyl) -3-chlorophenyl) -5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamide formate (270mg, 98.1% yield). MS (ESI, m/z): 532.2[ M + H ] +.
The following type II and type III examples were prepared analogously to example 17
Example type II: 28
N- [ (1S) -2-amino-1-methyl-ethyl ] -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide trifluoroacetate salt
Step 1: n- [ (2S) -2- [ [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carbonyl ] amino ] propyl ] carbamic acid tert-butyl ester
To 1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl at room temperature]Amino group]Benzoyl radical]Piperidine-4-carboxylic acid methyl esterTo a mixture of acid (intermediate 362, 300mg, 563. mu. mol), (S) - (2-aminopropyl) carbamic acid tert-butyl ester (98.1mg, 563. mu. mol) and DIPEA (218mg, 295. mu.l, 1.69mmol) in DMF (2mL) was added 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphospha-cyclohexane 2,4, 6-trioxide (358mg, 1.13 mmol). After stirring for 1 hour, the mixture was poured into water. The aqueous phase was extracted with DCM. The combined organic phases were concentrated and the residue was used in the next reaction without further purification. MS (ESI, m/z): 689.1[ M + H] +
Step 2: n- [ (1S) -2-amino-1-methyl-ethyl ] -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide; 2,2, 2-trifluoroacetic acid
TFA (5mL) and CH of tert-butyl (S) - (2- (1- (2-chloro-4- (5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamido) benzoyl) piperidine-4-carboxamido) propyl) carbamate from step 1 at room temperature 2 Cl 2 The solution was stirred (5mL) for 2 hours. The mixture was then concentrated. Water (10mL) was added. Subjecting the mixture to NH 3 .H 2 Basification to pH 8-9. The aqueous phase was extracted with DCM. The organic phase is passed through anhydrous Na 2 SO 4 Dried and concentrated. The residue was purified by preparative HPLC to give the title compound (61 mg). MS (ESI, m/z): 589.4[ M + H] +
Similar to example 28, the following type II or type III examples were prepared, with deprotection step 2 being applicable only to intermediates derived from Boc-protected amines.
Example type II: 11
N- [ 3-chloro-4- [4- [ (2-pyrrolidin-3-ylacetyl) amino ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide formate salt
Step 1: 3- [2- [ [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -4-piperidinyl ] amino ] -2-oxo-ethyl ] pyrrolidine-1-carboxylic acid tert-butyl ester
Reacting N- [4- (4-aminopiperidine-1-carbonyl) -3-chloro-phenyl]A mixture of-5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide (intermediate 373, 200mg, 397 μmol), 2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) acetic acid (182mg, 794 μmol), HATU (226mg, 595 μmol) and DIPEA (154mg, 208 μ l, 1.19mmol) in DMF (5mL) was stirred overnight. The mixture was then poured into water. The aqueous layer was extracted with DCM. The organic layer was washed with water and dried over anhydrous Na 2 SO 4 Dried and concentrated in vacuo to give the crude product (200mg), which was used directly in the next reaction. MS (ESI, m/z): 715.1[ M + H] +
Step 2: n- [ 3-chloro-4- [4- [ (2-pyrrolidin-3-ylacetyl) amino ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide; formate salt
At room temperature, 3- [2- [ [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl]Amino group]Benzoyl radical]-4-piperidinyl group]Amino group]-2-oxo-ethyl]A mixture of pyrrolidine-1-carboxylate (200mg, 280. mu. mol) in DCM (2mL) and TFA (3mL) was stirred for 1 hour. Et was added under ice cooling with stirring 3 N until pH 8-9. Water (10mL) was then added. The aqueous layer was extracted with DCM. The organic layer was concentrated to give the crude product, which was purified by preparative HPLC to give the title compound (62 mg). MS (ESI, m/z): 615.1[ M + H] +
The following form II or form III examples were prepared analogously to example 11.
Example type II: 235
N- [ 3-chloro-4- [4- (4-piperidinylsulfonylamino) piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide formate salt
Step 1: 4- [ [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -4-piperidinyl ] sulfamoyl ] piperidine-1-carboxylic acid tert-butyl ester
Reacting N- [4- (4-aminopiperidine-1-carbonyl) -3-chloro-phenyl]-5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide (intermediate 373, 300mg, 595 μmol), 4- (chlorosulfonyl) piperidine-1-carboxylic acid tert-butyl ester (253mg, 893 μmol) and Et 3 A mixture of N (120mg, 166. mu.l, 1.19mmol) in DCM (5mL) was stirred overnight. The organic layer was washed with water and dried over anhydrous Na 2 SO 4 Dried and concentrated in vacuo to give the crude product (300mg), which was used in the next reaction without further purification. MS (ESI, m/z): 750.8[ M + H ]] +
Step 2: n- [ 3-chloro-4- [4- (4-piperidinylsulfonylamino) piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide; formate salt
Tert-butyl 4- (N- (1- (2-chloro-4- (5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamido) benzoyl) piperidin-4-yl) sulfamoyl) piperidine-1-carboxylate (300mg, 399 μmol) was dissolved in DCM (5mL) and TFA(5 mL). The solution was stirred for 2 hours. Under ice-cooling, water (5mL) was added followed by Et 3 N until pH 8-9. The aqueous layer was extracted with DCM. The organic layer was concentrated to give the crude product, which was purified by preparative HPLC to give the title compound (126 mg). MS (ESI, m/z): 651.0[ M + H] +
The following examples of form II and III were prepared analogously to example 235
Example type II: 243
N- [ 3-chloro-4- [4- [3- (methylamino) propionyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide
N- (3-chloro-4- (piperazine-1-carbonyl) phenyl) -5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamide (intermediate 374, 250mg, 510. mu. mol), 2-chloro-N-methylethyl-1-amine (57.3mg, 612. mu. mol) and sodium iodide (76.5mg, 510. mu. mol), K 2 CO 3 A mixture of (141mg, 1.02mmol) in DMF (2mL) was stirred at 85 ℃ for 3 h. The mixture was then poured into water. The aqueous layer was extracted with DCM. The organic layer was washed with water and concentrated. The residue was purified by preparative HPLC to give the title compound (42 mg). MS (ESI, m/z): 547.2[ M + H] +
In analogy to example 243, the following form II example was prepared
Example type II: 245
N- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide trifluoroacetate salt
Step 1: 3- [ [ [1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carbonyl ] amino ] methyl ] azetidine-1-carboxylic acid tert-butyl ester
Tert-butyl 3- ((1- (4- (5-bromo-1-methyl-1H-imidazole-2-carboxamido) -2-chlorobenzoyl) piperidine-4-carboxamido) methyl) azetidine-1-carboxylate (intermediate 421, 530mg, 831. mu. mol), 2- (4- (difluoromethoxy) -2, 3-difluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (intermediate 315, 305mg, 997. mu. mol), Na 2 CO 3 A mixture of (440mg, 4.15mmol) and 1,1' -bis (di-tert-butylphosphino) ferrocene palladium dichloride (54.1mg, 83.1 μmol) in 1, 4-dioxane (15mL) and water (1.5mL) was irradiated under microwave at 100 ℃ for 50 minutes. The mixture was then concentrated and the residue was purified by flash column to give the title compound as a yellow oil (400mg, 65.3% yield). MS (ESI, m/z): 737.8[ M + H] +
Step 2: n- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide; 2,2, 2-Trifluoroacetate salt
At room temperature, reacting CF 3 COOH (6mL) was added to 3- [ [ [1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] s]-1-methyl-imidazole-2-carbonyl]Amino group]Benzoyl radical]Piperidine-4-carbonyl]Amino group]Methyl radical]Azetidine-1-carboxylic acid tert-butyl ester (400mg, 543. mu. mol) in DCM (10 mL). The solution was stirred for 40 minutes. Under ice-cooling, NH was added 3 .H 2 O until a pH of 8-9 is reached. The solution was concentrated and the aqueous layer was extracted with DCM. The organic layer was concentrated to give the crude product, which was purified by preparative HPLC to give the title compound (21 mg). MS (ESI,m/z)：637.3[M+H] +
In analogy to example 245, the following form II examples were prepared:
example type II: 269
5- [ 3-chloro-4- (cyanomethoxy) phenyl ] -N- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide trifluoroacetate salt
Reacting 5-bromo-N- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] ethyl]Piperazine-1-carbonyl]Phenyl radical]-1-methyl-imidazole-2-carboxamide (intermediate 431, 200mg, 402. mu. mol), 2- [ 2-chloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy]Acetonitrile (intermediate 325, 118mg, 402. mu. mol), Na 2 CO 3 (128mg, 1.21mmol) and 1,1' -bis (di-tert-butylphosphino)) A mixture of ferrocene palladium dichloride (26.2mg, 40.2 μmol) in 1, 4-dioxane (4mL) and water (0.4mL) was irradiated under microwave at 100 ℃ for 1 hour. The mixture was filtered and concentrated. Water was added and the aqueous layer was extracted with DCM. The organic layer was concentrated and the crude product was purified by preparative HPLC to give the desired product as a light brown powder (29 mg). MS (ESI, m/z): 584.3[ M + H] +
In analogy to example 269, the following form II examples were prepared:
example type II: 279
N- (4- (4- (3- (3-amino-3-oxopropoxy) propionyl) piperazine-1-carbonyl) -3-chlorophenyl) -5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamide
Step 1: n- [ 3-chloro-4- [4- (3-methoxypropionyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide
2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] group]Amino group]A mixture of benzoic acid (500.0mg, 0.950mmol), methyl 3- (3-oxo-3-piperazin-1-yl-propoxy) propionate and 3-methoxy-1- (piperazin-1-yl) propan-1-one (467mg), N-diisopropylethylamine (0.41mL, 2.37mmol) and a solution of 1-propylphosphonic anhydride, 50 wt.% ethyl acetate (1207mg, 1.9mmol) in DMF (6mL) was stirred at 25 ℃ for 16 h. The mixture was added to water (15mL) and extracted with ethyl acetate(10 mL. times.3). The combined organic layers were washed with saturated NaHCO 3 Washed with aqueous solution (15mL) and anhydrous Na 2 SO 4 Dried and concentrated under reduced pressure to give crude product as brown gum (637 mg). 200mg of the crude product are passed through preparative HPLC (column: Kromasil-C18100x21.2mm 5 um; 5% -95% ACN in H 2 O solution, 0.1% FA as eluent). The desired fractions were dried by lyophilization to give the final compound 3- [3- [4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl as a white solid]Amino group]Benzoyl radical]Piperazin-1-yl]-3-oxo-propoxy]Methyl propionate (22 mg). MS (ESI, m/z): 576.2[ M + H] + ；
Step 2: n- (4- (4- (3- (3-amino-3-oxopropoxy) propionyl) piperazine-1-carbonyl) -3-chlorophenyl) -5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamide
Reacting 3- [3- [4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl]Amino group]Benzoyl radical]Piperazin-1-yl]-3-oxo-propoxy]A mixture of methyl propionate (220mg, 0.34mmol) and aqueous ammonia (5.0mL, 0.340mmol) was stirred at 40 ℃ for 12 h. The mixture was added to water (100mL) and extracted with ethyl acetate (50 mL. times.3). The combined organic layers were washed with anhydrous Na 2 SO 4 Dried and concentrated under reduced pressure. The mixture was purified by preparative HPLC (column: Kromasil-C18100x21.2mm 5 um; 5% -95% ACN in H 2 O solution, 0.1% FA as eluent) to give the title compound (61.2mg) as a white solid. MS (ESI, m/z): 633.2[ M + H] + 。
The following form II examples were prepared in analogy to example 279:
example type III: 281
N- (2-aminoethyl) -4- (2-chloro-4- (5- (4- (cyanomethoxy) -2, 3-difluorophenyl) -1-methyl-1H-imidazole-2-carboxamido) benzoyl) piperazine-1-carboxamide 2,2, 2-trifluoroacetate salt
Step 1:
(tert-butyl 2- (4- (2-chloro-4- (5- (4- (cyanomethoxy) -2, 3-difluorophenyl) -1-methyl-1H-imidazole-2-carboxamido) benzoyl) piperazine-1-carboxamido) cyclobutyl) carbamate
A solution of triethylamine (0.06mL, 0.400mmol), N-Boc-ethylenediamine (64.68mg, 0.400mmol) and triethylamine (0.06mL, 0.400mmol) in DMF (1.45mL) was stirred at 25 ℃ for 1 hour, then N- [ 3-chloro-4- (piperazine-1-carbonyl) phenyl ] was added]-5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl]-1H-imidazole-2-carboxamide solution; a solution of 2,2, 2-trifluoroacetic acid (124.13mg, 0.200mmol) in DMF (2 mL). The reaction was quenched with water (20mL) and the resulting solution was extracted with ethyl acetate (20 mL. times.3). The combined organic layers were passed over anhydrous Na 2 SO 4 Dried and concentrated in vacuo to give the title compound (150mg) as a pale brown solid. MS (ESI, m/z): 701.2[ M + H] + 。
Step 2:
n- (2-aminoethyl) -4- (2-chloro-4- (5- (4- (cyanomethoxy) -2, 3-difluorophenyl) -1-methyl-1H-imidazole-2-carboxamido) benzoyl) piperazine-1-carboxamide 2,2, 2-trifluoroacetate salt
Reacting N- [2- [ [4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl)]-1-methyl-imidazole-2-carbonyl]Amino group]Benzoyl radical]Piperazine-1-carbonyl]Amino group]Ethyl radical]A solution of tert-butyl carbamate (150mg, 0.110mmol) and trifluoroacetic acid (1.0mL, 12.98mmol) in DCM (5mL) was stirred at 25 ℃ for 1 h. After concentration in vacuo, the residue was purified by preparative HPLC (column: Kromasil-C18100x21.2mm 5 um; 5% -95% ACN in H 2 O solution, 0.1% TFA as eluent) to give the title compound (17mg) as a white solid. MS (ESI, m/z): 601.2[ M + H] + 。
In analogy to example 281, the following form III examples were prepared:
example type III: 288
2- [4- [4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperazine-1-carbonyl ] -1-piperidinyl ] acetic acid trifluoroacetic acid
Step 1: 2- [4- [4- [4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperazine-1-carbonyl ] -1-piperidinyl ] acetic acid methyl ester
Reacting N- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl]Phenyl radical]-5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide (intermediate 413, 400mg, 666. mu. mol), methyl 2-bromoacetate (122mg, 799. mu. mol) and Et 3 A mixture of N (337mg, 464. mu.l, 3.33mmol) in acetonitrile (10mL) was stirred at 85 ℃ for 2h, then concentrated. Water (5mL) was added. The aqueous layer was extracted with DCM. The organic layer was washed with water and dried over anhydrous Na 2 SO 4 Dried and concentrated. The residue (400mg) was used in the next step without further purification. MS (ESI, m/z): 673.3[ M + H] +
Step 2 trifluoroacetic acid of 2- [4- [4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperazine-1-carbonyl ] -1-piperidinyl ] acetic acid
To 2- [4- [4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl]Amino group]Benzoyl radical]Piperazine-1-carbonyl]-1-piperidinyl group]To a solution of methyl acetate (400mg, 594. mu. mol) in THF (24mL), MeOH (1mL), and water (12mL) was added a solution of lithium hydroxide monohydrate (125mg, 2.97 mmol). The mixture was stirred at room temperature overnight. The mixture was then concentrated and acidified with HCl until pH 3-4. The aqueous layer was extracted with a 1:6iPrOH DCM mixture. The organic layer was concentrated and the residue was purified by preparative HPLC to give the title as a white powderCompound (30 mg). MS (ESI, m/z): 659.3[ M + H ]] +
In analogy to example 288, the following form III example was prepared
Example type III: 290
N- [4- [4- [1- (2-aminoethyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide formate salt
Step 1: n- [2- [4- [4- [ 2-fluoro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperazine-1-carbonyl ] -1-piperidinyl ] ethyl ] carbamic acid tert-butyl ester
In a 100mL round bottom flask, N- (3-chloro-4- (4- (piperidine-4-carbonyl) piperazine-1-carbonyl) phenyl) -5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamide (55mg, 91.5 μmol), (tert-butyl 2-oxoethyl) carbamate (58.3mg, 366 μmol), and sodium cyanoborohydride (28.8mg, 458 μmol) were mixed with MeOH (5mL) to give a colorless solution. The reaction mixture was heated to 40 ℃ and stirred for 1 hour. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 25mL saturated NaHCO3 and extracted with EtOAc (3 × 25 mL). The organic layer was washed with Na 2 SO 4 Dried and concentrated in vacuo to give tert-butyl (2- (4- (4- (2-chloro-4- (5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamido) benzoyl) piperazine-1-carbonyl) piperidin-1-yl) ethyl) carbamate (68mg, 8% yield). MS (ESI, m/z): 744.2[ M + H] +
And 2, step: n- [4- [4- [1- (2-aminoethyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide formate salt
In a 100mL round-bottom flask, (2- (4- (4- (2-chloro-4- (5- (2, 3-difluoro-4-methoxyphenyl)) was placed) -1-methyl-1H-imidazole-2-carboxamido) benzoyl) piperazine-1-carbonyl) piperidin-1-yl) ethyl) carbamic acid tert-butyl ester (68mg, 91.4 μmol) was mixed with THF (3mL) to give a colorless solution. A solution of HCl (1.14mL, 4.57mmol) in dioxane was added. The reaction was stirred at room temperature for 30 minutes. The crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to give N- (4- (4- (1- (2-aminoethyl) piperidine-4-carbonyl) piperazine-1-carbonyl) -3-chlorophenyl) -5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamide formate (19mg, 29.5% yield). MS (ESI, m/z): 644.3[ M + H] +
In analogy to example 290, the following form III examples were prepared
Example type III: 293
N- [ 3-chloro-4- [4- (2-pyrrolidin-1-ylacetyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide formate salt
Step 1 intermediate 447:
n- (3-chloro-4- (4- (2-chloroacetyl) piperazine-1-carbonyl) phenyl) -5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamide
In a 100mL round bottom flask, N- (3-chloro-4- (piperazine-1-carbonyl) phenyl) -5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamide (500mg, 1.02mmol) and DIPEA (264mg, 357. mu.l, 2.04mmol) were reacted with CH 2 Cl 2 (20mL) to give a light brown solution. 2-Chloroacetyl chloride (138mg, 1.22mmol) was added. The reaction was stirred at room temperature for 20 minutes. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 50mL of H 2 O and extracted with DCM (3 × 25 mL). The organic layers were combined, washed with saturated NaCl (1x50mL) and the crude reaction mixture was concentrated in vacuo to afford N- (3-chloro) which was used directly in the next step-4- (4- (2-chloroacetyl) piperazine-1-carbonyl) phenyl) -5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamide (530mg, 936 μmol, 91.7% yield). (ESI, m/z): 566.0[ M + H]+。
Step 2
N- [ 3-chloro-4- [4- (2-pyrrolidin-1-ylacetyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide formate salt
To a 5mL microwave vial was added N- (3-chloro-4- (4- (2-chloroacetyl) piperazine-1-carbonyl) phenyl) -5- (2, 3-difluoro-4-methoxyphenyl) -1-methyl-1H-imidazole-2-carboxamide (75mg, 132 μmol), pyrrolidine (47.1mg, 662 μmol), DIEA (17.1mg, 23.1 μ l, 132 μmol), and sodium iodide (3.97mg, 26.5 μmol) in acetonitrile (3 mL). The vial was capped and heated in a microwave at 80 ℃ for 30 minutes. The crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to give N- [ 3-chloro-4- [4- (2-pyrrolidin-1-ylacetyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide formate salt (19mg, 21.7% yield). (ESI, m/z): 601.3[ M + H ] +.
In analogy to example 293, the following form III examples were prepared:
example type III: 299
N- [ 3-chloro-4- [4- [3- [2- [ [2- (dimethylamino) acetyl ] amino ] ethoxy ] propanoyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide
Reacting N- [4- [4- [3- (2-aminoethoxy) propanoyl group]Piperazine-1-carbonyl]-3-chloro-phenyl radical]A mixture of-5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide formate (246, 90mg, 138. mu. mol), dimethylglycine (28.5mg, 276. mu. mol), HATU (233mg, 612. mu. mol) and DIPEA (158mg, 214. mu.l, 1.22mmol) in DMF (5mL) was stirred overnight. The mixture was poured into water. The aqueous layer was extracted with DCM. The organic phase was washed with water, dried and concentrated. The residue was purified by preparative HPLC to give the title compound (29 mg). MS (ESI, m/z): 690.3[ M + H] + 。
Measurement procedure
Antimicrobial susceptibility testing:
determination of 90% growth inhibitory concentration (IC90)
The in vitro antimicrobial activity of the compounds was determined according to the following procedure:
the assay uses 10-point Iso-Sensitest broth to quantitatively measure the in vitro activity of a compound on acinetobacter baumannii ATCC17978 or ATCC 17961.
Stock compounds in DMSO were serially diluted two-fold in 384-well microtiter plates (e.g., final concentrations ranging from 10 to 0.02. mu.M) and inoculated with 49. mu.l of bacterial suspension in Iso-Sensitest medium to a final cell concentration of approximately 5X10 (5) CFU/ml, final volume/well 50 ul/well. The microtiter plates were incubated at 35. + -. 2 ℃.
Bacterial cell growth was determined by measuring optical density at λ 600nm every 20 minutes over 16 hours. Growth inhibition was calculated during logarithmic growth of bacterial cells and the concentration that inhibited growth by 50% (IC50) and 90% (IC90) was determined.
Table 1 provides the 90% growth inhibitory concentration (IC90) obtained in micromoles per liter of the compound of the invention against acinetobacter baumannii ATCC17978 or ATCC17961 strain.
In particular, the compounds of the invention exhibit an IC90 of ≦ 25 μmol/L (Acinetobacter baumannii ATCC17978 and/or ATCC 17961).
More particularly, the compounds of the present invention exhibit an IC90 of ≦ 5 μmol/L (Acinetobacter baumannii ATCC17978 and/or ATCC 17961).
Most particularly, the compounds of the present invention exhibit an IC90 of ≦ 1 μmol/L (Acinetobacter baumannii ATCC17978 and/or ATCC 17961).
TABLE 1
Example A
The compounds of formula (I) can be used in a manner known per se as active ingredients to produce tablets of the following composition:
example B
The compounds of formula (I) can be used in a manner known per se as active ingredients for producing capsules of the following composition:
example C
The compounds of formula (I) can be used in a manner known per se as active ingredients for producing infusion solutions of the following composition:
active ingredient 100mg
Lactic acid 90% 100mg
Appropriate amount of NaOH or appropriate amount of HCl for adjusting pH to 4.0
Sodium chloride or glucose for regulating osmolality to 290mOsm/kg
Water for injection (WFI) to 100ml
Example D
The compounds of formula (I) can be used in a manner known per se as active ingredients for producing infusion solutions of the following composition:
active ingredient 100mg
Hydroxypropyl-beta-cyclodextrin 10mg
Appropriate amount of NaOH or appropriate amount of HCl for adjusting pH to 7.4
Sodium chloride or glucose for regulating osmolality to 290mOsm/kg
Water for injection (WFI) to 100ml

Claims (35)

1. A compound of formula (I)
Or a pharmaceutically acceptable salt thereof, wherein:
R 1 independently at each occurrence, selected from hydroxy, halogen, cyano, amino, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, amino-C 1 -C 6 -alkoxy-, radicalAnd a group C 1 -C 6 -alkyl-L 2 -; wherein C is 1 -C 6 -alkyl is optionally substituted with 1-3 substituents selected from: hydroxy, amino, halogen, cyano, C 1 -C 6 -alkyl-NH-, (C) 1 -C 6 -alkyl groups) 2 N-, amino-C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-, carbamoyl-C 1 -C 6 -alkoxy-, carbamimidoyl, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkoxy-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-C (O) -NH-C 1 -C 6 -alkoxy-, C 2 -C 6 -alkynyl-NH-, carboxy and C 1 -C 6 -an alkoxy group;
R 2 independently at each occurrence, selected from halogen, cyano, C 1 -C 6 Alkyl radical, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl and halo-C 1 -C 6 -an alkoxy group;
R 3 selected from hydrogen, C 1 -C 6 -alkyl and halo-C 1 -C 6 -an alkyl group;
R 4 independently at each occurrence selected from halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 -alkoxy, cyano, halo-C 1 -C 6 -alkyl, cyano-C 1 -C 6 Alkyl radicals, (C) 1 -C 6 -alkyl groups) 2 N-, halo-C 1 -C 6 -alkoxy, cyano-C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-, (C) 1 -C 6 -alkyl groups) 2 N-C (O) -and 5-to 14-membered heteroaryloxy; and is
R 5 Independently at each occurrence, selected from amino, hydroxy, C 1 -C 6 Alkyl, amino-C 1 -C 6 -alkyl-, hydroxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, (C) 1 -C 6 -alkyl groups) 2 N-、(C 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 alkyl-C (O) -, oxo, aminomethylAcyl, carbamoyl-C 1 -C 6 Alkyl, carboxyl-C 1 -C 6 Alkyl, halogen (fluoro), cyano, C 1 -C 6 aminoalkyl-S (O) 2 -and group
R 6 Independently at each occurrence, selected from amino, hydroxy, C 1 -C 6 Alkyl, amino-C 1 -C 6 -alkyl-, hydroxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, (C) 1 -C 6 -alkyl groups) 2 N–、(C 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 alkyl-C (O) -, oxo, carbamoyl-C 1 -C 6 Alkyl, carboxyl-C 1 -C 6 Alkyl, halogen, cyano and C 1 -C 6 aminoalkyl-S (O) 2 –；
A is a 3-to 14-membered heterocyclyl;
b and C are independently selected from 3-to 14-membered heterocyclyl, C 3 -C 10 -cycloalkyl, 5-to 14-membered heteroaryl and C 6 -C 10 -an aryl group;
L 1 and L 3 Independently selected from covalent bonds, -O-, -NH-, -N (C) 1 -C 6 -alkyl) -, -CH 2 O–、–OCH 2 –、–(CH 2 ) s C(O)–、–CH 2 NHC(O)–、–CH 2 C(O)NH–、–CH 2 –、–NHC(O)–、–S(O) 2 –、–S(O) 2 NH–、–C(O)NH(CH 2 ) 2 -and-NH-nhc (o) -;
L 2 selected from the group consisting of covalent bonds, carbonyl, -S (O) 2 -, -NHC (O) -, -C (O) NH-and-S (O) 2 NH–；
m is 1,2,3 or 4;
n is 0, 1,2,3 or 4;
p is 0, 1,2,3, 4 or 5;
q is 0, 1 or 2;
r is 0 or 1; and is
s is 0, 1,2,3 or 4.
2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
m is 1; and is
R 1 Selected from amino, amino-C 1 -C 6 -alkoxy-, radicalAnd a group C 1 -C 6 -alkyl-L 2 -; wherein:
C 1 -C 6 -alkyl is substituted with 1-2 substituents selected from: hydroxy, amino, cyano, C 1 -C 6 -alkyl-NH-, (C) 1 -C 6 -alkyl groups) 2 N-, amino-C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-, carbamoyl-C 1 -C 6 -alkoxy-, amidino, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkoxy-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-C (O) -NH-C 1 -C 6 -alkoxy-, C 2 -C 6 -alkynyl-NH-, carboxy and C 1 -C 6 -an alkoxy group;
L 1 is selected from-CH 2 O–、–(CH 2 ) s C(O)–、–CH 2 NHC(O)–、–CH 2 C(O)NH–、–CH 2 –、–NHC(O)–、–S(O) 2 –、–S(O) 2 NH–、–C(O)NH(CH 2 ) 2 -and-NH-nhc (o) -;
L 2 selected from the group consisting of covalent bonds, carbonyl, -S (O) 2 -, -NHC (O) -, -C (O) NH-and-S (O) 2 NH–；
q is 0, 1 or 2;
s is 0, 1 or 4;
b is selected from 3-to 14-membered heterocyclic group, C 3 -C 10 -cycloalkyl and 5-to 14-membered heteroaryl; and is
R 5 Independently at each occurrence, selected from amino, hydroxy, C 1 -C 6 Alkyl, amino-C 1 -C 6 -alkyl-, hydroxy-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl groups) 2 N–、(C 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 alkyl-C (O) -, oxo, carbamoyl-C 1 -C 6 Alkyl, carboxyl-C 1 -C 6 Alkyl, halogen, aminoalkyl-S (O) 2 -and groupWherein:
L 3 is a covalent bond or a carbonyl group;
r is 0 or 1;
c is C 3 -C 10 -cycloalkyl or 3-to 14-membered heterocyclyl; and is
R 6 Is a hydroxyl group.
3. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
m is 1; and is
R 1 Is a groupWherein:
L 1 selected from carbonyl, -CH 2 C(O)–、–CH 2 NHC (O) -and NHC (O) -;
q is 0 or 1;
b is a 3-to 14-membered heterocyclyl; and is
R 5 Selected from amino, hydroxy and hydroxy-C 1 -C 6 -alkyl-.
4. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
m is 1; and is
R 1 Is a groupWherein:
L 1 selected from carbonyl, -CH 2 C(O)–、–CH 2 NHC (O) -and NHC (O) -;
q is 0 or 1;
b is selected from azetidinyl, pyrrolidinyl, 3-azabicyclo [3.1.0] hexanyl, and piperidinyl; and is provided with
R 5 Selected from amino, hydroxyl and hydroxymethyl.
5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein n is 1 and R is 2 Selected from halogen and C 1 -C 6 -an alkyl group.
6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein n is 1 and R is 2 Selected from chlorine and methyl.
7. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, wherein the compound of formula (I) is a compound of formula (II):
8. a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 3 Is C 1 -C 6 -an alkyl group.
9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 3 Is methyl.
10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein p is 1,2,3 or 4 and R is 4 Independently at each occurrence, selected from halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 -alkoxy, cyano, halo-C 1 -C 6 -alkyl, cyano-C 1 -C 6 Alkyl radicals, (C) 1 -C 6 -alkyl groups) 2 N-, halo-C 1 -C 6 -alkoxy, cyano-C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-, (C) 1 -C 6 -alkyl groups) 2 N-C (O) -and heteroaryloxy.
11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein p is 2 or 3 and R 4 Independently at each occurrence, selected from halogen, C 1 -C 6 -alkoxy, halo-C 1 -C 6 Alkoxy and cyano-C 1 -C 6 -alkoxy groups.
12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein p is 2 or 3 and R is 4 Independently at each occurrence, is selected from the group consisting of fluorine, chlorine, methoxy, FCH 2 O–、F 2 CHO-and CNCH 2 O–。
13. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, wherein the compound of formula (I) is a compound of formula (III):
wherein:
R 4a selected from hydrogen, halogen, C 1 -C 6 -alkyl, cyano and halo-C 1 -C 6 -an alkyl group;
R 4b selected from hydrogen, halogen, cyano and C 1 -C 6 -an alkoxy group;
R 4c selected from halogen, C 1 -C 6 -alkoxy, cyano-C 1 -C 6 -alkyl, cyano-C 1 -C 6 -alkoxy, (C) 1 -C 6 -alkyl groups) 2 N-, halo-C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, (C) 1 -C 6 -alkyl groups) 2 N-C (O) -and heteroaryloxy; and is
R 4d Selected from hydrogen and halogen.
14. A compound of formula (III) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein:
R 4a is halogen;
R 4b selected from hydrogen and halogen;
R 4c is selected from C 1 -C 6 -alkoxy, cyano-C 1 -C 6 -alkoxy and halo-C 1 -C 6 -an alkoxy group; and is provided with
R 4d Is hydrogen.
15. A compound of formula (III) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein:
R 4a selected from fluorine and chlorine;
R 4b selected from hydrogen, fluorine and chlorine;
R 4c selected from methoxy, FCH 2 O–、F 2 CHO-and CNCH 2 O-; and is provided with
R 4d Is hydrogen.
16. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
m is 1; and is
R 1 Selected from amino, amino-C 1 -C 6 -alkoxy-, radicalAnd a group C 1 -C 6 -alkyl-L 2 -; wherein:
C 1 -C 6 -alkyl is substituted with 1-2 substituents selected from: hydroxy, amino, cyano, C 1 -C 6 -alkyl-NH-, (C) 1 -C 6 -alkyl groups) 2 N-, amino-C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-, carbamoyl-C 1 -C 6 -alkoxy-, carbamimidoyl, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkoxy-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-C (O) -NH-C 1 -C 6 -alkoxy-, C 2 -C 6 -alkynyl-NH-, carboxy and C 1 -C 6 -an alkoxy group;
L 1 is selected from-CH 2 O–、–(CH 2 ) s C(O)–、–CH 2 NHC(O)–、–CH 2 C(O)NH–、–CH 2 –、–NHC(O)–、–S(O) 2 –、–S(O) 2 NH–、–C(O)NH(CH 2 ) 2 -and-NH-nhc (o) -;
L 2 selected from the group consisting of covalent bonds, carbonyl, -S (O) 2 -, -NHC (O) -, -C (O) NH-and-S (O) 2 NH–；
q is 0, 1 or 2;
s is 0, 1 or 4;
b is selected from 3-to 14-membered heterocyclic group, C 3 -C 10 -cycloalkyl and 5-to 14-membered heteroaryl; and is
R 5 Independently at each occurrence, selected from amino, hydroxy, C 1 -C 6 Alkyl, amino-C 1 -C 6 -alkyl-, hydroxy-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl radical) 2 N–、(C 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 -alkyl-, (C) 1 -C 6 -alkyl groups) 2 N-C 1 -C 6 alkyl-C (O) -, oxo, carbamoyl-C 1 -C 6 Alkyl, carboxyl-C 1 -C 6 Alkyl, halogen, aminoalkyl-S (O) 2 -and groupWherein:
L 3 is a covalent bond or a carbonyl group;
r is 0 or 1;
c is C 3 -C 10 -cycloalkyl or 3-to 14-membered heterocyclyl;
R 6 is a hydroxyl group;
n is 1;
R 2 selected from halogen and C 1 -C 6 -an alkyl group;
R 3 is C 1 -C 6 -an alkyl group;
p is 1,2,3 or 4; and is
R 4 Independently at each occurrence selected from halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 -alkoxy, cyano, halo-C 1 -C 6 -alkyl, cyano-C 1 -C 6 Alkyl radicals, (C) 1 -C 6 -alkyl groups) 2 N-, halo-C 1 -C 6 -alkoxy, cyano-C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-, (C) 1 -C 6 -alkyl groups) 2 N-C (O) -and heteroaryloxy.
17. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
m is 1; and is
R 1 Is a groupWherein:
L 1 selected from carbonyl, -CH 2 C(O)–、–CH 2 NHC (O) -and NHC (O) -;
q is 0 or 1;
b is a 3-to 14-membered heterocyclyl; and is
R 5 Selected from amino, hydroxy and hydroxy-C 1 -C 6 -alkyl-
n is 1;
R 2 selected from halogen and C 1 -C 6 -an alkyl group;
R 3 is C 1 -C 6 -an alkyl group;
p is 2 or 3; and is
R 4 Independently at each occurrence, selected from halogen, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy and cyano-C 1 -C 6 -alkoxy groups.
18. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
m is 1; and is
R 1 Is a groupWherein:
L 1 selected from carbonyl, -CH 2 C(O)–、–CH 2 NHC (O) -and NHC (O) -;
q is 0 or 1;
b is selected from azetidinyl, pyrrolidinyl, 3-azabicyclo [3.1.0] hexanyl, and piperidinyl; and is
R 5 Selected from amino, hydroxyl and hydroxymethyl;
n is 1;
R 2 selected from chlorine and methyl;
R 3 is methyl;
p is 2 or 3; and is
R 4 Independently at each occurrence is selected from the group consisting of fluorine, chlorine, methoxy,FCH 2 O–、F 2 CHO-and CNCH 2 O–。
19. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from:
n- [ 3-chloro-4- [4- [ (3R) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4S) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,3S) -3-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [3- (dimethylamino) propyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [2- (methylamino) ethyl ] piperidine-4-carboxamide;
n- [4- [4- [ (3R) -3-aminopyrrolidine-1-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- (aminomethyl) morpholine-4-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3R) -3- (hydroxymethyl) piperazine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (2S,4S) -4-aminopyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S) -pyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S) -piperidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S) -piperidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (2-aminoethyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (methylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2R) -pyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (3-amino-2-hydroxy-propyl) -1- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-N- [ 3-methyl-4- [4- [ (3R) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S) -3- (hydroxymethyl) piperazine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (1, 1-dioxo-1, 4-thiazinane-4-carbonyl) piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-N- [ 3-methyl-4- [4- [2- (methylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (morpholine-4-carbonyl) piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-N- [ 3-methyl-4- [4- (morpholine-4-carbonyl) piperidine-1-carbonyl ] phenyl ] imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (2, 6-diazaspiro [3.3] heptane-2-carbonyl) piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -N- [4- [4- (1, 1-dioxo-1, 4-thiazinan-4-carbonyl) piperidine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (2R) -2- (aminomethyl) morpholine-4-carbonyl ] piperidine-1-carbonyl ] -3-methyl-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (thiomorpholine-4-carbonyl) piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-aminoazetidine-1-carbonyl) piperidine-1-carbonyl ] -3-methyl-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (aminomethyl) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (5-hydroxypiperidine-3-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (2-aminoethyl) -4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperazine-1-carboxamide;
n- [ 3-chloro-4- (4-piperazin-1-ylsulfonylpiperidine-1-carbonyl) phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ [ (2S) -pyrrolidine-2-carbonyl ] amino ] ethyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (2S) -2- (aminomethyl) morpholine-4-carbonyl ] piperidine-1-carbonyl ] -3-methyl-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-piperidinylsulfonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- [ (2-amino-2-oxo-ethyl) amino ] ethyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
(3R) -1- [2- [4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperazin-1-yl ] -2-oxo-ethyl ] pyrrolidine-3-carboxylic acid;
1- [2- [4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperazin-1-yl ] -2-oxo-ethyl ] azetidine-3-carboxylic acid;
5- [ 3-chloro-4- (cyanomethoxy) -2-fluoro-phenyl ] -N- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -5- (3-fluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ rac- (1R,5S) -3-azabicyclo [3.1.0] hexane-6-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (2-aminoethyl) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3R) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-aminocyclobutanecarbonyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-aminocyclobutanecarbonyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (3-hydroxypyrrolidine-3-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -3-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- (azetidin-3-yl) acetyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-3-fluoro-4- (fluoromethoxy) phenyl ] -N- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [ 2-chloro-3-fluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
5- [ 2-chloro-4- (difluoromethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-hydroxypyrrolidine-3-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ [ (3R) -pyrrolidin-3-yl ] methyl ] piperidine-4-carboxamide;
n- [4- [4- (2-aminoacetyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (2S) -azetidine-2-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (2-pyrrolidin-1-ylacetyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (2-pyrrolidin-3-ylacetyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2R) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3R) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2S) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3R) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ [ (3R) -pyrrolidin-3-yl ] methyl ] piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ [ (3S) -pyrrolidin-3-yl ] methyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- (3-hydroxypyrrolidin-1-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3-hydroxyazetidin-3-yl) methyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2S) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2S) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (3-hydroxyazetidin-3-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [1- (2-aminoethyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (azetidine-3-carbonyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (pyrrolidin-3-ylmethyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S) -pyrrolidin-3-yl ] piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ rac- (1S,5R) -3-azabicyclo [3.1.0] hex-6-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (dimethylamino) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-5- (2,3, 5-trifluoro-4-methoxy-phenyl) imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ rac- (1S,5R) -3-azabicyclo [3.1.0] hex-6-yl ] piperidine-4-carboxamide;
n- [4- [3- (2-aminoethoxy) azetidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [ 2-chloro-3-fluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ [ (3R) -pyrrolidin-3-yl ] methyl ] piperidine-4-carboxamide;
5- [ 2-chloro-4- (difluoromethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (4-ethoxy-2, 3-difluoro-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (5-hydroxypiperidine-3-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-4- (difluoromethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-3-fluoro-4- (fluoromethoxy) phenyl ] -N- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [1- (azetidine-3-carbonyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -3-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (azetidin-2-ylmethyl) -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- (3-hydroxyazetidin-3-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- (azetidin-3-yl) acetyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [1- (4-hydroxypiperidine-4-carbonyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2S) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -3-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R) -pyrrolidin-3-yl ] piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- [ 2-chloro-3-fluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S) -pyrrolidin-3-yl ] piperidine-4-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (4-ethoxy-2, 3-difluoro-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [3- [3- (aminomethyl) azetidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
3- [ [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carbonyl ] amino ] propanoic acid;
4- [ [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carbonyl ] amino ] butanoic acid;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (dimethylcarbamoyl) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ rac- (1R,5S) -3-azabicyclo [3.1.0] hexane-6-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [3- (aminomethyl) cyclobutanecarbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (2-amino-2-oxo-ethyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [ rac- (3aR,6aS) -5- (piperidine-4-carbonyl) -1,3,3a,4,6,6 a-hexahydropyrrolo [3,4-c ] pyrrole-2-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (3-hydroxyazetidin-1-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] azetidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [3- (piperazine-1-carbonyl) azetidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [ rac- (3aR,6aS) -5- [ rac- (3R) -pyrrolidine-3-carbonyl ] -1,3,3a,4,6,6 a-hexahydropyrrolo [3,4-c ] pyrrole-2-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [3- [ [2- (dimethylamino) acetyl ] amino ] azetidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [3- [ rac- (3aR,6aS) -2,3,3a,4,6,6 a-hexahydro-1H-pyrrolo [3,4-c ] pyrrole-5-carbonyl ] azetidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [ rac- (3aS,6aR) -2- [2- (dimethylamino) acetyl ] -1,3,3a,4,6,6 a-hexahydropyrrolo [3,4-c ] pyrrole-5-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-5- (2,3, 4-trifluorophenyl) imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (3-cyano-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [3- [ rac- (3aR,6aR) -2,3,3a,4,6,6 a-hexahydro-1H-pyrrolo [3,4-c ] pyrrole-5-carbonyl ] pyrrolidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (3-cyano-2, 4-difluoro-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [ [2- (dimethylamino) acetyl ] amino ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] -2-ethyl-benzoyl ] -N- [3- (prop-2-ynylamino) propyl ] piperidine-4-carboxamide;
5- (2, 3-difluoro-4-methoxy-phenyl) -N- [4- [4- [4- [3- (dimethylamino) propyl ] piperazine-1-carbonyl ] piperidine-1-carbonyl ] -3-ethyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (2-aminoethyl) -1- [4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] -2-ethyl-benzoyl ] piperidine-4-carboxamide;
1- [4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] -2-ethyl-benzoyl ] -N- [2- [2- (dimethylamino) ethoxy ] ethyl ] piperidine-4-carboxamide;
5- [4- (difluoromethoxy) phenyl ] -N- [4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] -3-ethyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- (2-chloro-4-methoxy-phenyl) -N- [4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] -3-ethyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] -3-ethyl-phenyl ] -5- (3-fluoro-4-isopropoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (3-cyclobutyl-1, 2, 4-oxadiazol-5-yl) methyl ] piperidine-1-carbonyl ] -3-ethyl-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
n- [ 3-chloro-4- [4- [ (3S,4S) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4S) -4-hydroxy-4-methyl-pyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S,4R) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
4- [4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] -2-methyl-benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4S) -4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -N- [4- [4- [ (2S,4S) -4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -N- [4- [4- [ (2S,4S) -4-hydroxy-4-methyl-pyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3R,4S) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- (2, 3-difluoro-4-methoxy-phenyl) -N- [4- [4- [ (3R,4R) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3R,4R) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
n- [ 3-chloro-4- (piperazine-1-carbonyl) phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S,4R) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (4-guanidinobutyryl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-aminopropionyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (5-aminopentanoyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
3-chloro-4- [4- (3-cyanopropionyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
4- [4- (3-aminopropionylamino) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-yl) -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [4- [4- [ (1S,3R) -3-aminocyclopentanecarbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (2-aminoethylsulfonylamino) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- (4-piperidinyl) piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- (4-pyridylmethyl) piperidine-4-carboxamide;
5- [ 2-chloro-4- (cyanomethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- [ (3R) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-4- (cyanomethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- [ (3S) -pyrrolidine-3-carbonyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4R) -4-fluoropyrrolidin-3-yl ] piperidine-4-carboxamide;
5- [ 3-chloro-2-fluoro-4- (fluoromethoxy) phenyl ] -N- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4R) -4-fluoropyrrolidin-3-yl ] piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ [ (3S) -pyrrolidin-3-yl ] methyl ] piperidine-4-carboxamide;
n- [4- [4- (2-aminoethoxy) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (azetidin-3-ylmethoxy) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (4-aminobutyryl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ (2S) -2-aminopropyl ] -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [4- [4- [1- (2-aminoethyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [1- [2- (dimethylamino) acetyl ] piperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (4-aminopiperidine-1-carbonyl) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [2- (difluoromethyl) -3-fluoro-4-methoxy-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (pyrrolidin-3-ylsulfonylamino) piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (3S) -3-aminopyrrolidine-1-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-4- (cyanomethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (3R) -3-aminopyrrolidine-1-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ [ (3R) -pyrrolidin-3-yl ] methyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- (4-piperidinylsulfonylamino) piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [3- (dimethylamino) azetidine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-4- (cyanomethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-carbamoylpyrrolidine-1-carbonyl) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [4- [4- [1- (2-amino-2-oxo-ethyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [1- (2-aminoethylsulfonyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4S) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- (4-methylsulfonylpiperazine-1-carbonyl) phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (methylsulfonylamino) piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (2-aminoethylsulfonyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (2-oxoimidazolidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [3- (2-aminoethyl) azetidine-1-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2-pyrrolidin-3-ylacetyl) amino ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [ 3-fluoro-4- (fluoromethoxy) -2-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 3-chloro-2-fluoro-4- (fluoromethoxy) phenyl ] -N- [4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (3S,4S) -3-amino-4-fluoro-pyrrolidine-1-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- (4-pyrrolidin-3-ylsulfonylpiperazine-1-carbonyl) phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-aminobicyclo [1.1.1] pentane-1-carbonyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ [ (1-methyl-4-piperidinyl) amino ] carbamoyl ] piperidine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2-cyano-3-fluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (5-oxopyrrolidin-3-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [3- (dimethylamino) propionylamino ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- [ 2-chloro-4- (cyanomethoxy) -3-fluoro-phenyl ] -N- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
5- [ 3-chloro-4- (cyanomethoxy) phenyl ] -N- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- (4-piperidinylmethyl) piperidine-4-carboxamide;
n- [4- [4- [3- (aminomethyl) azetidine-1-carbonyl ] piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (methylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-aminoazetidine-1-carbonyl) piperidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] amino ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [3- [2- (2-aminoethoxy) ethoxy ] propionyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (5-oxopyrrolidin-2-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (5-oxopyrrolidine-2-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [ 3-chloro-4- [4- [ (2S,4S) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- (4-aminopiperidine-1-carbonyl) -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (methylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (6-oxopiperidine-3-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (2-azaspiro [3.3] heptane-6-carbonyl) piperazine-1-carbonyl ] -3-methyl-phenyl ] -5- (2-chloro-3-fluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [ 3-chloro-4- [4- [ (3R) -3- (hydroxymethyl) piperazine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [ 3-chloro-4- [4- [ (2R,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [6- [ (3R) -3- (hydroxymethyl) piperazine-1-carbonyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [3- [2- [ [2- (dimethylamino) acetyl ] amino ] ethoxy ] propionyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -1-methyl-N- [ 3-methyl-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] imidazole-2-carboxamide;
n- [ 3-chloro-4- [3- [ [ rac- (3R) -pyrrolidine-3-carbonyl ] amino ] pyrrolidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- (2, 6-diazaspiro [3.3] heptane-2-carbonyl) phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ (1S) -2-amino-1-methyl-ethyl ] -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [ (3R) -3- (hydroxymethyl) piperazine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] pyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [ (3S) -3- (hydroxymethyl) piperazine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [2- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] -2, 6-diazaspiro [3.3] heptane-6-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2-fluoro-3, 4-dimethoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [5- [ (3aS,4S,6aR) -2-oxo-1, 3,3a,4,6,6 a-hexahydrothieno [3,4-d ] imidazol-4-yl ] pentanoyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (2, 5-dioxoimidazolidin-4-yl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [3- [3- (2-aminoethoxy) propionylamino ] pyrrolidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
2- [4- [4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperazine-1-carbonyl ] -1-piperidinyl ] acetic acid;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (2-methoxyethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (2-pyridinyloxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (4-pyridinyloxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- (3, 4-difluoro-5-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) ethyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-pyrimidin-2-yloxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethyl) -2-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl]-3-methyl-phenyl]-9-methoxy-6, 7-dihydro-5H-imidazo [5,1-a [ ]][2]Benzazepine compounds-3-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [3- (2-aminoethoxy) propionyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [1- (2-amino-2-oxo-ethyl) piperidine-4-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [ (3R) -3-aminopyrrolidine-1-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S) -pyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2S) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [ 2-fluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (2-aminoethyl) -1- [ 2-chloro-4- [ [5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- (2-aminoethyl) -1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- (4-piperidinyl) piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R) -pyrrolidin-3-yl ] piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- (4-piperidinyl) piperidine-4-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- (4-hydroxy-4-piperidinyl) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- (dimethylamino) acetyl ] piperazine-1-carbonyl ] phenyl ] -5- [ 2-fluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [2, 3-difluoro-4- (fluoromethoxy) phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R) -pyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [4- [3- [ [3- (aminomethyl) cyclobutanecarbonyl ] amino ] azetidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [3- [ (2-aminoacetyl) amino ] azetidine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- (3-carbamoylcyclobutanecarbonyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (3-hydroxycyclobutanecarbonyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (3-methoxypropionyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [3- (3-amino-3-oxo-propoxy) propionyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide; and
n- [4- [4- (5-amino-5-oxo-pentanoyl) piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide.
20. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from:
n- [ 3-chloro-4- [4- [ rac- (1R,5S) -3-azabicyclo [3.1.0] hexane-6-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- [ 3-chloro-2-fluoro-4- (fluoromethoxy) phenyl ] -N- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- (2-pyrrolidin-3-ylacetyl) piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- (azetidin-3-yl) acetyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
1- [ 2-chloro-4- [ [5- [4- (difluoromethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (3S) -pyrrolidin-3-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
5- [ 3-chloro-2-fluoro-4- (fluoromethoxy) phenyl ] -N- [4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4S) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,3S) -3-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
n- [ 3-chloro-4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- (piperidine-4-carbonyl) piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [4- [4- [2- (azetidin-3-yl) acetyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (difluoromethoxy) -2-fluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [2- [ (2S) -pyrrolidin-2-yl ] acetyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3R) -3- (hydroxymethyl) piperazine-1-carbonyl ] piperidine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
4- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3R,4R) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
n- [4- [4- [ (2S,4S) -4-aminopyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] -3-chloro-phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
4- [ 2-chloro-4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide;
n- [ 3-chloro-4- [4- [ (3S,4R) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- (azetidin-3-ylmethyl) -1- [ 2-chloro-4- [ [5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carbonyl ] amino ] benzoyl ] piperidine-4-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- [4- (cyanomethoxy) -2, 3-difluoro-phenyl ] -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (2S,4R) -4-hydroxypyrrolidine-2-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
n- [ 3-chloro-4- [4- [ (3S,4R) -3-hydroxypiperidine-4-carbonyl ] piperazine-1-carbonyl ] phenyl ] -5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carboxamide;
4- [4- [ [5- (2, 3-difluoro-4-methoxy-phenyl) -1-methyl-imidazole-2-carbonyl ] amino ] -2-methyl-benzoyl ] -N- [ (3S,4S) -4-hydroxypyrrolidin-3-yl ] piperazine-1-carboxamide; and
5- (2-chloro-3-fluoro-4-methoxy-phenyl) -N- [4- [4- (4-hydroxypiperidine-4-carbonyl) piperazine-1-carbonyl ] -3-methyl-phenyl ] -1-methyl-imidazole-2-carboxamide.
21. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 20, wherein the process is as described in any one of schemes 1 to 5 herein.
22. A compound of formula (I) according to any one of claims 1 to 20, when manufactured according to the process of claim 21.
23. A compound of formula (I) according to any one of claims 1 to 20 and claim 22, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.
24. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 20 and claim 22, and a therapeutically inert carrier.
25. A compound of formula (I) according to any one of claims 1 to 20 and claim 22, or a pharmaceutically acceptable salt thereof, for use as an antibiotic.
26. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 and claim 22 for use in the treatment or prevention of nosocomial infections and diseases caused thereby.
27. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 and claim 22 for use in the treatment or prevention of infections caused by gram-negative bacteria and diseases caused thereby.
28. The compound for use according to claim 27, wherein the gram-negative bacterium is selected from the group consisting of klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species and escherichia coli.
29. The compound for use according to claim 28, wherein the gram-negative bacterium is acinetobacter baumannii.
30. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 and 22 for use in the treatment or prevention of infection by and disease caused by enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli, or a combination thereof.
31. A method for the treatment or prophylaxis of infections caused by enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli or combinations thereof and diseases caused thereby, which comprises administering to a mammal a compound of formula (I) according to any one of claims 1 to 20 and claim 22 or a pharmaceutically acceptable salt thereof.
32. Use of a compound of formula (I) according to any one of claims 1 to 20 and claim 22, or a pharmaceutically acceptable salt thereof, as an antibiotic.
33. Use of a compound of formula (I) according to any one of claims 1 to 20 and claim 22 or a pharmaceutically acceptable salt thereof for the treatment or prevention of infections and diseases caused thereby by enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli or combinations thereof.
34. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 and 22 for the manufacture of a medicament for the treatment or prevention of infections and diseases caused thereby by enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter species or escherichia coli or a combination thereof.
35. The invention as hereinbefore described.
HK62023067104.7A 2020-01-22 2021-01-20 Novel heterocyclic compounds HK40078454B (en)

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Application Number Priority Date Filing Date Title
CNPCT/CN2020/073830 2020-01-22

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HK40078454B HK40078454B (en) 2024-08-23

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