CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of International Patent Application No. PCT/EP2021/074432, filed on Sep. 6, 2021, which claims benefit of priority to International Patent Application No. PCT/CN2020/113771, filed on Sep. 7, 2020, each of which is incorporated herein by reference in its entirety.

BACKGROUND

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

Acinetobacter baumannii is a Gram-negative, aerobic, nonfermenting bacterium recognized over the last decades as an emerging pathogen with very limited treatment options.

A. baumannii is considered to be a serious threat by the US Centers for Disease Control and Prevention and belongs to the so called ‘ESKAPE’ pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species & E. coli) that currently cause the majority of nosocomial infections and effectively “escape” the activity of antimicrobial agents.

A. baumannii is most often encountered in intensive care units and surgical wards, where extensive antibiotic use has enabled selection for resistance against all known antimicrobials and where it causes infections that include bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection.

A. baumannii has an exceptional ability to upregulate and acquire resistance determinants and shows an environmental persistance that allows its survival and spread in the nosocomial setting, making this organism a frequent cause of outbreaks of infection and an endemic, health care-associated pathogen.

Due to increasing antibiotic resistance to most if not all available therapeutic options, Muti-Drug Resistant (MDR) A. baumannii infections, especially those caused by Carbapenem resistant A. baumannii, are extremely difficult or even impossible to treat with high mortality rate as well as increased morbidity and length of stay in intensive care unit.

Acinetobacter baumannii has been defined and still remains “a prime example of a mismatch between unmet medical needs and the current antimicrobial research and development pipeline” according to the Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA). Thus, there is a high demand and need to identify compounds suitable for the treatment of diseases and infections caused by Acinetobacter baumannii.

The present invention provides novel compounds which exhibit activity against drug-susceptible as well as drug-resistant strains of Acinetobacter baumannii.

SUMMARY OF THE DISCLOSURE

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

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein R¹to R⁹and p are as defined herein.

In one aspect, the present invention provides a process of manufacturing the compounds of formula (I) described herein, wherein said process is as described in any one of Schemes 1 to 4 herein.

In a further aspect, the present invention provides a compound of formula (I) as described herein, when manufactured according to the processes described herein.

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

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

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

In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of nosocomial infections and resulting diseases.

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

In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

In a further aspect, the present invention provides a method for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof, which method comprises administering a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, to a mammal.

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

In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of medicaments useful for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

DETAILED DESCRIPTION OF THE DISCLOSURE
Definitions

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references referred to herein are incorporated by reference in their entirety.

The term “alkyl” refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“C₁-C₆-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2 or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, yet non-limiting examples of alkyl include methyl and ethyl.

The term “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“C₁-C₆-alkoxy”). In some preferred embodiments, the alkoxy group contains contains 1 to 4 carbon atoms. In still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, yet non-limiting example of alkoxy is methoxy.

The term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term “halogen” or “halo” refers to fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl).

The term “cycloalkyl” as used herein refers to a saturated or partly unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C₃-C₁₀-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and spiro[2.3]hexan-5-yl.

The term “aminoalkoxy” refers to an alkoxy group, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by an amino group. Preferably, “aminoalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by an amino group. Preferred, yet non-limiting examples of aminoalkoxy are aminomethoxy and 1-aminoethoxy.

The term “heterocyclyl” refers to a saturated or partly unsaturated mono- or bicyclic, preferably monocyclic ring system of 3 to 14 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 ring atoms wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon. “Bicyclic heterocyclyl” refers to heterocyclic moieties consisting of two cycles having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Some non-limiting examples of heterocyclyl groups include azetidin-3-yl; azetidin-2-yl; oxetan-3-yl; oxetan-2-yl; piperidyl; piperazinyl; pyrrolidinyl; 2-oxopyrrolidin-1-yl; 2-oxopyrrolidin-3-yl; 5-oxopyrrolidin-2-yl; 5-oxopyrrolidin-3-yl; 2-oxo-1-piperidyl; 2-oxo-3-piperidyl; 2-oxo-4-piperidyl; 6-oxo-2-piperidyl; 6-oxo-3-piperidyl; 1-piperidinyl; 2-piperidinyl; 3-piperidinyl; 4-piperidinyl; morpholino; morpholin-2-yl; morpholin-3-yl; pyrrolidinyl (e.g., pyrrolidin-3-yl); 3-azabicyclo[3.1.0]hexan-6-yl; 2,5-diazabicyclo[2.2.1]heptan-2-yl; 2-azaspiro[3.3]heptan-2-yl; 2,6-diazaspiro[3.3]heptan-2-yl; and 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl. The term “aryl” refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members (“C₆-C₁₀-aryl”) and wherein at least one ring in the system is aromatic. A particularly preferred, yet non-limiting example of aryl is phenyl.

The term “heteroaryl” refers to a mono- or multivalent, monocyclic or bicyclic, preferably bicyclic ring system having a total of 5 to 14 ring members, preferably, 5 to 12 ring members, and more preferably 5 to 10 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, “heteroaryl” refers to a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, “heteroaryl” refers to a 5-10 membered heteroaryl comprising 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1,2-benzoxazol-3-yl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl, 1,2-benzoxazol-7-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-4-yl, and 1,2,4-oxadiazol-3-yl. Most preferably, “heteroaryl” refers to pyridyl and pyrimidinyl.

The term “hydroxy” refers to an —OH group.

The term “amino” refers to an —NH₂group.

The term “cyano” refers to a —CN (nitrile) group.

The term “carbamoyl” refers to a —C(O)NH₂group.

The term “carbonyl” refers to a carbon radical having two of the four covalent bonds shared with an oxygen atom (C═O).

The term “haloalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Non-limiting examples of haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, 2-fluoroethyl, and 2,2-difluoroethyl. A particularly preferred, yet non-limiting example of haloalkyl is trifluoromethyl.

The term “cyanoalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by cyano group. Preferably, “cyanoalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a cyano group. Most preferably, “cyanoalkyl” refers to an alkyl group wherein 1 hydrogen atom of the alkyl group has been replaced by a cyano group. A preferred, yet non-limiting example of cyanoalkyl is cyanomethyl.

The term “haloalkoxy” refers to an alkoxy group, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkoxy are fluoromethoxy (FCH₂O—), difluoromethoxy (F₂CHO—), and trifluoromethoxy (F₃CO—).

The term “cyanoalkoxy” refers to an alkoxy group, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by cyano group. Preferably, “cyanoalkoxy” refers to an alkoxy group wherein 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 wherein 1 hydrogen atom of the alkoxy group has been replaced by a cyano group. A preferred, yet non-limiting example of cyanoalkoxy is cyanomethoxy.

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 “hydroxyalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group. Preferably, “hydroxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the alkyl group have been replaced by a hydroxy group. Preferred, yet non-limiting examples of hydroxyalkyl are hydroxymethyl, hydroxyethyl (e.g. 2-hydroxyethyl), and 3-hydroxy-3-methyl-butyl.

The term “aminoalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by 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 by an amino group. Preferred, yet non-limiting examples of aminoalkyl are aminomethyl, aminoethyl (e.g. 2-aminoethyl), 3-amino-3-methyl-butyl, aminopentyl (e.g., 5-aminopentyl), and aminohexyl (e.g., 6-aminohexyl).

The term “pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, lactic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. Particular pharmaceutically acceptable salts of compounds of formula (I) are hydrochlorides, fumarates, lactates (in particular derived from L-(+)-lactic acid), tartrates (in particular derived from L-(+)-tartaric acid) and trifluoroacetates.

The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention, the asymmetric carbon atom can be of the “R” or “S” configuration.

The term “treatment” as used herein includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and/or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.

The term “prophylaxis” as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.

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

The term “nosocomial infection” refers to a hospital-acquired infection (HAI), which is an infection that is acquired in a hospital or other health care facility. To emphasize both hospital and nonhospital settings, it is sometimes instead called a health care-associated infection (HAI or HCAI). Such an infection can be acquired in hospitals, nursing homes, rehabilitation facilities, outpatient clinics, or other clinical settings.

Compounds of the Invention

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

[Image Omitted]

- or a pharmaceutically acceptable salt thereof, wherein:
- R¹is, at each occurrence, independently selected from halogen, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, and halo-C₁-C₆-alkoxy;
- R², R³, R⁴, R⁵and R⁶are each independently selected from hydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, cyano, halo-C₁-C₆-alkyl, cyano-C₁-C₆-alkyl, (C₁-C₆-alkyl)₂N—, halo-C₁-C₆-alkoxy, cyano-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkoxy-, (C₁-C₆-alkyl)₂N—C(O)—, and carbamoyl-C₁-C₆-alkoxy;
- R⁷is selected from hydrogen, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl;
- R⁸is selected from C₁-C₆-alkyl, amino-C₁-C₆-alkyl, amino-C₁-C₆-alkyl-C(O)—, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-, C₁-C₆-alkyl-NH—C₁-C₆-alkyl-, amino-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₁-C₆-alkyl-NH—C₁-C₆-alkoxy-C₁-C₆-alkyl-, (C₁-C₆-alkyl)₂N—C₁-C₆-alkoxy-C₁-C₆-alkyl-, amino-C₁-C₆-alkoxy-C₁-C₆-alkyl-C(O)—, C₁-C₆-alkyl-NH—C₁-C₆-alkoxy-C₁-C₆-alkyl-C(O)—, (C₁-C₆-alkyl)₂N—C₁-C₆-alkoxy-C₁-C₆-alkyl-C(O)—, amino-C₁-C₆-alkyl-C(O)—NH—C₁-C₆-alkyl-, C₁-C₆-alkyl-NH—C₁-C₆-alkyl-C(O)—NH—C₁-C₆-alkyl-, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-C(O)—NH—C₁-C₆-alkyl-, and a group

[Image Omitted]

- R⁹is selected from hydrogen and C₁-C₆-alkyl;
- R¹⁰is selected from halogen, cyano, amino, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, amino-C₁-C₆-alkyl-, C₁-C₆-alkyl-NH—C₁-C₆-alkyl-, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-, amino-C₁-C₆-alkyl-C(O)—, C₁-C₆-alkyl-NH—C₁-C₆-alkyl-C(O)—, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-C(O)—, amino-C₁-C₆-alkyl-NH—C(O)—, amino-C₁-C₆-alkoxy-C₁-C₆-alkyl-C(O)—, hydroxy-C₁-C₆-alkyl, and a group

[Image Omitted]

- R¹¹is selected from halogen, cyano, amino, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, amino-C₁-C₆-alkyl-, C₁-C₆-alkyl-NH—C₁-C₆-alkyl-, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-, amino-C₁-C₆-alkyl-C(O)—, C₁-C₆-alkyl-NH—C₁-C₆-alkyl-C(O)—, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-C(O)—, amino-C₁-C₆-alkyl-NH—C(O)—, amino-C₁-C₆-alkoxy-C₁-C₆-alkyl-C(O)—, and hydroxy-C₁-C₆-alkyl;
- A and B are each independently selected from 3- to 14-membered heterocyclyl, C₃-C₁₀-cycloalkyl, 5- to 14-membered heteroaryl, and C₆-C₁₀-aryl;
- L¹is selected from a covalent bond, carbonyl, —NH—C(O)—, C₁-C₆-alkyl, —C(O)—NH—C₁-C₆-alkyl-, —C₁-C₆-alkyl-NH—C(O)—, and —NH—C(O)—NH—C₁-C₆-alkyl-;
- L²is selected from a covalent bond, carbonyl, —NH—C(O)—, —C(O)—NH—, C₁-C₆-alkyl, —C(O)—NH—C₁-C₆-alkyl-, —C₁-C₆-alkyl-NH—C(O)—, and —NH—C(O)—NH—C₁-C₆-alkyl-;
- p is selected from 0, 1, 2, 3, or 4; and
- q and r are independently selected from 0, 1, 2, and 3.

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

[Image Omitted]

- wherein R¹to R⁹are as defined herein.

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

[Image Omitted]

- wherein R¹to R⁶, R⁸and R⁹are as defined herein.

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

[Image Omitted]

- wherein R¹to R⁴, R⁶and R⁸are as defined herein.

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

- R¹is C₁-C₆-alkyl or halogen; and
- p is 1.

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

- R¹is halogen; and
- p is 1.

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

- R¹is chloro; and
- p is 1.

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

- R²is hydrogen or halogen;
- R³is hydrogen or halogen;
- R⁴is selected from C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, cyano-C₁-C₆-alkoxy, and carbamoyl-C₁-C₆-alkoxy;
- R⁵is hydrogen; and
- R⁶is hydrogen or halogen.

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

- R²and R³are both halogen;
- R⁴is selected from C₁-C₆-alkoxy and halo-C₁-C₆-alkoxy; and
- R⁵and R⁶are both hydrogen.

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

- R²and R³are both fluoro;
- R⁴is selected from methoxy and difluoromethoxy; and
- R⁵and R⁶are both hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁷is C₁-C₆-alkyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁷is methyl.

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

- R⁸is selected from C₁-C₆-alkyl, amino-C₁-C₆-alkyl, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-, amino-C₁-C₆-alkoxy-C₁-C₆-alkyl-, (C₁-C₆-alkyl)₂N—C₁-C₆-alkoxy-C₁-C₆-alkyl-, amino-C₁-C₆-alkyl-C(O)—NH—C₁-C₆-alkyl-, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-C(O)—NH—C₁-C₆-alkyl-, and a group

[Image Omitted]

R⁹is hydrogen;

- R¹⁰is selected from amino, hydroxy, C₁-C₆-alkyl, amino-C₁-C₆-alkyl-C(O)—, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-C(O)—, amino-C₁-C₆-alkyl-NH—C(O)—, amino-C₁-C₆-alkoxy-C₁-C₆-alkyl-C(O)—, hydroxy-C₁-C₆-alkyl, and a group

[Image Omitted]

- R¹¹is selected from hydroxy, amino, and amino-C₁-C₆-alkyl;
- A and B are each independently selected from 3- to 14-membered heterocyclyl and C₃-C₁₀-cycloalkyl;
- L¹is selected from a covalent bond, C₁-C₆-alkyl, —C(O)—NH—C₁-C₆-alkyl-, and —NH—C(O)—NH—C₁-C₆-alkyl-;
- L²is selected from carbonyl, C₁-C₆-alkyl, —C(O)—NH—, and —NH—C(O)—; and
- q and r are each independently selected from 0 and 1.

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

- R⁸is a group

[Image Omitted]

- R⁹is hydrogen;
- R¹⁰is selected from amino-C₁-C₆-alkyl-C(O)—, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-C(O)—, amino-C₁-C₆-alkoxy-C₁-C₆-alkyl-C(O)—, and a group

[Image Omitted]

- R¹¹is selected from hydroxy and amino;
- A and B are each independently selected from 3- to 14-membered heterocyclyl and C₃-C₁₀-cycloalkyl;
- L¹is selected from a covalent bond and C₁-C₆-alkyl;
- L²is selected from carbonyl, —C(O)—NH—, and —NH—C(O)—;
- q is 1; and
- r is selected from 0 and 1.

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

- R⁸is a group

[Image Omitted]

- R⁹is hydrogen;
- R¹⁰is selected from 2-aminoacetyl, 2-aminopropanoyl, 2-(dimethylamino)acetyl, 3-(2-aminoethoxy)propanoyl, and a group

[Image Omitted]

- R¹¹is selected from hydroxy and amino;
- A is selected from azetidinyl, cyclobutyl, pyrrolidinyl, and piperidyl;
- B is selected from cyclobutyl, pyrrolidinyl, and piperidyl;
- L¹is selected from a covalent bond and —(CH₂)₂—;
- L²is selected from carbonyl, —C(O)—NH—, and —NH—C(O)—;
- q is 1; and
- r is selected from 0 and 1.

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

- R¹is C₁-C₆-alkyl or halogen;
- R²is hydrogen or halogen;
- R³is hydrogen or halogen;
- R⁴is selected from C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, cyano-C₁-C₆-alkoxy, and carbamoyl-C₁-C₆-alkoxy;
- R⁵and R⁹are both hydrogen;
- R⁶is hydrogen or halogen;
- R⁷is C₁-C₆-alkyl;
- R⁸is selected from C₁-C₆-alkyl, amino-C₁-C₆-alkyl, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-, amino-C₁-C₆-alkoxy-C₁-C₆-alkyl-, (C₁-C₆-alkyl)₂N—C₁-C₆-alkoxy-C₁-C₆-alkyl-, amino-C₁-C₆-alkyl-C(O)—NH—C₁-C₆-alkyl-, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-C(O)—NH—C₁-C₆-alkyl-, and a group

[Image Omitted]

- R¹⁰is selected from amino, hydroxy, C₁-C₆-alkyl, amino-C₁-C₆-alkyl-C(O)—, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-C(O)—, amino-C₁-C₆-alkyl-NH—C(O)—, amino-C₁-C₆-alkoxy-C₁-C₆-alkyl-C(O)—, hydroxy-C₁-C₆-alkyl, and a group

[Image Omitted]

- R¹¹is selected from hydroxy, amino, and amino-C₁-C₆-alkyl;
- A and B are each independently selected from 3- to 14-membered heterocyclyl and C₃-C₁₀-cycloalkyl;
- L¹is selected from a covalent bond, C₁-C₆-alkyl, —C(O)—NH—C₁-C₆-alkyl-, and —NH—C(O)—NH—C₁-C₆-alkyl-;
- L²is selected from carbonyl, C₁-C₆-alkyl, —C(O)—NH—, and —NH—C(O)—;
- p is 1; and
- q and r are each independently selected from 0 and 1.

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

- R¹, R²and R³are each independently halogen;
- R⁴is selected from C₁-C₆-alkoxy and halo-C₁-C₆-alkoxy;
- R⁵, R⁶and R⁹are all hydrogen;
- R⁷is C₁-C₆-alkyl;
- R⁸is a group

[Image Omitted]

- R¹⁰is selected from amino-C₁-C₆-alkyl-C(O)—, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-C(O)—, amino-C₁-C₆-alkoxy-C₁-C₆-alkyl-C(O)—, and a group

[Image Omitted]

- R¹¹is selected from hydroxy and amino;
- A and B are each independently selected from 3- to 14-membered heterocyclyl and C₃-C₁₀-cycloalkyl;
- L¹is selected from a covalent bond and C₁-C₆-alkyl;
- L²is selected from carbonyl, —C(O)—NH—, and —NH—C(O)—;
- q is 1;
- r is selected from 0 and 1; and
- p is 1.

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

- R¹is chloro;
- R²and R³are both fluoro;
- R⁴is selected from methoxy and difluoromethoxy;
- R⁵, R⁶and R⁹are all hydrogen;
- R⁷is methyl;

R⁸is a group

[Image Omitted]

- R¹⁰is selected from 2-aminoacetyl, 2-aminopropanoyl, 2-(dimethylamino)acetyl, 3-(2-aminoethoxy)propanoyl, and a group

[Image Omitted]

- R¹¹is selected from hydroxy and amino;
- A is selected from azetidinyl, cyclobutyl, pyrrolidinyl, and piperidyl;
- B is selected from cyclobutyl, pyrrolidinyl, and piperidyl;
- L¹is selected from a covalent bond and —(CH₂)₂—;
- L²is selected from carbonyl, —C(O)—NH—, and —NH—C(O)—;
- q is 1;
- r is selected from 0 and 1; and
- p is 1.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹is C₁-C₆-alkyl or halogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R²is hydrogen or halogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R³is hydrogen or halogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁴is selected from C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, cyano-C₁-C₆-alkoxy, and carbamoyl-C₁-C₆-alkoxy. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁵is hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁶is hydrogen or halogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁷is C₁-C₆-alkyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁸is selected from C₁-C₆-alkyl, amino-C₁-C₆-alkyl, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-, amino-C₁-C₆-alkoxy-C₁-C₆-alkyl-, (C₁-C₆-alkyl)₂N—C₁-C₆-alkoxy-C₁-C₆-alkyl-, amino-C₁-C₆-alkyl-C(O)—NH—C₁-C₆-alkyl-, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-C(O)—NH—C₁-C₆-alkyl-, and a group

[Image Omitted]

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁹is hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹⁰is selected from amino, hydroxy, C₁-C₆-alkyl, amino-C₁-C₆-alkyl-C(O)—, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-C(O)—, amino-C₁-C₆-alkyl-NH—C(O)—, amino-C₁-C₆-alkoxy-C₁-C₆-alkyl-C(O)—, hydroxy-C₁-C₆-alkyl, and a group

[Image Omitted]

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹¹is selected from hydroxy, amino, and amino-C₁-C₆-alkyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from 3- to 14-membered heterocyclyl and C₃-C₁₀-cycloalkyl.

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 and C₃-C₁₀-cycloalkyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L¹is selected from a covalent bond, C₁-C₆-alkyl, —C(O)—NH—C₁-C₆-alkyl-, and —NH—C(O)—NH—C₁-C₆-alkyl-.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L²is selected from carbonyl, C₁-C₆-alkyl, —C(O)—NH—, and —NH—C(O)—.

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

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

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

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹is halogen.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R²is halogen.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R³is halogen.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁴is selected from C₁-C₆-alkoxy and halo-C₁-C₆-alkoxy.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁶is hydrogen.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁸is a group

[Image Omitted]

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹⁰is selected from amino-C₁-C₆-alkyl-C(O)—, (C₁-C₆-alkyl)₂N—C₁-C₆-alkyl-C(O)—, amino-C₁-C₆-alkoxy-C₁-C₆-alkyl-C(O)—, and a group

[Image Omitted]

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹¹is selected from hydroxy and amino.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L¹is selected from a covalent bond and C₁-C₆-alkyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L²is selected from carbonyl, —C(O)—NH—, and —NH—C(O)—.

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

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹is chloro.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R²is fluoro.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R³is fluoro.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁴is selected from methoxy and difluoromethoxy.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁷is methyl.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹⁰is selected from 2-aminoacetyl, 2-aminopropanoyl, 2-(dimethylamino)acetyl, 3-(2-aminoethoxy)propanoyl, and a group

[Image Omitted]

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from azetidinyl, cyclobutyl, pyrrolidinyl, and piperidyl.

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 cyclobutyl, pyrrolidinyl, and piperidyl.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L¹is selected from a covalent bond and —(CH₂)₂—.

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

N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

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

N-[3-chloro-4-(pyrrolidin-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[3-chloro-4-(4-piperidylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[3-chloro-4-(4-piperidylmethylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-(6-aminohexylcarbamoyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[[3-(aminomethyl)cyclobutyl]methylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[(3-aminocyclobutyl)methylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;

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

N-[3-chloro-4-(3-piperazin-1-ylpropylcarbamoyl)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-(3-piperazin-1-ylpropylcarbamoyl)phenyl]imidazole-2-carboxamide;

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(difluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide;

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(3-fluoro-4-isopropoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(2-chloro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(2,6-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-(3-Aminopropylcarbamoyl)-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(2-amino-2-oxo-ethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide;

N-[3-Chloro-4-[[1-(piperidine-4-carbonyl)pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[3-Chloro-4-[[1-[2-(dimethylamino)acetyl]pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

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

N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[3-chloro-4-[5-(dimethylamino)pentylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[3-chloro-4-(2-isopentyloxyethylcarbamoyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;

N-[3-chloro-4-[2-(3-hydroxypyrrolidin-1-yl)ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[3-chloro-4-[2-[3-(hydroxymethyl)pyrrolidin-1-yl]ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

5-(2,3-difluoro-4-methoxy-phenyl)-N-[4-[3-[2-(dimethylamino)ethoxy]propylcarbamoyl]-3-ethyl-phenyl]-1-methyl-imidazole-2-carboxamide;

N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[[1-[3-(2-aminoethoxy)propanoyl]pyrrolidin-3-yl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

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

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

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

N-[4-[[1-[3-(2-aminoethoxy)propanoyl]-4-piperidyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[[3-[[3-(aminomethyl)cyclobutanecarbonyl]amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[2-[1-(3-aminopropanoyl)azetidin-3-yl]ethylcarbamoyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;

N-[4-[3-(3-aminopropanoylamino)propylcarbamoyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;

N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]piperidine-4-carboxamide;

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

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

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

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

N-[4-[[1-(2-aminoacetyl)azetidin-3-yl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[[1-(2-aminoacetyl)azetidin-3-yl]methylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[[3-(2-aminoethylcarbamoyl)cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[[3-(3-aminoazetidine-1-carbonyl)cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[[3-[(3-aminocyclobutyl)carbamoyl]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[[3-(2-aminoethylcarbamoyl)cyclobutyl]carbamoyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[[1-(2-aminoacetyl)azetidin-3-yl]carbamoyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[2-[[(2R,4R)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[2-[[(2R,4R)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;

5-(2,3-difluoro-4-methoxy-phenyl)-N-[4-[2-[[(2R,4R)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;

5-(2,3-difluoro-4-methoxy-phenyl)-N-[4-[2-[[(2R,4R)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;

5-(2,3-difluoro-4-methoxy-phenyl)-N-[4-[2-[[(3R,4R)-4-hydroxypyrrolidin-3-yl]carbamoylamino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;

5-(2,3-difluoro-4-methoxy-phenyl)-N-[4-[2-[[(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamoylamino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[2-[[(3R,4R)-4-hydroxypyrrolidin-3-yl]carbamoylamino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[2-[[(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamoylamino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;

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

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

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

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

N-[3-chloro-4-[2-[[(2R,4R)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;

N-[3-chloro-4-[2-[[(2R,4R)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;

N-[3-chloro-4-[[3-[[(4R)-4-hydroxypyrrolidine-2-carbonyl]amino]cyclobutyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

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

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

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

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

N-[4-[2-[1-(Azetidin-3-ylmethyl)azetidin-3-yl]ethylcarbamoyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;

N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]-1-(pyrrolidin-3-ylmethyl)piperidine-4-carboxamide;

1-(azetidin-3-ylmethyl)-N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]piperidine-4-carboxamide;

N-[4-[[1-(azetidin-3-ylmethyl)-4-piperidyl]methylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

5-(4-Methoxyphenyl)-1-methyl-N-[3-methyl-4-(methylcarbamoyl)phenyl]imidazole-2-carboxamide;

N-[3-chloro-4-[[(exo)-3-[(2S,4R)-4-hydroxyprolyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; and

(exo)-6-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(trans)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide.

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

N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[[1-[3-(2-aminoethoxy)propanoyl]pyrrolidin-3-yl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

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

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

N-[4-[2-[1-(3-aminopropanoyl)azetidin-3-yl]ethylcarbamoyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;

N-[4-[[1-(2-aminoacetyl)azetidin-3-yl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[4-[[3-[(3-aminocyclobutyl)carbamoyl]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

N-[3-chloro-4-[[3-[[(4R)-4-hydroxypyrrolidine-2-carbonyl]amino]cyclobutyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;

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

(3S,4S)-N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-hydroxy-piperidine-4-carboxamide.

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

Example A1

N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

Example A2

N-[3-chloro-4-(2-piperazin-1-ylethylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

Example A3

N-[3-chloro-4-(pyrrolidin-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example A4

N-[3-chloro-4-(4-piperidylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example A5

N-[3-chloro-4-(4-piperidylmethylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example A6

N-[4-(6-aminohexylcarbamoyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

Example A7

N-[4-[[3-(aminomethyl)cyclobutyl]methylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example A8

N-[4-[(3-aminocyclobutyl)methylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example A9

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;formic acid

Example A10

N-[3-chloro-4-(2-piperazin-1-ylethylcarbamoyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid

Example A11

N-[3-chloro-4-(3-piperazin-1-ylpropylcarbamoyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid

Example A12

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-N-[3-methyl-4-(3-piperazin-1-ylpropylcarbamoyl)phenyl]imidazole-2-carboxamide;2,2,2-trifluoroacetic acid

Example A13

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example A14

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(difluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide;hydrochloride

Example A15

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(3-fluoro-4-isopropoxy-phenyl)-1-methyl-imidazole-2-carboxamide;hydrochloride

Example A16

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(2-chloro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;hydrochloride

Example A17

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;hydrochloride

Example A18

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-(2,6-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;hydrochloride

Example A19

N-[4-(3-Aminopropylcarbamoyl)-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide

Example A20

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;hydrochloride

Example A21

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[4-(2-amino-2-oxo-ethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;hydrochloride

Example A22

N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide;hydrochlorideExample B1

N-[3-Chloro-4-[[1-(piperidine-4-carbonyl)pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example A23

N-[3-Chloro-4-[[1-[2-(dimethylamino)acetyl]pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

Example A24

N-[3-chloro-4-[2-[[2-(dimethylamino)acetyl]amino]ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid

Example A25

N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

Example A26

N-[3-chloro-4-[5-(dimethylamino)pentylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

Example A27

N-[3-chloro-4-(2-isopentyloxyethylcarbamoyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;formic acid

Example A28

N-[3-chloro-4-[2-(3-hydroxypyrrolidin-1-yl)ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

Example A29

N-[3-chloro-4-[2-[3-(hydroxymethyl)pyrrolidin-1-yl]ethylcarbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

Example A30

5-(2,3-difluoro-4-methoxy-phenyl)-N-[4-[3-[2-(dimethylamino)ethoxy]propylcarbamoyl]-3-ethyl-phenyl]-1-methyl-imidazole-2-carboxamide

Example B2

N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B3

N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B4

N-[4-[[1-[3-(2-aminoethoxy)propanoyl]pyrrolidin-3-yl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B5

N-[3-chloro-4-[[1-(piperidine-4-carbonyl)-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B6

N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B7

N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

Example B8

N-[4-[[1-[3-(2-aminoethoxy)propanoyl]-4-piperidyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B9

N-[4-[[3-[[3-(aminomethyl)cyclobutanecarbonyl]amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B10

N-[4-[2-[1-(3-aminopropanoyl)azetidin-3-yl]ethylcarbamoyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid

Example B11

N-[4-[3-(3-aminopropanoylamino)propylcarbamoyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid

Example B12

N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]piperidine-4-carboxamide;formic acid

Example B13

N-[2-[[4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]amino]ethyl]piperidine-4-carboxamide;formic acid

Example B14

N-[2-[[4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]amino]ethyl]-4-hydroxy-piperidine-4-carboxamide;formic acid

Example B15

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

Example B16

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

Example B17

N-[4-[[1-(2-aminoacetyl)azetidin-3-yl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B18

N-[4-[[1-(2-aminoacetyl)azetidin-3-yl]methylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B19

N-[4-[[3-(2-aminoethylcarbamoyl)cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B20

N-[4-[[3-(3-aminoazetidine-1-carbonyl)cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B21

N-[4-[[3-[(3-aminocyclobutyl)carbamoyl]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid

Example B22

N-[4-[[3-(2-aminoethylcarbamoyl)cyclobutyl]carbamoyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid

Example B23

N-[4-[[1-(2-aminoacetyl)azetidin-3-yl]carbamoyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B24

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[2-[[(2R,4R)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;formic acid

Example B25

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[2-[[(2R,4R)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;formic acid

Example B26

5-(2,3-difluoro-4-methoxy-phenyl)-N-[4-[2-[[(2R,4R)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;formic acid

Example B27

5-(2,3-difluoro-4-methoxy-phenyl)-N-[4-[2-[[(2R,4R)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;formic acid

Example B28

5-(2,3-difluoro-4-methoxy-phenyl)-N-[4-[2-[[(3R,4R)-4-hydroxypyrrolidin-3-yl]carbamoylamino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;formic acid

Example B29

5-(2,3-difluoro-4-methoxy-phenyl)-N-[4-[2-[[(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamoylamino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;formic acid

Example B30

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[2-[[(3R,4R)-4-hydroxypyrrolidin-3-yl]carbamoylamino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;formic acid

Example B31

5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[2-[[(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamoylamino]ethylcarbamoyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide;formic acid

Example B32

(3R,4R)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxy-piperidine-4-carboxamide;formic acid

Example B33

(3S,4S)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxy-piperidine-4-carboxamide;formic acid

Example B34

(3S,4R)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxy-piperidine-4-carboxamide;formic acid

Example B35

(3R,4S)-N-[2-[[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]ethyl]-3-hydroxy-piperidine-4-carboxamide;formic acid

Example B36

N-[3-chloro-4-[2-[[(2R,4R)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;formic acid

Example B37

N-[3-chloro-4-[2-[[(2R,4R)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]amino]ethylcarbamoyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;formic acid

Example B38

N-[3-chloro-4-[[3-[[(4R)-4-hydroxypyrrolidine-2-carbonyl]amino]cyclobutyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B39

N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]piperidine-4-carboxamide;formic acid

Example B40

N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-4-hydroxy-piperidine-4-carboxamide;formic acid

Example B41

(3R,4R)-N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-hydroxy-piperidine-4-carboxamide;formic acid

Example B42

(3S,4S)-N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-hydroxy-piperidine-4-carboxamide;formic acid

Example C1

N-[4-[2-[1-(Azetidin-3-ylmethyl)azetidin-3-yl]ethylcarbamoyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid

Example C2

N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]-1-(pyrrolidin-3-ylmethyl)piperidine-4-carboxamide;formic acid

Example C3

1-(azetidin-3-ylmethyl)-N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]piperidine-4-carboxamide;formic acid

Example C4

N-[4-[[1-(azetidin-3-ylmethyl)-4-piperidyl]methylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid; and Example D1

5-(4-Methoxyphenyl)-1-methyl-N-[3-methyl-4-(methylcarbamoyl)phenyl]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 said compound of formula (I) is selected from:

Example A25

N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

Example B2

N-[3-chloro-4-[[1-[(3R)-pyrrolidine-3-carbonyl]pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B4

N-[4-[[1-[3-(2-aminoethoxy)propanoyl]pyrrolidin-3-yl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B5

N-[3-chloro-4-[[1-(piperidine-4-carbonyl)-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B7

N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-4-piperidyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

Example B10

N-[4-[2-[1-(3-aminopropanoyl)azetidin-3-yl]ethylcarbamoyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid

Example B17

N-[4-[[1-(2-aminoacetyl)azetidin-3-yl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B21

N-[4-[[3-[(3-aminocyclobutyl)carbamoyl]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid

Example B38

N-[3-chloro-4-[[3-[[(4R)-4-hydroxypyrrolidine-2-carbonyl]amino]cyclobutyl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide;formic acid

Example B39

N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]piperidine-4-carboxamide;formic acid; and

Example B42

(3S,4S)-N-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-hydroxy-piperidine-4-carboxamide;formic acid.

In one embodiment, the present invention provides pharmaceutically acceptable salts of the compounds of formula (I) as described herein, especially pharmaceutically acceptable salts selected from hydrochlorides, fumarates, lactates (in particular derived from L-(+)-lactic acid), tartrates (in particular derived from L-(+)-tartaric acid) and trifluoroacetates. In yet a further particular embodiment, the present invention provides compounds according to formula (I) as described herein (i.e., as “free bases” or “free acids”, respectively).

In some embodiments, the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Processes of Manufacturing

The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes. The skills required for carrying out the reactions and purifications of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary. In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition, Richard C. Larock. John Wiley & Sons, New York, N.Y. 2018). We find it convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between −78° C. to reflux temperature. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.

All substituents, in particular, R¹to R⁹are as defined above and in the claims, unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.

[Image Omitted]

Wherein PG1 denotes a suitable protective group, such as an alkyl group, e.g. Me, Et or iso-butyl.

Compound of formula Intermediate C can be prepared according to Scheme 1. 5-bromo-1-methyl-imidazole can react with isobutyl carbonochloridate under basic condition to afford compound A. Acid B can be obtained by hydrolysis of A. Coupling of B and amine C with a condensing agent, such as HATU/DIPEA in DMSO, affords Intermediate A. Suzuki coupling of Intermediate A with bronic acids or esters (Intermediate B) can be achieved using palladium catalysts and phosphine ligands to give compounds D. Hydrolysis compounds D yields Intermediate C.

[Image Omitted]

Wherein PG2 is a suitable amino protective group, such as Boc.

Wherein Y is a primary amine (Intermediate D) or a secondary amine (Example A, compound E).

Intermediate D (Y=NH₂)/Example A (Y=NHR⁸) can be prepared according to route 1 and 2 in Scheme 2. Coupling of acid Intermediate C with a free amine Y or with a protected amine PG2-Y using a condensing agent, such as HATU/DIPEA in DMSO, affords the compound of formula Example A (Route 1) or compound E. Deprotection of the Compound E yields Intermediate D or Example A (Route 2).

[Image Omitted]

Example A

Wherein PG2 is a suitable amino protective group, such as Boc; and Y is a primary amine (Intermediate D) or a secondary amine (Example A, compound E).

Intermediate D (Y=NH₂)/Example A (Y=NHR⁸) can also be prepared according to the route outlined in Scheme 3. Thus, coupling of acid Intermediate F with protected amine PG2-Y using a condensing agent, such as HATU/DIPEA in DMSO, affords compound G. Further coupling of B and amine G using a condensing agent, such as HATU/DIPEA in DMSO, then yields compound H. Suzuki coupling of Compound H with bronic acids or esters (Intermediate B) can be achieved using palladium catalysts and phosphine ligands to give compounds E. Deprotection of Compound E affords Intermediate D or Example A, respectively.

[Image Omitted]

Wherein PG3 is a suitable amino protective group, such as Boc; Y is a primary amine (Intermediate D) or a secondary amine (compound I, Examples B and C); and Z is an amine or a group R—C(O)—NH—, such that Y and Z taken together form a group R⁸as defined herein.

Compounds B and C can be prepared according to the route in Scheme 4. Coupling of acid D with protected amine PG3-Z using a condensing agent, such as HATU/DIPEA in DMSO, affords compound I, followed by deprotection of the PG3 of Z to give B. In some case, the compound I was prepared through reductive amination reaction between Intermediate D and aldehyde PG3-Z using e.g. NaBH₃CN in MeOH solution, followed by deprotection of the PG3 of Z to give B.

In one aspect, the present invention provides a process of manufacturing the compounds of formula (I) described herein, wherein said process is as described in any one of Schemes 1 to 4 above.

In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to the processes disclosed herein.

Using the Compounds of the Invention

As illustrated in the experimental section, the compounds of formula (I) and their pharmaceutically acceptable salts possess valuable pharmacological properties for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly by Acinetobacter species, most particularly by Acinetobacter baumannii.

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

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as antibiotics, i.e. as antibacterial pharmaceutical ingredients suitable in the treatment and prevention of bacterial infections, particularly in the treatment and prevention of bacterial infections caused by Acinetobacter species, more particularly in the treatment and prevention of bacterial infections caused by Acinetobacter baumannii.

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

In one aspect, the present invention provides compounds of formula (I) or their pharmaceutically acceptable salts as described herein for use as therapeutically active substances.

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

In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of nosocomial infections and resulting diseases.

In a particular embodiment, said nosocomial infections and resulting diseases are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection, or a combination thereof.

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

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

In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

In a further aspect, the present invention provides a method for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof, which method comprises administering a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, to a mammal.

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

In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of medicaments useful for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

In a particular embodiment, said infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof, are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection, or a combination thereof.

In a further aspect, the present invention provides compounds of formula (I) or their pharmaceutically acceptable salts as defined above for use in the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii.

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

In a further aspect, the present invention provides the use of compounds of formula (I) or their pharmaceutically acceptable salts as defined above for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii.

In a further aspect, the present invention provides the use of compounds of formula (I) or their pharmaceutically acceptable salts as defined above for the preparation of medicaments for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii. Such medicaments comprise compounds of formula (I) or their pharmaceutically acceptable salts as defined above.

Pharmaceutical Compositions and Administration

In one aspect, the present invention provides pharmaceutical compositions comprising compounds of formula (I) or their pharmaceutically acceptable salts as defined above and one or more pharmaceutically acceptable excipients. Exemplary pharmaceutical compositions are described in Examples 1-4.

In a further aspect, the present invention relates to pharmaceutical compositions comprising compounds of formula (I) or their pharmaceutically acceptable salts as defined above and one or more pharmaceutically acceptable excipients for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions or infusion solutions).

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such excipients for tablets, dragées and hard gelatin capsules.

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

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

Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

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

Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated.

Co-Administration of Compounds of Formula (I) and Other Agents

The compounds of formula (I) or salts thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof may be employed alone or in combination with other agents for treatment. For example, the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound of formula (I) such that they do not adversely affect each other. The compounds may be administered together in a unitary pharmaceutical composition or separately. In one embodiment a compound or a pharmaceutically acceptable salt can be co-administered with an antibiotic, in particular with an antibiotic for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

The term “co-administering” refers to either simultaneous administration, or any manner of separate sequential administration, of a compound of formula (I) or a salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof and a further active pharmaceutical ingredient or ingredients, including antibiotic agents. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered intravenously and another compound may be administered orally. Typically, any agent that has antimicrobial activity may be co-administered. Particular examples of such agents are Carbapenems (meropenem), Fluoroquinolone (Ciprofloxacin), Aminoglycoside (amikacin), Tetracyclines (tigecycline), Colistin, Sulbactam, Sulbactam+Durlobactam, Cefiderocol (Fetroja), macrocyclic peptides as exemplified e.g. in WO 2017072062 A1, WO 2019185572 A1 and WO 2019206853 A1, and Macrolides (erythromycin).

In one aspect, the present invention provides a pharmaceutical composition described herein, further comprising an additional therapeutic agent.

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

In one embodiment, said additional therapeutic agent is an antibiotic agent that is useful for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

In one embodiment, said additional therapeutic agent is an antibiotic agent selected from Carbapenems (meropenem), Fluoroquinolone (Ciprofloxacin), Aminoglycoside (amikacin), Tetracyclines (tigecycline), Colistin, Sulbactam, Sulbactam+Durlobactam, Cefiderocol (Fetroja), macrocyclic peptides as exemplified in WO 2017072062 A1, WO 2019185572 A1 and WO 2019206853 A1, and Macrolides (erythromycin).

EXAMPLES

The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.

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

All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.

Abbreviations used herein are as follows:

ACN or MeCN acetonitrile

BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene

CFU colony-forming unit

d day

DCM dichloromethane

DIPEA N,N-diisopropylethylamine

EtOAc or EA ethyl acetate

FA formic acid

h(s) or hr(s) hour(s)

HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

HPLC high performance liquid chromatography

HPLC-UV high performance liquid chromatography with ultraviolet detector

IC50 half maximal inhibitory concentration

IC90 90% inhibitory concentration

PE petroleum ether

PdCl₂(DPPF) [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

Pd₂(dba)₃Tris(dibenzylideneacetone)dipalladium(0)

PG Protecting group

Precat precatalyst

prep-HPLC preparative high performance liquid chromatography

RBF Round bottom flask

rt room temperature

sat saturated

SEM 2-methoxyethyl(trimethyl)silane

FA Formic acid

TFA Trifluoroacetic Acid

wt weight

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

Intermediate A1
Methyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate
Step 1: isobutyl 5-bromo-1-methyl-imidazole-2-carboxylate

To a solution of 5-bromo-1-methyl-imidazole (20 g, 124 mmol) and DIPEA (32.1 g, 43.4 mL, 248 mmol) in DCM (140 mL) at −70° C. was added slowly a solution of isobutyl carbonochloridate (22.1 g, 161 mmol) in DCM (60 mL). The dropwise time lasted about 30 min. The mixture was stirred at −70° C. for 2 h. Then the mixture was slowly warmed to room temperature and stirred overnight. Then the solution was washed with water and concentrated in vacuum. The crude product was then purified by flash column chromatography to afford isobutyl 5-bromo-1-methyl-1H-imidazole-2-carboxylate (29 g) as a yellow oil. MS [M+H]⁺: 261.2.

Step 2: 5-bromo-1-methyl-imidazole-2-carboxylic acid

To a solution of isobutyl 5-bromo-1-methyl-1H-imidazole-2-carboxylate (29 g, 111 mmol) in MeOH (5 mL) and THE (120 mL) was added a solution of lithium hydroxide monohydrate (9.32 g, 222 mmol) in water (60 mL). The mixture was stirred at room temperature for 3 h. The organic solvent was removed under reduced pressure. 12 N HCl aqueous solution was added under stirring until pH 4-5. The white solid was filtered, washed with MeOH and dried over anhydrous Na₂SO₄to afford 5-bromo-1-methyl-imidazole-2-carboxylic acid (20.5 g) as a white solid. MS [M+H]⁺: 204.8.

Step 3: methyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate

A mixture of 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid (13 g, 63.4 mmol), methyl 4-amino-2-chloro-benzoate (11.8 g, 63.4 mmol), HATU (24.1 g, 63.4 mmol) and DIPEA (24.6 g, 190 mmol) in DMF (50 mL) was stirred at room temperature overnight. Then the mixture was poured into water. The water phase was extracted with DCM. The combined organic phases were washed with water, dried over anhydrous Na₂SO₄and concentrated in vacuum. The solids precipitated from the concentrated solution. The solids were collected, washed with MeOH and dried to afford methyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate (18 g) as a light yellow solid. MS [M+H]⁺: 371.8.

Intermediate A2
tert-Butyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate
Step 1: tert-butyl 2-chloro-4-nitro-benzoate

To a mixture of 2-chloro-4-nitro-benzoic acid (15.0 g, 74.42 mmol), N,N-dimethylpyridin-4-amine (2.73 g, 22.33 mmol) and N,N-diethylethanamine (31.12 mL, 223.26 mmol) in THF (80 mL) was added a solution of tert-butoxycarbonyl tert-butyl carbonate (24.36 g, 111.63 mmol) in THE (20 mL) at −10° C. The resulting mixture was warmed to 25° C. and stirred for another 14 h. The mixture was concentrated. The residue was treated with EA (50 mL) and H₂O (50 mL). The mixture was extracted with EA. The combined organic layers were concentrated. The crude was then purified by flash column chromatography to afford tert-butyl 2-chloro-4-nitro-benzoate (18.8 g) as a colorless solid.

Step 2: tert-butyl 4-amino-2-chloro-benzoate

To a mixture of tert-butyl 2-chloro-4-nitro-benzoate (18.8 g, 72.96 mmol) and Ammonium chloride (19.51 g, 364.81 mmol) in ethanol (200 mL) and water (200 mL) was added Iron (20.37 g, 364.81 mmol). The mixture was stirred at 25° C. for 14 h. The mixture was filtered by Celite. The filtrate was concentrated to remove ethanol. The mixture was extracted with EA. The combined organic layers were dried over anhydrous Na₂SO₄and concentrated to afford tert-butyl 4-amino-2-chloro-benzoate (16.31 g) as a light yellow solid. MS [M+H]⁺: 228.1.

Step 3: tert-butyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate

A mixture of 5-bromo-1-methyl-imidazole-2-carboxylic acid hydrochloride (7.0 g, 28.99 mmol), tert-butyl 4-amino-2-chloro-benzoate (6.0 g, 26.35 mmol), HATU (13.23 g, 34.79 mmol) and DIPEA (16.16 mL, 92.77 mmol) in DMF (15 mL) was stirred at 25° C. for 3 h. The mixture was added water (10 mL) and extracted with EA. The combined organic layers were concentrated. The crude was purified by FCC to afford tert-butyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate (8 g, 19.29 mmol) as a white solid. MS [M+H]⁺: 414.0.

The following intermediates were prepared in analogy:

MS ESI

Int.
Name
[M + H]⁺
Starting Material

Intermediate
tert-butyl 4-[(5-bromo-1-methyl-
395.1
2-Methyl-4-nitro-

A3
imidazole-2-carbonyl)amino]-2-methyl-

benzoic acid

benzoate

Intermediate
tert-butyl 4-[(5-bromo-1-methyl-
409.1
2-Ethyl-4-nitro-

A4
imidazole-2-carbonyl)amino]-2-ethyl-

benzoic acid

benzoate

Intermediate B1
2-(4-(Difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Step 1: 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene

To a solution of 4-bromo-2,3-difluorophenol (25 g, 120 mmol), sodium 2-chloro-2,2-difluoroacetate (36.5 g, 239 mmol) and K₂CO₃(19.8 g, 144 mmol) in DMF (250 mL) and Water (57 mL). The reaction mixture was heated to 100° C. and stirred for 3.0 h at 100° C. under N₂, The reaction mixture was poured into 1.5 L 1 H2O and extracted with EtOAc (3×250 mL). The organic layers were combined, washed with sat NaCl (200 mL), The organic layers were dried over Na₂SO₄and concentrated in vacuum. The crude material was purified by flash chromatography to afford 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene (25.2 g).

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

To a 250 mL round flask was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (24.5 g, 96.5 mmol), 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene (25 g, 96.5 mmol), PdCl₂(DPPF)—CH₂Cl₂adduct (3.53 g, 4.83 mmol) and potassium acetate (18.9 g, 193 mmol) in Dioxane (150 mL). The vial was capped and heated at 80° C. for 15 h under N₂. The crude reaction mixture was concentrated in vacuum. The reaction mixture was poured into 50 mL H2O and extracted with EtOAc (50 mL×3). The organic layers were combined, washed with sat NaCl (50 mL), The organic layers were dried over Na₂SO₄and concentrated in vacuum. The crude material was purified by flash chromatography. to afford 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25 g, 81.7 mmol, 84.6% yield).

The following intermediates were prepared in analogy:

MS ESI

Int.
Name
[M + H]⁺
Starting Material

Intermediate
2-[2,3-difluoro-4-(4,4,5,5-
296.2
4-bromo-2,3-

B2
tetramethyl-1,3,2-dioxaborolan-2-

difluorophenol and

yl)phenoxy]acetonitrile

bromoacetonitrile

Intermediate
2-[3-chloro-2-fluoro-4-(4,4,5,5-
312.5
4-bromo-3-chloro-2-

B3
tetramethyl-1,3,2-dioxaborolan-2-

fluorophenol and

yl)phenoxy]acetonitrile

bromoacetonitrile

Intermediate C1
2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoic acid
Step 1: methyl 2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoate

Under N₂protection, a mixture of methyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate (1 g, 2.68 mmol), (2,3-difluoro-4-methoxyphenyl)boronic acid (504 mg, 2.68 mmol), Na₂CO₃(853 mg, 8.05 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (350 mg, 537 μmol) in 1,4-Dioxane (15 mL) and water (1.5 mL) was irritated under microwave at 100° C. for 60 min. Repeat this reaction for eight times. The combined reaction solutions were concentrated. Water (40 mL) was added and the mixture was filtered. The water phase was extracted with DCM. The combined organic phases were washed with water, dried over anhydrous Na₂SO₄and concentrated. The concentrated organic phase was filtrated and the solid was dried to afford the crude methyl 2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoate (8.3 g) as a brown solid. MS [M+H]⁺: 435.9.

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

To a solution of methyl 2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoate (8.3 g, 19 mmol) in MeOH (2 mL), THE (48 mL) and water (24 mL) was added a solution of lithium hydroxide monohydrate (3.2 g, 76.2 mmol) in water (24 mL). The mixture was stirred at room temperature overnight. Then the mixture was concentrated and acidified by 6 N HCl under stirring until pH 3-4. Some solids precipitated from the concentrated solution. The solids were filtered and dried to afford 2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoic acid (7 g) as a brown solid. MS [M+H]⁺: 422.3.

Intermediate C2
2-Chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoic acid
Step 1: tert-butyl 2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoate

To a 25 mL microwave vial was added tert-butyl 4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoate (1 g, 2.41 mmol), 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (775 mg, 2.53 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (157 mg, 241 μmol) and Na₂CO₃(767 mg, 7.23 mmol) in Dioxane (18 mL) Water (1.8 mL) under N₂. the reaction was heated at 100° C. for 15 h under N₂. The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography to afford tert-butyl 2-chloro-4-(5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoate (1.2 g, 2.34 mmol, 96.8% yield). MS [M+H]⁺: 514.0.

Step 2: 2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoic acid

In a 100 mL round-bottomed flask, tert-butyl 2-chloro-4-(5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoate (1.2 g, 2.34 mmol) was combined with DCM (4 mL) to give a light yellow solution. TFA (5.4 mL, 70.1 mmol) was added. The reaction was stirred at room temperature for 30 min. The crude reaction mixture was concentrated in vacuum. The crude product was directly used to the next step, to afford 2-chloro-4-(5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoic acid (1.07 g). MS [M+H]⁺: 458.0.

The following intermediates were prepared in analogy:

MS ESI

Int.
Name
[M + H]⁺
Starting Material

C3
2-chloro-4-[[5-[4-
447.1
IntermediateA2 and B2

(cyanomethoxy)-2,3-difluoro-

phenyl]-1-methyl-imidazole-2-

carbonyl]amino]benzoic acid

C4
4-[[5-[4-(cyanomethoxy)-2,3-
427.1
IntermediateA3 and B2

difluoro-phenyl]-1-methyl-

imidazole-2-carbonyl]amino]-2-

methyl-benzoic acid

C5
4-[[5-(2,3-difluoro-4-methoxy-
436.1
IntermediateA4 and (2,3-

phenyl)-1-methyl-imidazole-2-

difluoro-4-

carbonyl]amino]-2-ethyl-benzoic

methoxyphenyl)boronic

acid

acid

C6
4-[[5-[4-
416.2
Intermediate A4 and 2-(4-

(difluoromethoxy)phenyl]-1-

(difluoromethoxy)phenyl)-

methyl-imidazole-2-

4,4,5-trimethyl-1,3,2-

carbonyl]amino]-2-ethyl-benzoic

dioxaborolane

acid

C7
2-ethyl-4-[[5-(3-fluoro-4-
426.3
Intermediate A4 and (3-

isopropoxy-phenyl)-1-methyl-

fluoro-4-

imidazole-2-

isopropoxyphenyl)boronic

carbonyl]amino]benzoic acid

acid

C8
4-[[5-(2-chloro-4-methoxy-
414.2
Intermediate A4 and (2-

phenyl)-1-methyl-imidazole-2-

chloro-4-

carbonyl]amino]-2-ethyl-benzoic

methoxyphenyl)boronic

acid

acid

C9
4-[[5-[4-(difluoromethoxy)-2,3-
452.3
Intermediate A4 and 2-(4-

difluoro-phenyl]-1-methyl-

(difluoromethoxy)-2,3-

imidazole-2-carbonyl]amino]-2-

difluorophenyl)-4,4,5,5-

ethyl-benzoic acid

tetramethyl-1,3,2-

dioxaborolane

C10
4-[[5-(2,6-difluoro-4-methoxy-
414.3
Intermediate A4 and (2,6-

phenyl)-1-methyl-imidazole-2-

difluoro-4-

carbonyl]amino]-2-ethyl-benzoic

methoxyphenyl)boronic

acid

acid

C11
4-[[5-(2,3-difluoro-4-methoxy-
402.3
Intermediate A3 and (2,3-

phenyl)-1-methyl-imidazole-2-

difluoro-4-

carbonyl]amino]-2-methyl-

methoxyphenyl)boronic

benzoic acid

acid

Intermediate D1
N-[3-Chloro-4-(pyrrolidin-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide
Step 1: tert-butyl 3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]pyrrolidine-1-carboxylate

At room temperature, a mixture of tert-butyl 3-aminopyrrolidine-1-carboxylate (1.04 g, 5.6 mmol), 2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoic acid (1.97 g, 4.67 mmol), DIPEA (1.81 g, 14 mmol) and HATU (1.77 g, 4.67 mmol) in DMF (10 mL) was stirred for 35 min. Then the solution was poured into water. The water layer was extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na₂SO₄and concentrated. The residue was purired by flash column to afford tert-butyl 3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]pyrrolidine-1-carboxylate (2.3 g) as a yellow oil. MS [M+H]⁺: 590.0.

Step 2: N-[3-chloro-4-(pyrrolidin-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-p-methyl-imidazole-2-carboxamide

At room temperature, a solution of tert-butyl 3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]pyrrolidine-1-carboxylate (2.3 g, 3.9 mmol) in TFA (10 mL) and DCM (10 mL) was stirred for 30 min. Then the mixture was concentrated. Water (10 mL) was added. The water layer was basified by NH₃·H₂O and extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na₂SO₄and concentrated to afford N-[3-chloro-4-(pyrrolidin-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide (1.8 g). MS [M+H]: 490.2.

The following intermediates were prepared in analogy:

MS ESI

Int.
Name
[M + H]⁺
Starting Material

D2
N-[3-chloro-4-(4-
504.2
Intermediate C1 and tert-butyl

piperidylcarbamoyl)phenyl]-5-

4-aminopiperidine-1-

(2,3-difluoro-4-methoxy-

carboxylate

phenyl)-1-methyl-imidazole-2-

carboxamide

D3
N-[4-(2-
464.1
Intermediate C1 and tert-butyl

aminoethylcarbamoyl)-3-

N-(2-aminoethyl)carbamate

chloro-phenyl]-5-(2,3-difluoro-

4-methoxy-phenyl)-1-methyl-

imidazole-2-carboxamide

D4
N-(4-(((1s,3s)-3-
490.2
Intermediate C1 and tert-butyl

aminocyclobutyl)carbamoyl)-

((1s,3s)-3-

3-chlorophenyl)-5-(2,3-

aminocyclobutyl)carbamate

difluoro-4-methoxyphenyl)-1-

methyl-1H-imidazole-2-

carboxamide

D5
N-(4-((2-(azetidin-3-
540.0
Intermediate C2 and tert-butyl

yl)ethyl)carbamoyl)-3-

3-(2-aminoethyl)azetidine-1-

chlorophenyl)-5-(4-

carboxylate

(difluoromethoxy)-2,3-

difluorophenyl)-1-methyl-1H-

imidazole-2-carboxamide

D6
N-(4-((3-
514.1
Intermediate C2 and tert-butyl

ami nopropyl)carbamoyl)-3-

(4-aminobutyl)carbamate

chlorophenyl)-5-(4-

(difluoromethoxy)-2,3-

difluorophenyl)-1-methyl-1H-

imidazole-2-carboxamide

D8
N-[4-(2-
468.9
Intermediate C4 and tert-butyl

aminoethylcarbamoyl)-3-

N-(2-aminoethyl)carbamate

methyl-phenyl]-5-[4-

(cyanomethoxy)-2,3-difluoro-

phenyl]-1-methyl-imidazole-2-

carboxamide

D9
N-[4-(2-
489.1
Intermediate C3 and tert-butyl

aminoethylcarbamoyl)-3-

N-(2-aminoethyl)carbamate

chloro-phenyl]-5-[4-

(cyanomethoxy)-2,3-difluoro-

phenyl]-1-methyl-imidazole-2-

carboxamide

D10
N-[4-(azetidin-3-ylcarbamoyl)-
476.1
Intermediate C1 and tert-butyl

3-chloro-phenyl]-5-(2,3-

3-aminoazetidine-1-

difluoro-4-methoxy-phenyl)-1-

carboxylate

methyl-imidazole-2-

carboxamide; 2,2,2-

trifluoroacetic acid

D11
N-[4-(azetidin-3-
490.1
Intermediate C1 and tert-butyl

ylmethylcarbamoyl)-3-chloro-

3-(aminomethyl)azetidine-1-

phenyl]-5-(2,3-difluoro-4-

carboxylate

methoxy-phenyl)-1-methyl-

imidazole-2-

carboxamide; 2,2,2-

trifluoroacetic acid

D12
3-[[2-chloro-4-[[5-(2,3-
519.0
Intermediate C1 and tert-butyl

difluoro-4-methoxy-phenyl)-1-

3-

methyl-imidazole-2-

aminocyclobutanecarboxylate

carbonyl]amino]benzoyl]amino

]cyclobutanecarboxylic

acid; 2,2,2-trifluoroacetic acid

D13
3-[[4-[[5-(2,3-difluoro-4-
512.0
Intermediate C5 and tert-butyl

methoxy-phenyl)-1-methyl-

3-

imidazole-2-carbonyl]amino]-

aminocyclobutanecarboxylate

2-ethyl-

benzoyl]amino]cyclobutanecarboxylic

acid; 2,2,2-

trifluoroacetic acid

D14
N-[4-(2-
444.2
Intermediate C11 and tert-

aminoethylcarbamoyl)-3-

butyl N-(2-

methyl-phenyl]-5-(2,3-

aminoethyl)carbamate

difluoro-4-methoxy-phenyl)-1-

methyl-imidazole-2-

carboxamide

Intermediate D7 (Example A19)
N-[4-(3-Aminopropylcarbamoyl)-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide
Step 1: tert-butyl N-[3-[(4-amino-2-ethyl-benzoyl)amino]propyl]carbamate

To a solution of intermediate 4-amino-2-ethylbenzoic acid (825 mg, 5.0 mmol), tert-butyl (3-aminopropyl) carbamate (1.30 g, 7.5 mmol) in anhydrous DMF (15 mL) was added DIPEA (1.30 g, 10 mmol) and then the resultant mixture was stirred for 10 min at room temperature, HATU (2.85 g, 7.5 mmol) was added in the mixture and stirred for extra 10 hr.

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

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

To a solution of 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid (1.0 g, 5.0 mmol), tert-butyl (3-(4-amino-2-ethylbenzamido)propyl)carbamate (1.6 g, 5.0 mmol) in anhydrous DMF (25 mL) was added DIPEA (1.3 g, 10 mmol) and then the resultant mixture was stirred for 10 min at room temperature, HATU (3.8 g, 10 mmol) was added in the mixture and stirred for extra 10 hr. The mixture was poured into water (50 mL) and the aqueous solution was extracted with DCM (150 mL×2). The organic layers were combined and washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a red oil which was purified by flash column to afford tert-butyl N-[3-[[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-ethyl-benzoyl]amino]propyl]carbamate (1.8 g) as a yellow solid. MS [M+H]⁺: 508.3

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

A mixture of tert-butyl (3-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-ethylbenzamido)propyl)carbamate (1.73 g, 3.4 mmol), 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.56 g, 5.1 mmol), sodium carbonate (1.1 g, 10.2 mmol) and 1,1′-Bis (di-t-butylphosphino)ferrocene palladium dichloride (220 mg, 0.34 mmol) in 1,4-dioxane (25 ml) and water (2.5 ml) was stirred at 100° C. for 4.0 h. After cooling to room temperature, the mixture was poured into water (50 mL) and the aqueous solution was extracted with DCM (100 mL×2). The organic layers were combined and washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a red oil which was purified by flash column to provide the desired compound as a yellow oil to afford tert-butyl N-[3-[[4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]propyl]carbamate (1.2 g). MS [M+H]⁺: 608.2

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

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

The following intermediates were prepared in analogy:

MS ESI
Starting

Ex.
Name
Structure
[M + H]⁺
Material

A20
N-[4-[2-(2- aminoethoxy) ethylcarbamoyl]- 3-ethyl-phenyl]-5- [4-(cyanomethoxy)- 2,3-difluoro- phenyl]-1-methyl- imidazole-2- carboxamide; hydrochloride

[Image Omitted]

527.4
tert-butyl N-[2-(2- aminoethoxy) ethyl]carbamate in step 1 and Intermediate B2 in step 4

A21
N-[4-[2-(2- aminoethoxy) ethylcarbamoyl]- 3-ethyl-phenyl]-5- [4-(2-amino-2-oxo- ethoxy)-2,3- difluoro-phenyl]- 1-methyl- imidazole-2- carboxamide; hydrochloride

[Image Omitted]

545.4
Byproduct of Example in Step 4

A22
N-[4-[2-(2- aminoethoxy) ethylcarbamoyl]- 3-ethyl-phenyl]- 5-[2-chloro-4- (cyanomethoxy)- 3-fluoro-phenyl]-1- methyl-imidazole- 2-carboxamide; hydrochloride

[Image Omitted]

543.4
tert-butyl N-[2-(2- aminoethoxy) ethyl] carbamate in step 1 and Intermediate B3 in step 4

Intermediate E1
(2S,4S)-1-tert-Butoxycarbonyl-4-hydroxy-4-methyl-pyrrolidine-2-carboxylic acid

(2S)-1-tert-butoxycarbonyl-4-oxo-pyrrolidine-2-carboxylic acid (2 g, 8.72 mmol) in THE (20 mL) was added dropwise to a solution of methyllithium (8.72 mL, 13.09 mmol) at −20° C. under a nitrogen atmosphere. The resulting mixture was stirred at the same temperature for 1 h and then further stirred at 25° C. for 11 h. The reaction mixture was added into 1 N aqueous hydrochloric acid solution (50 mL) under ice cooling, followed by extraction with ethyl acetate (50 mL×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 prep-HPLC (FA) to afford 2 final compounds: P1, (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-4-methyl-pyrrolidine-2-carboxylic acid (50 mg) as a dark green solid and the title compound P2, (2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-4-methyl-pyrrolidine-2-carboxylic acid (600 mg) as an off-white solid. MS[M+H]⁺:190.0.

The following intermediates were prepared in analogy:

MS ESI

Int.
Name
[M + H]⁺
Starting Material

E2
(1R,4S)-2-tert-
282.0
(2S)-1-tert-butoxycarbonyl-4-oxo-

butoxycarbonyl-4-ethyl-4-

pyrrolidine-2-carboxylic acid and

hydroxy-

Ethylmagnesium bromide

cyclopentanecarboxylic acid

Example A1
N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

[Image Omitted]

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

At room temperature, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (226 mg, 711 μmol) was added a mixture of 2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoic acid (150 mg, 356 μmol), tert-butyl N-[2-(2-aminoethoxy)ethyl]carbamate (72.6 mg, 356 μmol) and DIPEA (138 mg, 1.07 mmol) in DMF (2 mL). After stirring for 3 h, the reaction was completed. Then the mixture was poured into water. The water layer was extracted with DCM. The combined organic layers were dried over anhydrous Na₂SO₄and concentrated to afford the crude product tert-butyl N-[2-[2-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]ethoxy]ethyl]carbamate (200 mg). The crude product was used into next step reaction without further purification. MS [M+H]⁺: 607.9.

Step 2: N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

At room temperature, tert-butyl N-[2-[2-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]ethoxy]ethyl]carbamate (200 mg, 329 μmol) in TFA (3 mL) and CH₂Cl₂(3 mL) was stirred for 1 h. Then the mixture was concentrated. Water (5 mL) was added. The solution was basified by K₂CO₃to pH 8-9. The water phase was extracted with DCM. The combined organic phases were dried over anhydrous Na₂SO₄and concentrated. The residue was purified by Prep-HPLC to afford N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide (31 mg) as a white powder. MS [M+H]⁺: 508.2.

The following compounds were prepared in analogy:

MS ESI
Starting

Ex#
Name
Structure
[M + H]⁺
Material

Ex- ample A2
N-[3-chloro-4-(2- piperazin-1- ylethylcarbamoyl) phenyl]- 5-(2,3-difluoro-4- methoxy-phenyl)-1- methyl-imidazole-2- carboxamide

[Image Omitted]

533.3
Intermediate C1 and tert- butyl 4-(2- aminoethyl) piperazine-1- carboxylate

Ex- ample A3
N-[3-chloro-4- (pyrrolidin-3- ylcarbamoyl)phenyl]- 5-(2,3-difluoro-4- methoxy-phenyl)- 1-methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

490.2
Intermediate C1 and tert- butyl 3-amino- pyrrolidine- 1-carboxylate

Ex- ample A4
N-[3-chloro-4-(4- piperidylcarbamoyl) phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

504.2
Intermediate C1 and tert- butyl 4-amino- piperidine- 1-carboxylate

Ex- ample A5
N-[3-chloro-4-(4- piperidylmethyl- carbamoyl) phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

518.1
Intermediate C1 and tert- butyl 4- (aminomethyl) piperidine-1- carboxylate

Ex- ample A6
N-[4-(6- aminohexyl- carbamoyl)-3-chloro- phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide

[Image Omitted]

520.5
Intermediate C1 and tert- butyl N-(6- aminohexyl) carbamate

Ex- ample 47
N-[4-[[3- (aminomethyl) cyclobutyl] methylcarbamoyl]-3- chloro-phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

518.3
Intermediate C1 and tert- butyl N-[[3- (aminomethyl) cyclobutyl] methyl] carbamate

Ex- ample A8
N-[4-[(3- aminocyclobutyl) methylcarbamoyl]- 3-chloro-phenyl]-5- (2,3-difluoro-4- methoxy-phenyl)-1- methyl-imidazole-2- carboxamide; formic acid

[Image Omitted]

504.3
Intermediate C1 and tert- butyl N-[3- (aminomethyl) cyclobutyl] carbamate

Ex- ample A9
N-[4-[2-(2- aminoethoxy) ethylcarbamoyl]- 3-chloro-phenyl]-5- [4-(cyanomethoxy)- 2,3-difluoro-phenyl]- 1-methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

533.1
Intermediate C3 and tert- butyl N-[2-(2- aminoethoxy) ethyl] carbamate

Ex- ample A10
N-[3-chloro-4-(2- piperazin-1- ylethylcarbamoyl) phenyl]-5-[4- (cyanomethoxy)- 2,3-difluoro-phenyl]- 1-methyl-imidazole- 2-carboxamide; 2,2,2-trifluoroacetic acid

[Image Omitted]

558.2
Intermediate C3 and tert- butyl 4-(2- aminoethyl) piperazine-1- carboxylate

Ex- ample A11
N-[3-chloro-4-(3- piperazin-1- ylpropylcarbamoyl) phenyl]-5-[4- (cyanomethoxy)-2,3- difluoro-phenyl]-1- methyl-imidazole-2- carboxamide;2,2,2- trifluoroacetic acid

[Image Omitted]

572.2
Intermediate C3 and tert- butyl 4-(3- aminopropyl) piperazine-1- carboxylate

Ex- ample A12
5-[4-(cyanomethoxy)- 2,3-difluoro-phenyl]- 1-methyl-N-[3-methyl- 4-(3-piperazin-1- ylpropylcarbamoyl) phenyl]imidazole-2- carboxamide; 2,2,2- trifluoroacetic acid

[Image Omitted]

552.3
Intermediate C4 and tert- butyl 4-(3- aminopropyl) piperazine-1- carboxylate

Ex- ample A13
N-[4-[2-(2- aminoethoxy) ethylcarbamoyl]-3- ethyl-phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

502.2
Intermediate C5 and tert- butyl N-[2-(2- aminoethoxy) ethyl] carbamate

Ex- ample A14
N-[4-[2-(2- aminoethoxy) ethylcarbamoyl]-3- ethyl-phenyl]-5-[4- (difluoromethoxy) phenyl]-1-methyl- imidazole-2- carboxamide; hydrochloride

[Image Omitted]

502.3
Intermediate C6 and tert- butyl N-[2-(2- aminoethoxy) ethyl] carbamate

Ex- ample A15
N-[4-[2-(2- aminoethoxy) ethylcarbamoyl]-3- ethyl-phenyl]-5-(3- fluoro-4-isopropoxy- phenyl)-1-methyl- imidazole-2- carboxamide; hydrochloride

[Image Omitted]

512.3
Intermediate C7 and tert- butyl N-[2-(2- aminoethoxy) ethyl] carbamate

Ex- ample A16
N-[4-[2-(2- aminoethoxy) ethylcarbamoyl]-3- ethyl-phenyl]-5- (2-chloro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; hydrochloride

[Image Omitted]

500.3
Intermediate C8 and tert- butyl N-[2-(2- aminoethoxy) ethyl] carbamate

Ex- ample A17
N-[4-[2-(2- aminoethoxy) ethylcarbamoyl]-3- ethyl-phenyl]-5-[4- (difluoromethoxy)- 2,3-difluoro-phenyl]- methyl-imidazole-2- 1-carboxamide; hydrochloride

[Image Omitted]

538.1
Intermediate C9 and tert- butyl N-[2-(2- aminoethoxy) ethyl] carbamate

Ex- ample A18
N-[4-[2-(2- aminoethoxy) ethylcarbamoyl]-3- ethyl-phenyl]-5-(2,6- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; hydrochloride

[Image Omitted]

502.3
Intermediate C10 and tert- butyl N-[2-(2- aminoethoxy) ethyl] carbamate

Example B1
N-[3-Chloro-4-[[1-(piperidine-4-carbonyl)pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; formic acid

[Image Omitted]

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

A mixture of N-[3-chloro-4-(pyrrolidin-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide (200 mg, 408 μmol), 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (187 mg, 816 μmol), HATU (233 mg, 612 μmol) and DIPEA (158 mg, 1.22 mmol) in DMF (5 mL) was stirred overnight. Then the mixture was poured into water. The water layer was extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na₂SO₄and concentrated to afford the crude product tert-butyl 4-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]pyrrolidine-1-carbonyl]piperidine-1-carboxylate (200 mg). The crude product was used into next step reaction directly.

Step 2: N-[3-chloro-4-[[1-(piperidine-4-carbonyl)pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; formic acid

A solution of tert-butyl 4-[3-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]pyrrolidine-1-carbonyl]piperidine-1-carboxylate (200 mg, 285 μmol) in TFA (5 mL) and DCM (5 mL) was stirred for 30 min. Then the mixture was concentrated. Water (5 mL) was added. The water layer was basified by NH₃·H₂O. The water layer was extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na₂SO₄and concentrated. The residue was purified by Prep-HPLC to afford N-[3-chloro-4-[[1-(piperidine-4-carbonyl)pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; formic acid (85 mg). MS [M+H]: 601.4.

The following compounds were prepared in analogy:

MS ESI
Starting

Ex#
Name
Structure
[M + H]⁺
Material

Ex- ample B2
N-[3-chloro-4-[[1- [(3R)-pyrrolidine-3- carbonyl]pyrrolidin- 3-yl]carbamoyl] phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

587.3
Intermediate D1 and (3R)-1-tert- butoxy- carbonyl- pyrrolidine- 3-carboxylic acid

Ex- ample B3
N-[3-chloro-4-[[1- [(2S,4R)-4- hydroxypyrrolidine- 2-carbonyl] pyrrolidin-3-yl] carbamoyl]phenyl]- 5-(2,3-difluoro-4- methoxy-phenyl)-1- methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

603.3
Intermediate D1 and (2S,4R)-1- tert-butoxy- carbonyl- 4-hydroxy- pyrrolidine- 2-carboxylic acid

Ex- ample B4
N-[4-[[1-[3-(2- aminoethoxy) propanoyl] pyrrolidin-3-yl] carbamoyl]-3-chloro- phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

605.4
Intermediate D1 and 3-[2-(tert- butoxy- carbonyl- amino) ethoxy] propanoic acid

Ex- ample B5
N-[3-chloro-4-[[1- (piperidine-4- carbonyl)-4- piperidyl]carbamoyl] phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

615.2
Intermediate D2 and 1- tert-butoxy- carbonyl- piperidine- 4- carboxylic acid

Ex- ample B6
N-[3-chloro-4- [[1-[(3R)-pyrrolidine- 3-carbonyl]-4- piperidyl]carbamoyl] phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

601.2
Intermediate D2 and (3R)-1-tert- butoxy- carbonyl- pyrrolidine- 3- carboxylic acid

Ex- ample B7
N-[3-chloro-4-[[1- [(2S,4R)-4- hydroxypyrrolidine- 2-carbonyl]-4- piperidyl]carbamoyl] phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide

[Image Omitted]

617.4
Intermediate D2 and (2S,4R)-1- tert-butoxy- carbonyl- 4-hydroxy- pyrrolidine- 2- carboxylic acid

Ex- ample B8
N-[4-[[1-[3-(2- aminoethoxy) propanoyl]-4- piperidyl] carbamoyl]-3-chloro- phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

619.2
Intermediate D2 and 3-[2-(tert- butoxy- carbonyl- amino) ethoxy] propanoic acid

Ex- ample B9
N-[4-[[3-[[3- (aminomethyl) cyclobutanecarbonyl] amino]cyclobutyl] carbamoyl]-3- chloro-phenyl]-5- (2,3-difluoro-4- methoxy-phenyl)-1- methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

601.4
Intermediate D4 and 3- [(tert- butoxy- carbonyl- amino) methyl] cyclobutane- carboxylic acid

Ex- ample B10
N-[4-[2-[1-(3- aminopropanoyl) azetidin-3-yl] ethylcarbamoyl]-3- chloro-phenyl]-5- [4- (difluoromethoxy)- 2,3-difluoro-phenyl]- 1-methyl-imidazole- 2-carboxamide; 2,2,2-trifluoroacetic acid

[Image Omitted]

611.2
Intermediate D5 and 3- (tert-butoxy- carbonyl- amino) propanoic acid

Ex- ample B11
N-[4-[3-(3- aminopropanoyl- amino) propylcarbamoyl]-3- chloro-phenyl]-5-[4- (difluoromethoxy)- 2,3-difluoro-phenyl]- 1-methyl-imidazole- 2-carboxamide; 2,2,2-trifluoroacetic acid

[Image Omitted]

585.1
Intermediate D6 and 3- (tert-butoxy- carbonyl- amino) propanoic acid

Ex- ample B12
N-[3-[[4-[[5-[4- (difluoromethoxy)- 2,3-difluoro- phenyl]-1-methyl- imidazole-2- carbonyl]amino]- 2-ethyl-benzoyl] amino] propyl]piperidine- 4-carboxamide; formic acid

[Image Omitted]

619.4
Intermediate D7 and 1- tert-butoxy- carbonyl- piperidine- 4-carboxylic acid

Ex- ample B13
N-[2-[[4-[[5-[4- (cyanomethoxy)-2,3- difluoro-phenyl]-1- methyl-imidazole-2- carbonyl]amino]-2- methyl-benzoyl] amino]ethyl] piperidine-4- carboxamide; formic acid

[Image Omitted]

580.1
Intermediate D8 and 1- tert-butoxy- carbonyl- piperidine- 4-carboxylic acid

Ex- ample B14
N-[2-[[4-[[5-[4- (cyanomethoxy)-2,3- difluoro-phenyl]-1- methyl-imidazole-2- carbonyl]amino]-2- methyl-benzoyl] amino]ethyl]-4- hydroxy-piperidine- 4-carboxamide; formic acid

[Image Omitted]

596.1
Intermediate D8 and 1- tert-butoxy- carbonyl- 4-hydroxy- piperidine- 4- carboxylic acid

Ex- ample B15
N-[2-[[2-chloro-4- [[5-[4- (cyanomethoxy)- 2,3- difluoro-phenyl]-1- methyl-imidazole- 2-carbonyl]amino] benzoyl]amino] ethyl]piperidine- 4-carboxamide; 2,2,2-trifluoroacetic acid

[Image Omitted]

600.2
Intermediate D9 and 1- tert-butoxy- carbonyl- piperidine- 4-carboxylic acid

Ex- ample B16
N-[2-[[2-chloro-4- [[5-[4- (cyanomethoxy)- 2,3-difluoro- phenyl]-1- methyl-imidazole- 2-carbonyl]amino] benzoyl]amino] ethyl]-4- hydroxy-piperidine- 4-carboxamide; 2,2,2-trifluoroacetic acid

[Image Omitted]

618.2
Intermediate D9 and 1- tert-butoxy- carbonyl- 4-hydroxy- piperidine-4- carboxylic acid

Ex- ample B17
N-[4-[[1-(2- aminoacetyl) azetidin-3-yl] carbamoyl]- 3-chloro-phenyl]- 5-(2,3-difluoro-4- methoxy-phenyl)- 1-methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

533.1
Intermediate D10 and 2- (tert-butoxy- carbonyl- amino) acetic acid acid

Ex- ample B18
N-[4-[[1-(2- aminoacetyl) azetidin-3-yl] methylcarbamoyl]- 3-chloro-phenyl]- 5-(2,3-difluoro-4- methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

547.1
Intermediate D11 and 2- (tert-butoxy- carbonyl- amino) acetic acid acid

Ex- ample B19
N-[4-[[3-(2- aminoethyl- carbamoyl) cyclobutyl] carbamoyl]-3- chloro-phenyl]-5- (2,3-difluoro-4- methoxy-phenyl)-1- methyl-imidazole-2- carboxamide; formic acid

[Image Omitted]

561.1
Intermediate D12 and tert-butyl N-(2- aminoethyl) carbamate

Ex- ample B20
N-[4-[[3-(3- aminoazetidine-1- carbonyl)cyclobutyl] carbamoyl]-3-chloro- phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

573.1
Intermediate D12 and tert-butyl N-(azetidin- 3-yl) carbamate

Ex- ample B21
N-[4-[[3-[(3- aminocyclobutyl) carbamoyl] cyclobutyl] carbamoyl]-3- chloro-phenyl]-5- (2,3-difluoro-4- methoxy-phenyl)-1- methyl-imidazole-2- carboxamide; 2,2,2- trifluoroacetic acid

[Image Omitted]

587.2
Intermediate D12 and tert-butyl N-(3- amino- cyclobutyl) carbamate

Ex- ample B22
N-[4-[[3-(2- aminoethyl- carbamoyl) cyclobutyl] carbamoyl]-3-ethyl- phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; 2,2,2- trifluoroacetic acid

[Image Omitted]

555.2
Intermediate D13 and tert-butyl N-(2- aminoethyl) carbamate

Ex- ample B23
N-[4-[[1-(2- aminoacetyl) azetidin-3-yl] carbamoyl]-3-ethyl- phenyl]-5-(2,3- difluoro-4- methoxy-phenyl)-1- methyl-imidazole-2- carboxamide; formic acid

[Image Omitted]

527.2
Intermediate D13 and 2- (tert- butoxy- carbonyl- amino) acetic acid acid

Ex- ample B24
5-[4- (cyanomethoxy)- 2,3-difluoro- phenyl]-N-[4-[2- [[(2R,4R)-4- hydroxy-4-methyl- pyrrolidine-2- carbonyl]amino] ethylcarbamoyl]- 3-methyl-phenyl]-1- methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

596.2
Intermediate D8 and E1

Ex- ample B25
5-[4- (cyanomethoxy)- 2,3-difluoro- phenyl]-N-[4-[2- [[(2R,4R)-4- ethyl-4-hydroxy- pyrrolidine- 2-carbonyl]amino] ethylcarbamoyl]-3- methyl-phenyl]-1- methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

610.2
Intermediate D8 and E2

Ex- ample B26
5-(2,3-difluoro-4- methoxy-phenyl)- N-[4-[2-[[(2R,4R)- 4- hydroxy-4-methyl- pyrrolidine-2- carbonyl]amino] ethylcarbamoyl]-3- methyl-phenyl]-1- methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

571.3
Intermediate D14 and E1

Ex- ample B27
5-(2,3-difluoro-4- methoxy-phenyl)- N-[4-[2-[[(2R,4R)- 4-ethyl-4-hydroxy- pyrrolidine-2- carbonyl]amino] ethylcarbamoyl]-3- methyl-phenyl]-1- methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

585.4
Intermediate D14 and E2

Ex- ample B28
5-(2,3-difluoro-4- methoxy-phenyl)- N-[4-[2-[[(3R,4R)- 4- hydroxypyrrolidin- 3-yl] carbamoylamino] ethylcarbamoyl]-3- methyl-phenyl]-1- methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

572.4
Intermediate D14 and tert-butyl (3R,4R)-3- amino-4- hydroxy- pyrrolidine- 1- carboxylate

Ex- ample B29
5-(2,3-difluoro-4- methoxy-phenyl)- N-[4-[2-[[(3S,4S)- 4- hydroxypyrrolidin- 3-yl] carbamoylamino] ethylcarbamoyl]-3- methyl-phenyl]-1- methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

527.4
Intermediate D14 and tert-butyl (3S,4S)- 3-amino-4- hydroxy- pyrrolidine- 1- carboxylate

Ex- ample B30
5-[4- (cyanomethoxy)- 2,3-difluoro- phenyl]-N-[4-[2- [[(3R,4R)-4- hydroxypyrrolidin- 3-yl] carbamoylamino] ethylcarbamoyl]-3- methyl-phenyl]-1- methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

597.4
Intermediate D8 and tert- butyl (3R,4R)-3- amino-4- hydroxy- pyrrolidine- 1- carboxylate

Ex- ample B31
5-[4- (cyanomethoxy)- 2,3-difluoro- phenyl]-N-[4-[2- [[(3S,4S)-4- hydroxypyrrolidin- 3-yl] carbamoylamino] ethylcarbamoyl]-3- methyl-phenyl]-1- methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

597.4
Intermediate D8 and tert- butyl (3S,4S)- 3-amino-4- hydroxy- pyrrolidine- 1- carboxylate

Ex- ample B32
(3R,4R)-N-[2-[[2- chloro-4-[[5-[4- (cyanomethoxy)- 2,3-difluoro- phenyl]-1-methyl- imidazole-2- carbonyl]amino] benzoyl]amino] ethyl]-3-hydroxy- piperidine-4- carboxamide; formic acid

[Image Omitted]

616.2
Intermediate D9 and (3R,4R)-1- tert-butoxy- carbonyl- 3-hydroxy- piperidine- 4- carboxylic acid

Ex- ample B33
(3S,4S)-N-[2-[[2- chloro-4-[[5-[4- (cyanomethoxy)- 2,3-difluoro- phenyl]-1-methyl- imidazole-2- carbonyl]amino] benzoyl]amino] ethyl]-3-hydroxy- piperidine-4- carboxamide; formic acid

[Image Omitted]

616.3
Intermediate D9 and (3S,4S)-1- tert-butoxy- carbonyl- 3-hydroxy- piperidine- 4- carboxylic acid

Ex- ample B34
(3S,4R)-N-[2-[[2- chloro-4-[[5-[4- (cyanomethoxy)- 2,3-difluoro- phenyl]-1-methyl- imidazole-2- carbonyl]amino] benzoyl]amino] ethyl]-3-hydroxy- piperidine-4- carboxamide; formic acid

[Image Omitted]

616.1
Intermediate D9 and (3S,4R)-1- tert-butoxy- carbonyl- 3-hydroxy- piperidine- 4- carboxylic acid

Ex- ample B35
(3R,4S)-N-[2-[[2- chloro-4-[[5-[4- (cyanomethoxy)- 2,3-difluoro- phenyl]-1-methyl- imidazole-2- carbonyl]amino] benzoyl]amino] ethyl]-3-hydroxy- piperidine- 4-carboxamide; formic acid

[Image Omitted]

616.1
Intermediate D9 and (3R,4S)-1- tert-butoxy- carbonyl- 3-hydroxy- piperidine- 4- carboxylic acid

Ex- ample B36
N-[3-chloro-4-[2- [[(2R,4R)-4- hydroxy-4-methyl- pyrrolidine- 2-carbonyl]amino] ethylcarbamoyl] phenyl]-5-[4- (cyanomethoxy)- 2,3-difluoro- phenyl]-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

616.2
Intermediate D9 and E1

Ex- ample B37
N-[3-chloro-4-[2- [[(2R,4R)-4-ethyl- 4-hydroxy- pyrrolidine-2- carbonyl]amino] ethylcarbamoyl] phenyl]-5-[4- (cyanomethoxy)- 2,3-difluoro- phenyl]-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

630.2
Intermediate D9 and E2

Ex- ample B38
N-[3-chloro-4-[[3- [[(4R)-4- hydroxypyrrolidine- 2-carbonyl]amino] cyclobutyl] carbamoyl] phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide; formic acid

[Image Omitted]

603.3
Intermediate D4 and BOC- HYP-OH

Ex- ample B39
N-[3-[[2-chloro-4- [[5-(2,3-difluoro-4- methoxy-phenyl)-1- methyl-imidazole- 2-carbonyl]amino] benzoyl]amino] cyclobutyl] piperidine-4- carboxamide; formic acid

[Image Omitted]

601.3
Intermediate D4 and N- BOC- isonipecotic acid

Ex- ample B40
N-[3-[[2-chloro-4- [[5-(2,3-difluoro-4- methoxy-phenyl)-1- methyl-imidazole- 2-carbonyl]amino] benzoyl]amino] cyclobutyl]-4- hydroxy-piperidine- 4-carboxamide; formic acid

[Image Omitted]

617.3
Intermediate D4 and 1- tert-butoxy- carbonyl- 4-hydroxy- piperidine- 4- carboxylic acid

Ex- ample B41
(3R,4R)-N-[3-[[2- chloro-4-[[5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carbonyl]amino] benzoyl]amino] cyclobutyl]-3- hydroxy-piperidine- 4-carboxamide; formic acid

[Image Omitted]

617.3
Intermediate D4 and (3R,4R)-1- tert-butoxy- carbonyl- 3-hydroxy- piperidine- 4- carboxylic acid

Ex- ample B42
(3S,4S)-N-[3-[[2- chloro-4-[[5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carbonyl]amino] benzoyl]amino] cyclobutyl]-3- hydroxy-piperidine- 4-carboxamide; formic acid

[Image Omitted]

617.3
Intermediate D4 and (3S,4S)-1- tert-butoxy- carbonyl- 3-hydroxy- piperidine- 4- carboxylic acid

Example C1
N-[4-[2-[1-(Azetidin-3-ylmethyl)azetidin-3-yl]ethylcarbamoyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

[Image Omitted]

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

In a 50 mL round-bottomed flask, N-(4-((2-(azetidin-3-yl)ethyl)carbamoyl)-3-chlorophenyl)-5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamide (118 mg, 219 μmol), tert-butyl 3-formylazetidine-1-carboxylate (121 mg, 656 μmol) and NaBH₃CN (68.7 mg, 1.09 mmol) were combined with MeOH (6 mL) to give a light yellow solution. The reaction mixture was heated to 45° C. and stirred for 3 h. The crude reaction mixture was concentrated in vacuum. The reaction mixture was poured into 25 mL sat NaHCO₃and extracted with EtOAc (25 mL×3). The organic layers were combined, washed with sat NaCl (25 mL), The organic layers were dried over Na₂SO₄and concentrated in vacuum to afford tert-butyl 3-((3-(2-(2-chloro-4-(5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamido)benzamido) ethyl)azetidin-1-yl)methyl)azetidine-1-carboxylate (155 mg), MS [M+H]⁺: 709.1.

Step 2: N-[4-[2-[1-(azetidin-3-ylmethyl)azetidin-3-yl]ethylcarbamoyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

In a 50 mL round-bottomed flask, tert-butyl 3-((3-(2-(2-chloro-4-(5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamido)benzamido)ethyl)azetidin-1-yl)methyl)azetidine-1-carboxylate (35 mg, 49.4 μmol) was combined with DCM (3 mL) to give a light brown solution. 2,2,2-trifluoroacetic acid (1.13 g, 9.87 mmol) was added. The reaction was stirred at room temperature for 30 min. The crude reaction mixture was concentrated in vacuum. The crude material was purified by preparative HPLC to afford N-(4-((2-(1-(azetidin-3-ylmethyl)azetidin-3-yl)ethyl)carbamoyl)-3-chlorophenyl)-5-(4-(difluoromethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamide bis(2,2,2-trifluoroacetate) (12 mg), MS [M+H]⁺: 609.2.

The following compounds were prepared in analogy:

MS ESI
Starting

Ex#
Name
Structure
[M + H]⁺
Material

Ex- ample C2
N-[3-[[4-[[5- [4-(difluoro- methoxy)- 2,3-difluoro- phenyl]-1- methyl- imidazole-2- carbonyl] amino]-2- ethyl- benzoyl] amino] propyl]-1- (pyrrolidin-3- ylmethyl) piperidine-4- carboxamide; formic acid

[Image Omitted]

702.4
Example B15 and tert-butyl 3-formyl- pyrrolidine- 1- carboxylate

Ex- ample C3
1-(azetidin-3- ylmethyl)- N-[3-[[4-[[5- [4-(difluoro- methoxy)- 2,3-difluoro- phenyl]-1- methyl- imidazole-2- carbonyl] amino]-2- ethyl-benzoyl] amino]propyl] piperidine-4- carboxamide; formic acid

[Image Omitted]

688.0
Example B15 and tert-butyl 3-formyl- azetidine- 1- carboxylate

Ex- ample C4
N-[4-[[1- (azetidin- 3-ylmethyl)- 4-piperidyl] methyl- carbamoyl]- 3-chloro- phenyl]-5- (2,3-difluoro- 4-methoxy- phenyl)-1- methyl- imidazole-2- carboxamide; 2,2,2- trifluoroacetic acid

[Image Omitted]

587.4
Example A5 and tert-butyl 3-formyl- azetidine- 1- carboxylate

Example A23
N-[3-Chloro-4-[[l-[2-(dimethylamino)acetyl]pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

[Image Omitted]

A mixture of N-[3-chloro-4-(pyrrolidin-3-ylcarbamoyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide (300 mg, 612 μmol), 2-(dimethylamino)acetic acid (126 mg, 1.22 mmol), HATU (349 mg, 919 μmol) and DIPEA (237 mg, 1.84 mmol) in DMF (5 mL) was stirred overnight. The mixture was poured into water. The water layer was extracted with DCM. The organic layer was washed with water, dried over anhydrous Na₂SO₄and concentrated. The residue was purified by Prep-HPLC to afford N-[3-chloro-4-[[1-[2-(dimethylamino)acetyl]pyrrolidin-3-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide 130 mg. MS [M+H]⁺: 575.5.

The following compounds were prepared in analogy:

MS ESI
Starting

Ex#
Name
Structure
[M + H]⁺
Material

Example A24
N-[3-chloro-4-[2-[[2- (dimethylamino) acetyl]amino] ethylcarbamoyl] phenyl]-5-(2,3- difluoro-4- methoxy-phenyl)-1- methyl-imidazole-2- carboxamide; 2,2,2- trifluoroacetic acid

[Image Omitted]

549.3
Intermediate D3 and 2- (dimethyl- amino) acetic acid

Example A25
N-[3-chloro-4-[[1-[2- (dimethylamino) acetyl]-4-piperidyl] carbamoyl]phenyl]-5- (2,3-difluoro-4- methoxy-phenyl)-1- methyl-imidazole-2- carboxamide

[Image Omitted]

589.2
Intermediate D2 and 2- (dimethyl- amino) acetic acid

Example A26
N-[3-chloro-4-[5- (dimethylamino) pentylcarbamoyl] phenyl]-5-(2,3- difluoro-4-methoxy- phenyl)-1-methyl- imidazole-2- carboxamide

[Image Omitted]

534.0
Intermediate C1 and N′,N′- dimethyl- pentane- 1,5-diamine

Example A27
N-[3-chloro-4-(2- isopentyloxyethyl- carbamoyl)phenyl]-5- [4-(cyanomethoxy)- 2,3-difluoro-phenyl]- 1-methyl-imidazole- 2-carboxamide; formic acid

[Image Omitted]

561.1
Intermediate C3 and 2-[2- (dimethyl- amino) ethoxy] ethanamine dihydro- chloride

Example A28
N-[3-chloro-4-[2-(3- hydroxypyrrolidin-1- yl)ethylcarbamoyl] phenyl]-5-(2,3- difluoro-4- methoxy-phenyl)-1- methyl-imidazole-2- carboxamide

[Image Omitted]

534.1
Intermediate C1 and 1-(2- aminoethyl) pyrrolidin- 3-ol

Example A29
N-[3-chloro-4-[2-[3- (hydroxymethyl) pyrrolidin- 1-yl]ethylcarbamoyl] phenyl]-5-(2,3- difluoro-4- methoxy-phenyl)-1- methyl-imidazole-2- carboxamide

[Image Omitted]

548.1
Intermediate C1 and [1-(2- aminoethyl) pyrrolidin-3- yl]methanol

Example A30
5-(2,3-difluoro-4- methoxy-phenyl)-N- [4-[3-[2- (dimethylamino) ethoxy] propylcarbamoyl]-3- ethyl-phenyl]-1- methyl-imidazole-2- carboxamide

[Image Omitted]

530.3
Intermediate C5 and 2-(2- amino- ethoxy)- N,N- dimethyl- ethan-1- amine

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

[Image Omitted]

Step 1: Ethyl 5-bromo-1-methyl-imidazole-2-carboxylate

To a stirred solution of ethyl chloroformate (2.38 mL, 24.84 mmol) and N,N-diisopropylethylamine (4.33 mL, 24.84 mmol) in ACN (50 mL) was slowly added a solution of 5-bromo-1-methyl-1H-imidazole (2 g, 12.42 mmol) in ACN (20 mL) at 0° C. The mixture was stirred at 10° C. for 16 h. The mixture was concentrated and the residue was treated with water (100 mL) and extracted with EtOAc (100 mL×3). The combined extracts were washed with brine, dried with MgSO₄, filtered, concentrated and purified on flash column chromatography (0-50% of EtOAc in hexanes) to afford the title compound (2.4 g) as a light yellow oil. MS (ESI, m/z): 233.0 [M+H]⁺.

Step 2: Ethyl 5-(4-methoxyphenyl)-1-methyl-imidazole-2-carboxylate

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

Step 3: 5-(4-methoxyphenyl)-1-methyl-imidazole-2-carboxylic acid

A solution of ethyl 5-(4-methoxyphenyl)-1-methyl-imidazole-2-carboxylate (710 mg, 2.73 mmol) in THE (10 mL)/water (10 mL)/methanol (5 mL) was added lithium hydroxide (218.2 mg, 5.46 mmol) and it was stirred at 5° C. for 16 h. The mixture was poured into water (50 mL) and extracted with EtOAc (30 mL×2), then the water layer was acidified to pH=3 with HCl solution (1N) and extracted with EtOAc (50 mL×2). The organic layers were concentrated to afford the title compound (205 mg) as a light yellow solid. MS (ESI, m/z): 233.0 [M+H]⁺.

Step 4: N, 2-dimethyl-4-nitro-benzamide

A solution of methyl 2-methyl-4-nitro-benzoate (2.8 g, 14.4 mmol) in methylamine in Ethanol (30 mL, 5.0 mmol) was stirred at 70° C. for 3 h. The solution was concentrated and washed by MTBE/DCM (100 mL, 50:1) to afford the title compound (2.65 g, 13.65 mmol) as an off-white solid.

Step 5: 4-amino-N,2-dimethyl-benzamide

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

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

To a stirred solution of 5-(4-methoxyphenyl)-1-methyl-imidazole-2-carboxylic acid (100 mg, 0.43 mmol), triethylamine (0.18 mL, 1.3 mmol) and 4-amino-N, 2-dimethyl-benzamide (70.7 mg, 0.43 mmol) in THE (5 mL) was added 1-propanephosphonic anhydride in EtOAc (548 mg) and it was stirred at 10° C. for 16 h. The solution was poured into water (30 mL), extracted with EtOAc (30 mL) and concentrated to afford the title compound (55.1 mg) as a white solid. MS (ESI, m/z): 379.1 [M+H]⁺.

Intermediate D15
N-[4-[[(exo)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1:1 hydrogen chloride
Step 1: tert-butyl (exo)-6-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[Image Omitted]

To a light brown suspension of 4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoic acid trifluoroacetate [2489205-90-3] (600 mg, 1.27 mmol, Eq: 1) and tert-butyl (exo)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (378 mg, 1.9 mmol, Eq: 1.5) in DMF (5 ml) at RT was added DIPEA (1.33 ml, 7.62 mmol, Eq: 6), followed by addition of HATU (724 mg, 1.9 mmol, Eq: 1.5). The reaction mixture was stirred at RT overnight. Then water was added and the resulting suspension was filtered, washed with water and the collected solid dried in vacuo to afford the title compound as light brown solid (885 mg, quant yield) which was used without further purification. MS: 538.1 [M+H]⁺, ESI pos.

Step 2: (exo)-6-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[Image Omitted]

To a solution of (exo)-6-[[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (225 mg, 0.401 mmol, 1 eq) in 1,4-dioxane (2.5 mL) and water (0.250 mL) at RT, were added (2,3-difluoro-4-methoxy-phenyl)boronic acid (90 mg, 0.481 mmol, 1.2 eq), Na₂CO₃(85 mg, 0.802 mmol, 2 eq) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (26 mg, 0.040 mmol, 0.100 eq). After degazing for 5 min with Ar, the mixture was stirred at 90° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, filtered over celite and concentrated. The residue was purified by column chromatography on silica gel using EtOAc in Heptane as eluent to give the title compound (151.1 mg, 58.23%) as off-white solid. MS: 602.2 [M+H]⁺, ESI pos.

Step 3: N-[4-[[(exo)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1:1 hydrogen chloride

[Image Omitted]

To a light brown solution of (exo)-6-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (151.1 mg, 0.233 mmol, 1 eq) in dichloromethane (0.500 mL) was added 4 M hydrogen chloride in dioxane (583 uL, 2.33 mmol, 10 eq) and the reaction mixture stirred at RT for 3 h. The reaction mixture was concentrated to dryness to afford the title compound (149.1 mg, 92.55%) as light brown solid. MS: 502.1 [M+H]⁺, ESI pos.

Example B43
N-[3-chloro-4-[[(exo)-3-[(2S,4R)-4-hydroxyprolyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1:1 hydrogen chloride

[Image Omitted]

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

[Image Omitted]

To a light brown solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-proline (25 mg, 0.109 mmol, 1.5 eq) and N-[4-[[(exo)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1:1 hydrogen chloride (50 mg, 0.072 mmol, 1 eq) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (63.1 uL, 0.362 mmol, 5 eq) and HATU (41 mg, 0.109 mmol, 1.5 eq) were added, and the reaction mixture was stirred at RT for 1.5 hours. Then water was added and the mixture extracted with DCM. The organic layer was then washed twice with a 5% LiCl solution, brine. The organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using DCM:MeOH as eluent to afford the title compound (28.4 mg, 50.98%) as white solid. MS: 715.2 [M+H]⁺, ESI pos.

Step 2: N-[3-chloro-4-[[(exo)-3-[(2S,4R)-4-hydroxyprolyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1:1 hydrogen chloride

[Image Omitted]

To a light brown solution of (2S,4R)-2-[(exo)-6-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (28.4 mg, 0.037 mmol, 1 eq) in dichloromethane (300 uL) was added 4 M HCl 4M in dioxane (46 uL, 0.185 mmol, 5 eq), and the reaction mixture was stirred at RT for 1.5 hours. The reaction mixture was concentrated to dryness to afford the title compound (31.7 mg, quant yield) as off-white solid. MS: 615.2 [M+H]⁺, ESI pos.

Example B44
(exo)-6-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(trans)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; 1:1 hydrogen chloride

[Image Omitted]

Step 1: (trans)-3-[[(exo)-6-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester

[Image Omitted]

To a colorless solution of (trans)-3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (43.95 mg, 0.217 mmol, 3 eq) in N,N-dimethylformamide were added triethylamine (50.5 uL, 0.362 mmol, 5 eq) and 1,1′-carbonyldiimidazole (29.37 mg, 0.181 mmol, 2.5 eq), and the reaction mixture was stirred at RT for 20 min. Then N-[4-[[(exo)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide 0.1:1 hydrogen chloride (50 mg, 0.072 mmol, 1 eq) was added and the stirring was continued at RT for 1.5 hours. Then water was added and the mixture extracted with DCM. The organic layer was then washed twice with a 5% LiCl solution, brine. The organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using DCM:MeOH as eluent to afford the title compound (51.1 mg, 87.91%) as white solid. MS: 730.3 [M+H]⁺, ESI pos.

Step 2: (exo)-6-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(trans)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; 1:1 hydrogen chloride

[Image Omitted]

A light brown solution of (trans)-3-[[(exo)-6-[[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (51.1 mg, 0.064 mmol, 1 eq) in dichloromethane (500 uL) was added 4 M HCl in dioxane (79.6 uL, 0.318 mmol, 5 eq) and the reaction mixture was stirred at RT for 1.5 hours. The reaction mixture was concentrated to dryness to afford the title compound (30.6 mg, 65.6%) as off-white solid. MS: 630.2 [M+H]⁺, ESI pos.

Assay Procedures

Antimicrobial Susceptibility Testing:

90% Growth Inhibitory Concentration (IC90) Determination

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

The assay used a 10-points Iso-Sensitest broth medium to measure quantitatively the in vitro activity of the compounds against Acinetobacter baumannii ATCC17978 or ATCC17961.

Stock compounds in DMSO were serially twofold diluted (e.g. range from 50 to 0.097 μM final concentration) in 384 wells microtiter plates and inoculated with 49 μl the bacterial suspension in Iso-Sensitest medium to have a final cell concentration of ˜5×10⁽⁵⁾CFU/ml in a final volume/well of 50 ul/well. Microtiter plates were incubated at 35±2° C.

Bacterial cell growth was determined with the measurement of optical density at X=600 nm each 20 minutes over a time course of 16 h. Growth inhibition was calculated during the logarithmic growth of the bacterial cells with determination of the concentration inhibiting 50% (IC50) and 90% (IC90) of the growth.

Table 1 provides the 90% growth inhibitory concentrations (IC90) in micromoles per liter of the compounds of present invention obtained against the strain Acinetobacter baumannii ATCC17978.

Table 2 provides the 90% growth inhibitory concentrations (IC90) in micromoles per liter of the compounds of present invention obtained against the strain Acinetobacter baumannii ATCC17961.

Particular compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17978 and/or ATCC17961)<25 μmol/l.

More particular compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17978 and/or ATCC17961)<5 μmol/l.

Most particular compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17978 and/or ATCC17961)<1 μmol/l.

TABLE 1

ATCC 17978

Example
IC90 [uM]

A1
0.24

A2
0.61

A3
0.31

A4
0.44

A5
0.55

A6
0.15

A7
0.24

A8
0.5

A9
0.25

A10
0.36

A11
0.31

A12
0.34

A13
0.59

A14
3

A15
4.5

A16
1.5

A17
0.4

A18
1.2

A19
1.4

A20
0.96

A21
4.7

A22
0.18

A23
0.22

A24
0.67

A25
0.13

A26
0.2

A27
0.24

A28
1.2

A29
/

A30
0.25

B1
0.11

B2
0.13

B3
0.28

B4
0.2

B5
0.079

B6
0.1

B7
0.082

B8
0.14

B9
0.21

B10
0.14

B11
0.23

B12
0.76

B13
0.91

B14
0.99

B15
0.36

B16
0.35

B17
0.084

B18
0.24

B19
0.16

B20
0.21

B21
0.098

B22
0.32

B23
0.3

B24
1

B25
0.87

B26
1.2

B27
1.1

B28
0.51

B29
0.61

B30
0.65

B31
0.74

B32
1.2

B33
1.1

B34
1.7

B35
1.3

B36
1.1

B37
0.85

B38
0.055

B39
0.057

B40
0.12

B41
0.13

B42
0.073

C1
0.83

C2
0.37

C3
0.45

C4
0.75

D1
3.2

TABLE 2

ATCC 17961

Example
IC90 [uM]

B43
0.139

B44
0.155

Example 1

A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

Per tablet

Active ingredient
200
mg

Microcrystalline cellulose
155
mg

Corn starch
25
mg

Talc
25
mg

Hydroxypropylmethylcellulose
20
mg

425
mg

Example 2

A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

Per capsule

Active ingredient
100.0
mg

Corn starch
20.0
mg

Lactose
95.0
mg

Talc
4.5
mg

Magnesium stearate
0.5
mg

220.0
mg

Example 3

A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of an infusion solution of the following composition:

Active ingredient
100 mg

Lactic acid 90%
100 mg

NaOH q.s. or HCl q.s. for adjustment to pH 4.0

Sodium chloride q.s. or glucose q.s. for

adjustment of the osmolality to 290 mOsm/kg

Water for injection (WFI)
ad 100 ml

Example 4

A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of an infusion solution of the following composition:

Active ingredient
100
mg

Hydroxypropyl-beta-cyclodextrin
10
g

NaOH q.s. or HCl q.s. for adjustment to pH 7.4

Sodium chloride q.s. or glucose q.s. for

adjustment of the osmolality to 290 mOsm/kg

Water for injection (WFI)
ad 100 ml