Novel imidazole-pyrazole derivatives

Abstract

The present invention relates to a compound represented by general formula (I) TIFF2022525029000346.tif6179, and pharmaceutically acceptable salts thereof, wherein X 1 , R A and R 3 ~R 7 Also provided are pharmaceutical compositions containing the compounds, methods for making the compounds, and methods for using the compounds as medicines, particularly as antibiotics for the treatment or prevention of bacterial infections and diseases resulting therefrom.

Description

Technical Field

[0001] The present invention relates to novel imidazole-pyrazole derivatives exhibiting antibacterial properties. The present invention also relates to a method of using a compound for the treatment or prevention of bacterial infections and diseases resulting therefrom, particularly for the treatment or prevention of infections and diseases resulting from Acinetobacter baumannii.

Background Art

[0002] Acinetobacter baumannii is a Gram-negative, aerobic, and non-fermentative bacterium that has been recognized as a novel pathogen with extremely limited treatment options in the last few decades.

[0003] Acinetobacter baumannii is considered a serious threat by the US Centers for Disease Control and Prevention, and currently causes most nosocomial infections and belongs to the so-called "ESKAPE" pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species and Escherichia coli) that can successfully "escape" the activity of antibacterial agents.

[0004] Acinetobacter baumannii is most frequently encountered in intensive care units and surgical wards where the use of a wide range of antibiotics has enabled the selection of resistance to all known antibacterial drugs, and causes infectious diseases including bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0005] Acinetobacter baumannii has an excellent ability to upregulate and acquire resistance determinants, shows environmental persistence that allows its survival and spread in the hospital environment, and as a result, the organism frequently causes infectious diseases and becomes a healthcare-related pathogen specific to that environment.

[0006] Due to increasing antibiotic resistance to most, if not all, available treatment options, multidrug-resistant (MDR) Acinetobacter baumannii infections, particularly those caused by carbapenem-resistant Acinetobacter baumannii, are extremely difficult, and in some cases even impossible, to treat and are associated with high mortality rates, as well as increased morbidity and intensive care unit stays.

[0007] Acinetobacter baumannii has been defined by the Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA) as "a classic example of a mismatch between unmet medical needs and the current antimicrobial drug research and development pipeline," and remains so. Therefore, there is a high demand and need for the identification of compounds suitable for the treatment of diseases and infections caused by Acinetobacter baumannii. The present invention provides novel compounds that exhibit activity against drug-susceptible and drug-resistant strains of Acinetobacter baumannii. Summary of the Invention

[0008] In a first aspect, the present invention provides a compound of formula (I) [ka] [In the formula, R A and R 3 From R 7 and X 1 is as defined herein, or a pharmaceutically acceptable salt thereof.

[0009] In one aspect, the present invention provides a method of preparing a compound of formula (I) described herein, comprising: (i) Heteroaryl bromides 5 or 15 [ka] [In the formula, R 1 ~R 3 , R 6 and R 7as defined herein], with a boronate, such as heteroarylboronic acid 6b

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0010] In a further aspect, the present invention provides a compound of formula (I) as described herein when manufactured according to the methods described herein.

[0011] 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 a therapeutic agent.

[0012] 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.

[0013] 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 an antibiotic.

[0014] 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 diseases caused thereby.

[0015] 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 caused by Gram-negative bacteria and diseases caused thereby.

[0016] 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 caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, and diseases caused thereby.

[0017] In a further aspect, the present invention provides a method for the treatment or prevention of an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, and a disease resulting therefrom, the method comprising administering to a mammal a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0018] 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.

[0019] 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 an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, and a disease resulting therefrom.

[0020] 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 a medicament useful for the treatment or prevention of an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, and a disease resulting therefrom.

Mode for Carrying Out the Invention

[0021] Definition Features, integers, characteristics, compounds, chemical moieties or groups described in connection with a particular aspect, embodiment or example of the invention are to be understood as applicable to any other aspect, embodiment or example described herein, unless incompatible. All features disclosed in this specification (including the 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 any details of any of the foregoing embodiments. The invention extends to any novel feature, or any novel combination of features, disclosed in this specification (including the claims, abstract and drawings), or to any novel step, or any novel combination of steps, of any method or process so disclosed.

[0022] The term "alkyl" refers to a monovalent or polyvalent, e.g., monovalent or divalent, straight-chain or branched saturated hydrocarbon group having from 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms ("C1-C6-alkyl"). In some embodiments, the alkyl group contains from 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred, but non-limiting, example of alkyl is methyl.

[0023] The term "alkenyl" means a monovalent straight-chain or branched hydrocarbon group having from 2 to 6 carbon atoms and having at least one double bond, e.g., 1 or 2 double bonds ("C2-C6-alkenyl"). In certain embodiments, alkenyl has from 2 to 4 carbon atoms and has at least one double bond, e.g., 1 or 2 double bonds. Examples of alkenyl include ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl, iso-butenyl, allyl, and prop-1,2-dienyl. Particular alkenyl groups are allyl and prop-1,2-dienyl.

[0024] The term "alkynyl" means a monovalent straight-chain or branched hydrocarbon group of 2 to 6 carbon atoms having at least one triple bond ("C2-C6-alkynyl"). In certain embodiments, alkynyl has 2 to 4 carbon atoms having at least one triple bond. Examples of alkynyl include ethynyl, propynyl, n-butynyl or isobutynyl. A preferred, but non-limiting, example of alkynyl is prop-2-ynyl.

[0025] The term "alkoxy" refers to an alkyl group as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, an alkoxy group contains 1 to 6 carbon atoms ("C1-C6-alkoxy"). In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, but non-limiting, example of alkoxy is methoxy.

[0026] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, but non-limiting, examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0027] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or bicyclic hydrocarbon group of 3 to 12 ring carbon atoms ("C3-C 12-Cycloalkyl"). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 10 ring carbon atoms, particularly 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbon rings having two carbon atoms in common, i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms, and "bicyclic cycloalkyl" also refers to a spirocyclic moiety, i.e., the two rings are connected via one common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 6 ring carbon atoms, for example, a saturated monocyclic hydrocarbon group having 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. Particularly preferred but non-limiting examples of cycloalkyl include cyclopropyl.

[0028] The term "aminocycloalkyl" refers to a cycloalkyl group in which at least one of the hydrogen atoms of the cycloalkyl group is replaced by an amino group. Preferably, "aminocycloalkyl" refers to a cycloalkyl group in which 1, 2, or 3 hydrogen atoms of the cycloalkyl group are replaced by an amino group. Preferred but non-limiting examples of aminocycloalkyl are aminocyclopentyl (e.g., (1R,3S)-3-aminocyclopentyl or (1R,2S)-2-aminocyclopentyl) and aminocyclobutyl (e.g., 3-aminocyclobutyl).

[0029] The term "aminoalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by an amino group. Preferably, "aminoalkyl" refers to an alkyl group in which 1, 2, or 3 hydrogen atoms of the alkyl group are replaced by an amino group. Preferred but non-limiting examples of aminoalkyl are aminomethyl and 1-aminoethyl.

[0030] The term "aminoalkynyl" refers to an alkynyl group in which at least one of the hydrogen atoms of the alkynyl group is replaced by an amino group. Preferably, "aminoalkynyl" refers to an alkynyl group in which one, two or three hydrogen atoms of the alkynyl group are replaced by an amino group. A preferred, but non-limiting, example of aminoalkynyl is 4-aminobut-2-ynyl.

[0031] The term "hydroxyalkynyl" refers to an alkynyl group in which at least one of the hydrogen atoms of the alkynyl group is replaced by a hydroxy group. Preferably, "hydroxyalkynyl" refers to an alkynyl group in which one, two or three hydrogen atoms of the alkynyl group are replaced by a hydroxy group. A preferred, but non-limiting, example of hydroxyalkynyl is 4-hydroxybut-2-ynyl. The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic ring system having from 3 to 10 ring atoms, preferably from 3 to 8 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, one or two of said ring atoms are selected from N and O, and the remaining ring atoms are carbon. "Bicyclic heterocyclyl" refers to a heterocyclic moiety consisting of two cycles having two ring atoms in common, i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms, and "bicyclic heterocyclyl" also refers to a spirocyclic moiety, i.e., the two rings are connected via one common ring atom. Some non-limiting examples of heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, 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), piperazinyl (e.g., piperazin-1-yl), 3-azabicyclo[3.1.0]hexan-6-yl, or 2,5-diazabicyclo[2.2.1]heptan-2-yl. Particularly preferred, but non-limiting, examples of heterocyclyl include piperidyl, piperazinyl, pyrrolidinyl, and 3-azabicyclo[3.1.0]hexan-6-yl.

[0032] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members ("C6-C 14 -aryl"), preferably 6 to 12 ring members, more preferably 6 to 10 ring members, wherein at least one ring of the system is aromatic. A particularly preferred, but non-limiting, example of aryl is phenyl.

[0033] The term "heteroaryl" refers to a monovalent or polyvalent, monocyclic or bicyclic, preferably bicyclic ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, more preferably 5 to 10 ring members, where at least one ring of the system is aromatic and at least one ring of the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl include 2-pyridyl, 3-pyridyl, 4-pyridyl, 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 3-pyridyl, 4-pyridyl, 1H-pyrazol-5-yl, thiazol-4-yl, or 1,2,4-oxadiazol-3-yl.

[0034] The term "hydroxy" refers to the -OH group.

[0035] The term "amino" refers to the -NH2 group.

[0036] The term "cyano" refers to the -CN (nitrile) group.

[0037] The term "oxo" refers to a double-bonded oxygen (=O).

[0038] The term "carbamoyl" refers to the -C(O)NH2 group.

[0039] The term "carbonyl" refers to a carbon radical having two of four covalent bonds shared with an oxygen atom (C=O).

[0040] The term "alkoxycarbonyl" refers to a -C(O)-O-alkyl group (i.e., an alkyl ester).

[0041] The term "haloalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by a halogen atom, preferably fluorine. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by a halogen atom, preferably fluorine. Particularly preferred, but non-limiting, examples of haloalkyl are trifluoromethyl, trifluoroethyl, 2-fluoroethyl, and 2,2-difluoroethyl.

[0042] The term "haloalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group is replaced by a halogen atom, preferably fluorine. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group are replaced by a halogen atom, most preferably fluorine. Particularly preferred, but non-limiting, examples of haloalkoxy are difluoromethoxy and trifluoromethoxy.

[0043] The term "alkoxyalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group is replaced by an alkoxy group, preferably a methoxy group. Preferably, "alkoxyalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkoxy group are replaced by an alkoxy group, most preferably a methoxy group. A particularly preferred but non-limiting example of alkoxyalkoxy is 2-methoxyethoxy.

[0044] The term "alkoxyalkynyl" refers to an alkynyl group in which at least one of the hydrogen atoms of the alkynyl group is replaced by an alkoxy group. Preferably, "alkoxyalkynyl" refers to an alkynyl group in which one, two or three hydrogen atoms of the alkynyl group are replaced by an alkoxy group. A specific but non-limiting example of an alkoxyalkynyl group is 4-methoxybut-2-ynyl.

[0045] The term "hydroxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by a hydroxy group. Preferably, "hydroxyalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group, most preferably one hydrogen atom, are replaced by a hydroxy group. Preferred but non-limiting examples of hydroxyalkyl are hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), and 3-hydroxy-3-methyl-butyl.

[0046] The term "pharmaceutically acceptable salt" refers to salts which retain the biological effect and the properties of the free base or free acid and which are not undesirable for biological or other reasons. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, lactic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts and the like. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resin and the like. Specific pharmaceutically acceptable salts of the compound of formula (I) are hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid) and trifluoroacetate.

[0047] The compound of formula (I) can contain a plurality of asymmetric centers and can exist in the form of a mixture of enantiomers such as optically pure enantiomers, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomarasemates or mixtures of diastereomarasemates.

[0048] According to the Cahn-Ingold-Prelog convention, an asymmetric carbon atom can be of the "R" or "S" configuration.

[0049] As used herein, the term "treatment" includes: (1) suppressing a condition, disorder or state (e.g., in maintenance therapy, arresting, reducing or delaying the onset or recurrence of a disease in at least one clinical symptom or its asymptomatic symptom); and / or (2) alleviating a state (i.e., causing regression of at least one of a condition, disorder or state or its clinical or asymptomatic symptoms). The benefit to the patient being treated is statistically significant or at least perceptible to the patient or physician. However, it will be understood that when a medicament is administered to a patient to treat a disease, the outcome may not necessarily be an effective treatment.

[0050] As used herein, the term "prevention" includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or state initiated in mammals, particularly humans, who may be at risk of or prone to suffering from a condition, disorder or state but who have not yet experienced or exhibited clinical or asymptomatic symptoms of the condition, disorder or state.

[0051] As used herein, the term "mammal" includes both humans and non-humans and includes, but is not limited to, humans, non-human primates, dogs, cats, mice, cows, horses, and pigs. In particularly preferred embodiments, the term "mammal" refers to humans.

[0052] The term "nosocomial infection" refers to healthcare-associated infections (HAI), which are infections acquired in a hospital or other healthcare facility. To emphasize both hospital and non-hospital settings, it may also be referred to as healthcare-associated infection (HAI or HCAI). Such infections can be acquired in a hospital, nursing home, rehabilitation facility, outpatient clinic, or other clinical setting.

[0053] The compounds of the present invention In a first aspect, the present invention relates to formula (I)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0054] In one embodiment, the present invention provides: (i) R 1 and R 2 together with the nitrogen atom to which they are attached form a C2-C9 heterocyclic ring which may be substituted with R 8 ; or (ii) R 1 is hydrogen, C1-C6-alkyl, amino-C1-C6-alkyl-, amino-C1-C6-alkyl-O-C1-C6-alkyl-, or the group [Chemical formula] ; and R 2 is hydrogen or C1-C6 alkyl; R 3 and R 7 are each independently hydrogen, halogen or C1-C6-alkyl; R 4 is halo-C1-C6-alkyl or C6-C 14 -aryl; R 5 is hydrogen, CF3, C1-C6-alkyl substituted with R 11 and R 12 , C2-C6-alkenyl, C2-C6-alkynyl, amino-C2-C6-alkynyl-, C1-C6-alkoxy-C2-C6-alkynyl-, hydroxy-C2-C6-alkynyl-, or the group [Chemical formula] ; R6 is C1-C6 alkyl; R 8 is C1-C6-alkoxycarbonyl, amino-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, C1-C6-alkyl-NH-C1-C6-alkyl-C(O)-, C1-C6-alkyl-NH-C1-C6-alkyl-NH-C(O)-, or the group

Chemical formula

[0055] In one embodiment, the present invention provides that the compound of formula (I) is a compound of formula (I-A):

Chemical formula

[0056] In one embodiment, the present invention provides that the compound of formula (I) is a compound of formula (I-B):

Chemical formula

[0057] In one embodiment, the present invention provides that the compound of formula (I) is a compound of formula (I-C):

Chemical formula

[0058] In one embodiment, the present invention provides that the compound of formula (I) is a compound of formula (I-D):

Chemical formula

[0059] In one embodiment, the present invention provides that the compound of formula (I) is a compound of formula (I-E):

Chemical formula

[0060] In one embodiment, the present invention provides that the compound of formula (I) is a compound of formula (I-F):

Chemical formula

[0061] In a particularly preferred embodiment, the present invention relates to R A being a radical

Chemical formula

[0062] In one embodiment, the present invention provides: (i) R 1 and R 2 together with the nitrogen atom to which they are attached form a C2-C9 heterocyclic ring which may be substituted with one or two R 8 ; or (ii) R 1 is hydrogen, C1-C6-alkyl, amino-C1-C6-alkyl-, amino-C1-C6-alkyl-O-C1-C6-alkyl-, C1-C6-alkoxycarbonyl-NH-C1-C6-alkyl-, C1-C6-alkoxycarbonyl-C1-C6-alkyl-NH-C1-C6-alkyl- or the group

Chemical formula

[0063] In a preferred embodiment, the present invention provides: (i) R 1 and R 2 together with the nitrogen atom to which they are attached form a C2-C9 heterocyclic ring which may be substituted with one or two R 8 ; or (ii) R 1 is amino-C1-C6-alkyl-O-C1-C6-alkyl- or the group

Chemical formula

[0064] In a particularly preferred embodiment, the present invention is: (i) R 1 and R 2 together with the nitrogen atom to which they are attached form a piperazinyl or piperidyl ring which may be substituted with one or two R 8 ; or (ii) R 1 is 2-(2-amino-2-methyl-propoxy)ethyl or the group

Chemical formula

[0065] In a preferred embodiment, the present invention is: (i) R 1 and R 2 together with the nitrogen atom to which they are attached form a C2-C9 heterocyclic ring which may be substituted with R 8 ; or (ii) R 1 is the group

Chemical formula

[0066] In a particularly preferred embodiment, the present invention is: (i) R 1 and R 2 together with the nitrogen atom to which they are attached form a piperazinyl ring which may be substituted with R 8 ; or (ii) R 1 is the group

Chemical formula

[0067] In one embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is halogen or C1-C6-alkyl.

[0068] In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is chloro or ethyl.

[0069] In a preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is halogen.

[0070] In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is chloro.

[0071] In a preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo-C1-C6-alkyl.

[0072] In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is CF3.

[0073] In one embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, R 11 and R 12C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halo-C2-C6-alkenyl, amino-C2-C6-alkynyl-, halo-C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C2-C6-alkynyl-, hydroxy-C2-C6-alkynyl-, or a group replaced by

Chemical formula

[0074] In a preferred embodiment, the present invention relates to R 5 wherein R 11 and R 12 is C1-C6-alkyl, C2-C6-alkenyl, halo-C2-C6-alkenyl, C2-C6-alkynyl, or a group replaced by

Chemical formula

[0075] In a particularly preferred embodiment, the present invention relates to R 5 wherein R 11 and R 12 is C1-C6-alkyl, allyl, vinyl, 2-fluoroallyl, 2-methylallyl, prop-2-ynyl, or a group replaced by

Chemical formula

[0076] In one embodiment, the present invention relates to R 5 wherein R is hydrogen, R 11 and R 12C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, amino-C2-C6-alkynyl-, C1-C6-alkoxy-C2-C6-alkynyl-, hydroxy-C2-C6-alkynyl-, or a group replaced by

Chemical formula

[0077] In a preferred embodiment, the present invention relates to R 5 is R 11 and R 12 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, or a group replaced by

Chemical formula

[0078] In a particularly preferred embodiment, the present invention relates to R 5 is R 11 and R 12 C1-C6-alkyl, allyl, prop-2-ynyl, or a group replaced by

Chemical formula

[0079] In a particularly preferred embodiment, the present invention relates to R 6 is methyl, provide the compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0080] In a preferred embodiment, the present invention relates to R 7 is hydrogen or halogen, provide the compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0081] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen.

[0082] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is C1-C6-alkoxycarbonyl, amino-C1-C6-alkyl, C1-C6-alkyl-NH-, amino-C1-C6-alkyl-C(O)-, amino-C1-C6-alkyl-NH-C(O)-C1-C6-alkyl-, amino-C1-C6-alkyl-CH(OH)-, amino-C1-C6-alkyl-CH(NH2)-C(O)-, (C1-C6-alkyl)2N-C1-C6-alkyl-, (C1-C6-alkyl)2N-C1-C6-alkyl-N(C1-C6-alkyl)-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, C1-C6-alkyl-NH-C1-C6-alkyl-NH-C(O)-, oxo, amino, halogen, or a group

Chemical formula

[0083] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is halogen, or a group

Chemical formula

[0084] In a particularly preferred embodiment, the present invention relates to R 8 being fluoro or a group

Chemical formula

[0085] In one embodiment, the present invention relates to R 8 being C1-C6-alkoxycarbonyl, amino-C1-C6-alkyl-C(O)-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, C1-C6-alkyl-NH-C1-C6-alkyl-NH-C(O)-, or a group

Chemical formula

[0086] In a preferred embodiment, the present invention relates to R 8 being a group

Chemical formula

[0087] In one embodiment, the present invention relates to R 9 being hydrogen, amino, hydroxy, alkyl, alkoxy, amino-C1-C6-alkyl-C(O)-NH- or a group

Chemical formula

[0088] In a preferred embodiment, the present invention relates to R 9 being amino or a group [Chemical formula] [wherein R 19 , R 20 , X 5 and D are as defined herein], provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0089] In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 9 is amino.

[0090] In one embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 10 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy.

[0091] In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 10 is hydrogen.

[0092] In one embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 11 is hydrogen, halogen, hydroxy, cyano, CF3, carbamoyl, halo-C1-C6-alkoxy-, (C1-C6-alkyl)2N-C(O)-, C1-C6-alkyl-NH-C(O)-, or C1-C6-alkoxy-C1-C6-alkoxy. In a preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 11 is hydrogen, cyano, CF3, or halogen.

[0093] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 11 is hydrogen, cyano, CF3, or fluoro.

[0094] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 12 is hydrogen or halogen.

[0095] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 12 is hydrogen or fluoro.

[0096] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 13 is hydrogen, oxo, halogen, C3-C 12 -cycloalkyl, C1-C6-alkyl, halo-C1-C6-alkyl or hydroxy-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 R 13 is hydrogen or halogen.

[0097] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 13 is hydrogen or fluoro.

[0098] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 14 is hydrogen, oxo, halogen, or C1-C6-alkyl.

[0099] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 14 is hydrogen or halogen.

[0100] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 14 is hydrogen or fluoro.

[0101] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 15 is hydrogen or halogen.

[0102] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 15 is hydrogen.

[0103] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 16 is hydrogen, amino, or hydroxy.

[0104] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 17 is hydrogen, amino or C1-C6-alkyl.

[0105] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 17 is hydrogen or C1-C6-alkyl.

[0106] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 17 is hydrogen.

[0107] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 18 is hydrogen or amino.

[0108] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R18 Provided is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

[0109] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, amino, hydroxy, C1-C6-alkyl, amino-C1-C6-alkyl or HO-SO2-C1-C6-alkyl. 19 Provided is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, amino, hydroxy, C1-C6-alkyl, amino-C1-C6-alkyl or HO-SO2-C1-C6-alkyl.

[0110] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, amino or hydroxy. 19 Provided is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, amino or hydroxy.

[0111] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or hydroxy. 20 Provided is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or hydroxy.

[0112] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen. 20 Provided is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

[0113] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is C2-C9-heterocyclyl or C3-C 12 -cycloalkyl.

[0114] 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 cyclobutyl, cyclopropyl or 3-azabicyclo[3.1.0]hexan-6-yl.

[0115] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is C3-C 12 -cycloalkyl.

[0116] 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 cyclobutyl.

[0117] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is C3-C 12 -cycloalkyl.

[0118] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is cyclopropyl, cyclobutyl, or spiro[2.3]hexan-5-yl.

[0119] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein C is C3-C 12 -cycloalkyl or C2-C9-heterocyclyl.

[0120] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein C is cyclobutyl, cyclopentyl, 3-piperidyl, 4-piperidyl, pyrrolidin-3-yl, azetidin-3-yl, 3-azabicyclo[3.1.0]hexan-6-yl, or 2,5-diazabicyclo[2.2.1]heptan-2-yl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein C is cyclobutyl, cyclopentyl, 4-piperidyl, pyrrolidin-3-yl, 3-azabicyclo[3.1.0]hexan-6-yl, or 2,5-diazabicyclo[2.2.1]heptan-2-yl.

[0121] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein D is C3-C 12 -cycloalkyl or C2-C9-heterocyclyl.

[0122] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein D is pyrrolidin-3-yl, 4-piperidyl or cyclobutyl.

[0123] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 1 is -S-, a covalent bond, carbonyl, SO2 or the group

Chemical formula

[0124] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 1 is carbonyl or SO2.

[0125] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 1 is carbonyl.

[0126] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 2 is a covalent bond or C1-C6-alkyl.

[0127] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 2 is a covalent bond or -CH2-.

[0128] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 2 is a covalent bond.

[0129] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 3Provided is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X is a covalent bond or C1-C6-alkyl.

[0130] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 3 is a covalent bond or -CH2-, or a pharmaceutically acceptable salt thereof.

[0131] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 4 is a covalent bond, carbonyl, -NH-C(O)-, -NH-C(O)-NH-, -NH-C(O)-NH-C1-C6-alkyl-, -C1-C6-alkyl-NH-C(O)-, -C1-C6-alkyl-C(O)- or -SO2-.

[0132] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 4 is carbonyl, -NH-C(O)-, -NH-C(O)-NH-C1-C6-alkyl- or -C1-C6-alkyl-NH-C(O)-.

[0133] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 4 is carbonyl, -NH-C(O)-, -NH-C(O)-NH-CH2- or -CH2-NH-C(O)-.

[0134] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 4 is a covalent bond, carbonyl, -NH-C(O)-, or -C1-C6-alkyl-NH-C(O)-.

[0135] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 4is carbonyl, —NH—C(O)—, or —C1-C6-alkyl-NH—C(O)—, or a pharmaceutically acceptable salt thereof.

[0136] In a particularly preferred embodiment, the present invention provides 4 is carbonyl, —NH—C(O)—, or —CH—NH—C(O)—, or a pharmaceutically acceptable salt thereof.

[0137] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 5 is carbonyl, —C(O)—NH—, —NH—C(O)— or —NH—C(O)—NH—, or a pharmaceutically acceptable salt thereof.

[0138] In a preferred embodiment, the present invention provides a method for producing a compound comprising: 5 is carbonyl or —NH—C(O)—, or a pharmaceutically acceptable salt thereof.

[0139] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: (i)R 1 and R 2 together with the nitrogen atom to which they are attached, R 8 forming a C2-C9 heterocyclic ring optionally substituted with (ii)R 1 is hydrogen, C1-C6-alkyl, amino-C1-C6-alkyl-, amino-C1-C6-alkyl-O-C1-C6-alkyl- or a group [ka] and R 2 is hydrogen or C1-C6 alkyl; R 3 is halogen or C1-C6 alkyl; R 4 is halo-C1-C6-alkyl or C6-C 14 -aryl; R 5 is hydrogen, R 11 and R 12 substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, amino-C2-C6-alkynyl-, C1-C6-alkoxy-C2-C6-alkynyl-, hydroxy-C2-C6-alkynyl-, or the group

Chemical formula

Chemical formula

[0140] In preferred embodiments, the present invention relates to (i) R 1 and R 2 together with the nitrogen atom to which they are attached form a C2-C9-heterocyclic ring optionally substituted with R 8 ; or (ii) R 1 is the group

Chemical formula

Chemical formula

Chemical formula

[0141] Provided are compounds of formula (I-I) described herein, or pharmaceutically acceptable salts thereof. In a particularly preferred embodiment, the present invention (i) R1 and R 2 together with the nitrogen atom to which they are attached form a piperazinyl ring which may be substituted with R 8 ; or (ii) R 1 is the group

Chem.

Chem.

Chem.

[0142] In one embodiment, the present invention is (i) R 1 and R 2 together with the nitrogen atom to which they are attached form a C2 - C9 - heterocyclic ring which may be substituted with R 8 ; or (ii) R 1 is hydrogen, C1 - C6 - alkyl, amino - C1 - C6 - alkyl -, amino - C1 - C6 - alkyl - O - C1 - C6 - alkyl -, or the group

Chemical formula

Chemical formula

[0143] There is provided a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the present invention is: (i) R 1 and R 2 together with the nitrogen atom to which they are attached form a C2-C9-heterocyclic ring which may be substituted with R 8 ; or (ii) R 1 is the group

Chemical formula

Chemical formula

[0144] In a particularly preferred embodiment, the present invention (i) R 1 and R 2 together with the nitrogen atom to which they are attached form a piperazinyl ring optionally substituted with R 8 ; or (ii) R 1 is the group

Chemical formula

Chemical formula

[0145] In one embodiment, the present invention R 5 is hydrogen, R 11 and R 12C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, amino-C2-C6-alkynyl-, C1-C6-alkoxy-C2-C6-alkynyl-, hydroxy-C2-C6-alkynyl-, or a group replaced by [Chemical formula] being; R 11 is hydrogen, halogen, hydroxy, cyano, CF3, carbamoyl, halo-C1-C6-alkoxy-, (C1-C6-alkyl)2N-C(O)-, C1-C6-alkyl-NH-C(O)-, or C1-C6-alkoxy-C1-C6-alkoxy; R 12 is hydrogen or halogen; R 13 is hydrogen, oxo, halogen, C3-C 12 -cycloalkyl, C1-C6-alkyl, or hydroxy-C1-C6-alkyl; R 14 is hydrogen, oxo, halogen, or C1-C6-alkyl; R 15 is hydrogen or halogen; B is C6-C 14 -aryl, C1-C 13 -heteroaryl, C3-C 12 -cycloalkyl, or C2-C9-heterocyclyl; and X 3 is a covalent bond or C1-C6-alkyl, Provided is a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0146] In a preferred embodiment, the present invention: R 5 is R 11 and R 12 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, or a group substituted by [Chemical formula] and; R 11 is hydrogen, cyano, CF3, or halogen; R 12 , R 13 , and R 14 are each independently hydrogen or halogen; B is C3-C 12 -cycloalkyl; and X 3 is a covalent bond or C1-C6-alkyl, provide a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0147] In a particularly preferred embodiment, the present invention is: R 5 is C1-C6-alkyl, allyl, prop-2-ynyl, or the group 11 and R 12 substituted with R

Chemical formula

[0148] In one embodiment, the present invention is R 3 is halogen or C1-C6-alkyl; and R 7 is hydrogen or halogen, Provided is a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0149] In a preferred embodiment, the present invention: R 3 is halogen; and R 7 is hydrogen, Provided is a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0150] In a particularly preferred embodiment, the present invention: R 3 is chloro; and R 7 is hydrogen, Provided is a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0151] In one embodiment, the present invention R A is C1-C6-alkyl or a group

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

[0152] In a preferred embodiment, the present invention: R A is the group

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

[0153] In a particularly preferred embodiment, the present invention is: R A is the group

Chemical formula

Chemical formula

Chemical formula

[0154] In one embodiment, the present invention provides R A is C1-C6-alkyl or a group

Chemical formula

Chemical formula

Chem.

Chem.

Chemical formula

[0155] There is provided a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the present invention: R A is the group

Chemical formula

Chemical formula

[0156] In a particularly preferred embodiment, the present invention is: ]>R A is a group [Chemical formula] ; where: (i) R 1 and R 2 together with the nitrogen atom to which they are attached form a piperazinyl or piperidyl ring which may be substituted with one or two R 8 ; or (ii) R 1is 2-(2-amino-2-methyl-propoxy)ethyl or a group

Chemical formula

Chemical formula

Chemical formula

[0157] In one embodiment, the present invention is R 5 is hydrogen, R 11 and R 12 substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halo-C2-C6-alkenyl, amino-C2-C6-alkynyl-, halo-C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C2-C6-alkynyl-, hydroxy-C2-C6-alkynyl-, or the group

Chemical formula

[0158] In a preferred embodiment, the present invention is: R 5 is R 11 and R 12 substituted C1-C6-alkyl, C2-C6-alkenyl, halo-C2-C6-alkenyl, C2-C6-alkynyl, or group

Chemical formula

[0159] In a particularly preferred embodiment, the present invention is: R 5 is R 11 and R 12 substituted C1-C6-alkyl, allyl, prop-2-ynyl, or group

Chemical formula

[0160] In a preferred embodiment, the present invention provides that R A is a group

Chemical formula

[0161] In a preferred embodiment, the present invention provides: R 1 is a group

Chemical formula

Chemical formula

[0162] In a preferred embodiment, the present invention provides: R 5 is a group

Chemical formula

[0163] In a particularly preferred embodiment, the present invention provides: R A Based on [ka] and; R 1 Based on [ka] and; R 2 is hydrogen; R 3 is a halogen; R 4 is halo-C1-C6-alkyl; R 5 Based on [ka] and; R 6 is C1-C6 alkyl; R 7 is hydrogen; R 9 Based on [ka] and; R 10 is hydrogen; R 13 is a halogen; R 14 is a halogen; R 15 is hydrogen; R19 is hydroxy; R 20 is hydrogen; X 1 is carbonyl; X 2 is a covalent bond; X 3 is a covalent bond; X 5 is -NH-C(O)-; A is C2-C9-heterocyclyl; B is C3-C 12 -cycloalkyl; and D is C2-C9-heterocyclyl, provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0164] In a preferred embodiment, the present invention: R 1 and R 2 together with the nitrogen atom to which they are attached form a C2-C9-heterocyclic ring substituted with one R 8 ; R 8 is the group

Chemical formula

[0165] In a preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is C2-C6-alkynyl.

[0166] In a particularly preferred embodiment, the present invention: R A is a group

Chem.

Chem.

[0167] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the compounds disclosed in Table 1.

[0168] In one embodiment, the present invention provides that the compound of formula (I) is: N-(Azetidin-3-yl)-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pent-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S,4S)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-(dimethylcarbamoyl)phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-1,2-dienyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[2-[(2R)-2-aminopropoxy]ethylcarbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[2-(2-amino-2-methyl-propoxy)ethylcarbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2R)-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(1-methylprop-2-ynyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-But-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-Allyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4-methoxybut-2-ynyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-[(2S)-2-aminopropoxy]ethylcarbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-isobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-(methylcarbamoyl)phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[4-(3-aminopropylcarbamoyl)-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(4-aminobut-2-ynyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4-hydroxy-2-butynyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(4-carbamoyl-3-chloro-phenyl)-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazin-1-yl]sulfonyl-phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(2S)-2-aminopropanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-N-[3-methyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]imidazole-2-carboxamide; N-[3-chloro-4-[[(3S)-pyrrolidin-3-yl]methylcarbamoyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[[(3S,4R)-4-hydroxypyrrolidin-3-yl]methylcarbamoyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazin-1-yl]sulfonyl-phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[[(3R)-pyrrolidin-3-yl]methylcarbamoyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[2-(isopropylamino)-2-oxo-ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-cyanoethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; tert-Butyl 4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate; 5-[1-(2-Amino-1-methyl-2-oxo-ethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(1,1-dioxothietan-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(2-pyrazol-1-ylethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 1-Methyl-N-[3-methyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[2-(methylamino)-2-oxo-ethyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(2-Amino-2-oxo-ethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[2-(dimethylamino)-2-oxo-ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(1-cyclopropyl-2-oxo-pyrrolidin-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[2-(2-methoxyethoxy)ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(6-Aminohexylcarbamoyl)-3-methyl-phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(3-Amino-3-oxo-propyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(1S,3R)-3-Aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-(5-Aminopentylcarbamoyl)-3-methyl-phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[(1S,2R)-2-aminocyclopentyl]-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(1,6-diazaspiro[3.3]heptane-6-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(3S)-3-aminopiperidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[(3-aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Aminopiperidine-1-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(3,6-diazabicyclo[3.2.0]heptane-3-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(2S)-2-Aminopropanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-N-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]piperazine-1-carboxamide; N-[4-[4-[(3aS,6aS)-2,3,3a,4,6,6a-Hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-(3-Amino-3-methyl-azetidine-1-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-(2-Azaspiro[3.3]heptan-6-yl)-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-N-[2-(methylamino)ethyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-spiro[2.3]hexan-5-yl-3-(trifluoromethyl)pyrazol-ill]imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperazine-1-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[(2,2-difluorocyclopropyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[(1S,3S)-3-aminocyclopentyl]-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 4-[4-[[5-[1-Allyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-N-(azetidin-3-yl)piperazine-1-carboxamide; 5-[1-Allyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[4-[(3-aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(Azetidin-3-yl)-4-[2-chloro-4-[[5-[1-cyclobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[(3,3-difluorocyclobutyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[3-(trifluoromethyl)-1-(3,3,3-trifluoropropyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(fluoromethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(3-Aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[3-[[(2R)-2-aminopropanoyl]amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(1-cyanoethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[(3-methylthietan-3-yl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-isopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[2-(difluoromethoxy)ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[(3-aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-5-[1-cyclobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(difluoromethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[[3-[[(1S,3R)-3-aminocyclopentanecarbonyl]amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[4-(aminomethyl)-4,5-dihydrooxazol-2-yl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[1-methyl-5-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[(3-aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[(3-aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 5-[1-[1-(Chloromethyl)-2-hydroxy-ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(Cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-[2-(Chloromethyl)-3-hydroxy-2-methyl-propyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Amino-4-methyl-piperidine-1-carbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(2,2-Difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide;<J N-[4-[4-[(1S,3R)-3-Aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-fluoro-5-methyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-Aminopiperidine-1-carbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-?carboxamide; 5-[1-(Cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-[rac-(3S,4S)-3-amino-4-methyl-piperidine-1-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-(6-amino-2-azaspiro[3.3]heptane-2-carbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-(3-phenyl-1H-pyrazol-4-yl)imidazole-2-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-fluoro-5-methyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(Cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(3-methylpiperazine-1-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(Cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[4-[4-(2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[3-(Aminomethyl)pyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[4-(Aminomethyl)-4,5-dihydrooxazol-2-yl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(Cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(Cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(2,2-Difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(2S)-2-aminopropanoyl]piperazine-1-carbonyl]-3-fluoro-5-methyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(Cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-fluoro-5-methyl-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(Azetidine-3-carbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(3-hydroxy-3-methyl-butyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(1H-pyrazol-5-ylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-(3-azabicyclo[3.1.0]hexan-6-yl)-4-[4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]piperazine-1-carboxamide; 5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Ethyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[2-(aminomethyl)pyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; 5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-ethyl-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-ethyl-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 4-[2-Ethyl-4-[[1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; N-[3-Ethyl-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-[[3-Chloro-1-(hydroxymethyl)-3-methyl-cyclobutyl]methyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(azetidine-3-carbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(3-Aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-[(2-methylthiazol-4-yl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(Cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-fluoro-4-[4-(3-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]-5-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxy piperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(4-aminocyclohexyl)carbamoyl]-3-chloro-phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[4-[(1-aminocyclopropyl)methylcarbamoyl]-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1S)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1R,5S)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-chloro-4-[[rac-(1S,5R)-3-(piperazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[rac-(1S,5R)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(5-aminopentylcarbamoyl)-3-chloro-phenyl]-5-[1-(2-fluoroallyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(1R,2S)-2-aminocyclopentyl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[4-(6-aminohexylcarbamoyl)-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-chloro-4-piperazin-1-ylsulfonyl-phenyl)-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-(2-fluoroallyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1R,5S)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3S)-pyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1S)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[4-[4-aminobutyl(methyl)carbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-aminoethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[rac-(1S,5R)-3-[rac-(3R)-3-aminopyrrolidine-1-carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(6-aminospiro[3.3]heptan-2-yl)carbamoyl]-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-fluoro-4-[[[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamoylamino]methyl]piperidine-1-carbonyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(Cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-fluoro-4-[4-[rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[(3R)-3-(Aminomethyl)pyrrolidine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-ylmethylcarbamoyl)-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(Azetidin-3-yl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(Azetidin-3-yl)-4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1-vinyl-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-[(2R,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazin-1-yl]sulfonyl-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(4-aminobutylcarbamoyl)-3-chloro-phenyl]-1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-(2-Aminoacetyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(Aminomethyl)-4-fluoro-piperidine-1-carbonyl]-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-Aminoacetyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[rac-(1S,5R)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 5-[1-(2,2-Difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-N-[4-(2-oxopyrrolidin-1-yl)phenyl]imidazole-2-carboxamide; N-[4-(5-Aminopentylcarbamoyl)-3-chloro-phenyl]-1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(1R,3R)-3-Aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(Aminomethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(Azetidine-3-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-6-[[2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[4-[4-(2-Aminoacetyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[1-methyl-5-[1-spiro[2.3]hexan-5-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[4-[(1S,3R)-3-Aminocyclopentanecarbonyl]piperazin-1-yl]sulfonyl-3-chloro-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-cyclobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-amino-2-methyl-propoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(6-amino-3-azabicyclo[3.1.0]hexane-3-carbonyl)-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-fluoro-4-[4-[rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-ylmethyl)-4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 5-[1-allyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-Aminoazetidine-1-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(3S)-3-(Aminomethyl)pyrrolidine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[4-[[5-[1-(Cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-fluoro-benzoyl]piperazine-1-carboxamide; tert-Butyl 2-[5-[[4-[[5-[1-(2,2-Difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]pentylamino]acetate; N-[3-Chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-[(2,2-Difluorocyclopropyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[5-[1-(Cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-(5-Aminopentylcarbamoyl)-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-Amino-2-methyl-propoxy)ethylcarbamoyl]-3-ethyl-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3R)-piperidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(azetidine-3-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 3-[[[2-Chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]methyl]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]piperidine-1-carboxamide; N-[3-Chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-Aminoethyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(1R,3R)-3-Aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Aminocyclohexanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[(1R,3R)-3-Aminocyclopentyl]-4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-(Azetidin-3-yl)-4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[(3-Aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-pyrrolidin-3-yl-piperazine-1-carboxamide; N-(3-aminocyclobutyl)-4-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]piperidine-1-carboxamide; N-(3-amino-3-methyl-cyclobutyl)-4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[4-(2-aminoethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 5-[1-benzyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(1R,2S)-2-Aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(2,2-Difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-N-(4-piperazin-1-ylsulfonylphenyl)imidazole-2-carboxamide; N-[3-Chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(3R)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(5-Aminopentylcarbamoyl)-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1R,5S)-N-[1-(Aminomethyl)-2-chloro-ethyl]-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-Chloro-4-(3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2R)-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[5-[1-(2-chloroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[4-(3-aminopropanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[[3-[[(3R)-pyrrolidine-3-carbonyl]amino]cyclobutyl]carbamoyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-4-[2-chloro-4-[[5-[1-[(2,2-difluorocyclopropyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-(3-aminopropylcarbamoyl)-3-chloro-phenyl]-1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[3-(methylamino)cyclobutyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S)-2-methylpyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[[rac-(1S,5R)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-5-[1-(3-fluorocyclobuta-2-en-1-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[5-[l-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Fluoro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[6-[(3-Aminocyclobutyl)carbamoylamino]hexylcarbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Bromo-4-[4-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[[rac-(1S,5R)-3-[4-(3-aminopropyl)piperazine-1-carbonyl]-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1R,5S)-N-(3-aminocyclobutyl)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[(1R,3S)-3-amino-2,2-dimethyl-cyclobutyl]-4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[3-[(3-Aminocyclobutanecarbonyl)amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-Amino-2-hydroxy-propanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[(rac-(3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl)phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-fluoro-benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-[(2R)-piperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopentyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[3-[[(1R,3S)-3-aminocyclopentyl]carbamoylamino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[3-(aminomethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(2S)-2-aminopropanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]phenyl]sulfonyl-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-chloro-4-[[rac-(3S,4S)-4-methoxypyrrolidin-3-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-4-[2-chloro-4-[[5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[4-(Azetidine-2-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-Aminoacetyl)piperazin-1-yl]sulfonylphenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[[rac-(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(6-Aminohexylcarbamoyl)-3-bromo-phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S)-2,5-diaminopentanoyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(5-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(1R,3R)-3-aminocyclohexanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(3aR,6aS)-2-[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxamide; N-[4-[(4-aminocyclohexyl)methylcarbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-aminoethyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[N-(3-aminopropyl)-S-methyl-sulfonimidoyl]-3-methyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-4-[2-chloro-4-[[5-[1-isobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-(3-aminocyclobutyl)-4-[2-chloro-4-[[5-[1-[(3,3-difluorocyclobutyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-(3-aminocyclobutyl)-4-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-methyl-amino]piperidine-1-carboxamide; N-[4-[4-(3-Aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(4-methylpiperazine-1-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-Aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[6-[[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamoylamino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-fluoro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Aminobutanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyclopentylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[1-methyl-5-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-[[rac-(1S,5R)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(3-Aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-5-[1-(3,3-difluoroallyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(2,2-Difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-N-(3-methyl-4-methylsulfanyl-phenyl)imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(4-Piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[[[2-Chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]methyl]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxamide; N-[3-Chloro-4-[4-(4-Hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-[(E)-But-2-enyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2R,4S)-4-Hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; tert-Butyl N-[4-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]butyl]carbamate; N-[3-Chloro-4-[[3-[[(3R)-Pyrrolidine-3-carbonyl]amino]cyclobutyl]carbamoyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[3-[[(3R)-3-aminopyrrolidin-1-carbonyl]amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(6-aminospiro[3.3]heptan-2-yl)carbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxypyrrolidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(3-azabicyclo[3.2.0]heptan-6-ylcarbonyl)-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(4-hydroxy-4-piperidyl)methyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[(1S,5R)-3-[(3R)-3-Aminopyrrolidine-1-carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-piperidyl)piperidine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[4-[[(2S)-2-aminopropanoyl]amino]cyclohexyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-4-[2-bromo-4-[[5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 3-amino-N-[3-[[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]piperidine-1-carboxamide; N-[4-[4-[(1S,3R)-3-aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-4-[2-chloro-4-[[1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-[[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide; N-[3-chloro-4-[(rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-aminoacetyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[methyl-[[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamoyl]amino]butylcarbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[2-(trifluoromethoxy)ethyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-(3-aminocyclobutyl)-4-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-4-methyl-piperidine-1-carboxamide; (1S,5R)-N-[(1R,2S)-2-aminocyclopentyl]-6-[[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]piperidine-1-carboxamide; N-[3-chloro-4-(4-piperazine-1-ylsulfonylpiperazine-1-carbonyl)phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-1-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[(4-hydroxypyrrolidin-3-yl)carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[N-(3-aminopropyl)-S-methyl-sulfonimidoyl]-3-methyl-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 4-[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; N-[3-chloro-4-[(4-methylpiperidin-4-yl)carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(4-aminobutylcarbamoyl)-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[rac-(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.2.0]heptane-3-carboxamide; N-[4-[4-[(2R)-azetidine-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[4-methoxy-1-[[rac-(3S,4S)-4-hydroxypyrrolidine-3-yl]carbamoyl]pyrrolidine-3-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(4-aminocyclohexyl)carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-cyclopropylethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[N-(3-aminopropyl)-S-methyl-sulfonimidoyl]-3-methyl-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-[[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-methyl-piperazine-1-carboxamide; N-[4-[4-(3-Aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(5-Aminopentylcarbamoyl)-3-ethyl-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)ethyl-methyl-amino]piperidine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[3-[[3-(Aminomethyl)pyrrolidine-1-carbonyl]amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[3-(dimethylamino)-3-methyl-butyl]piperidine-1-carbonyl]phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[3-[[2-(Aminomethyl)pyrrolidine-1-carbonyl]amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Aminopiperidine-1-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[6-(piperidine-4-carbonyl)-1,6-diazaspiro[3.3]heptane-1-carbonyl]phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(2,2-difluoroethyl)-3-(difluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 6-[[[2-Chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]methyl]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-Chloro-4-[4-(methylamino)piperidine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4S)-4-fluoropyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[methyl(4-piperidyl)carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[(1R,3R)-3-aminocyclopentyl]-4-[2-chloro-4-[[5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(4-hydroxy-1-piperidyl)piperidine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[4-[(3-aminocyclobutanecarbonyl)amino]cyclohexyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[1-[(3-aminocyclobutyl)carbamoyl]azetidin-3-yl]methylcarbamoyl]-3-chloro-phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-bromo-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(2-aminoethylamino)-2-oxo-ethyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1R,5S)-N-(azetidin-3-yl)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1S,5R)-8-[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxamide; N-[4-[6-(azetidin-3-ylmethylcarbamoylamino)hexylcarbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[3-(trifluoromethyl)-1-[2-(trifluoromethyl)cyclopropyl]pyrazol-4-yl]imidazole-2-carboxamide; (1S,5R)-6-[[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-[(2,2-difluorocyclopropyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; (1S,5R)-6-[[2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; (1S,5R)-6-[[4-[[5-[1-allyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide or (1S,5R)-6-[[2-chloro-4-[[5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide There is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0169] In a preferred embodiment, the present invention provides that the compound of formula (I) is: N-(azetidin-3-yl)-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 4-[2-chloro-4-[[(1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl)amino]benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[4-[(3R)-3-Aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[(1S,2R)-2-Aminocyclopentyl]-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[(3-Aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-N-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-spiro[2.3]hexan-5-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[(2,2-difluorocyclopropyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[4-[[5-[1-Allyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-N-(azetidin-3-yl)piperazine-1-carboxamide; N-[3-Chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(Azetidin-3-yl)-4-[2-chloro-4-[[5-[1-cyclobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[(3,3-difluorocyclobutyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-isopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[4-[(1-aminocyclopropyl)methylcarbamoyl]-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1S)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1R,5S)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-chloro-4-[[rac-(1S,5R)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-(2-fluoroallyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1R,5S)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1S)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-chloro-4-[4-fluoro-4-[[[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamoylamino]methyl]piperidine-1-carbonyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1-vinyl-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[[rac-(1S,5R)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-6-[[2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-cyclobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-amino-2-methyl-propoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-4-[2-chloro-4-[[5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-(3-aminocyclobutyl)-4-[2-chloro-4-[[5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(3-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide or N-(3-aminocyclobutyl)-4-[2-chloro-4-[[1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide There is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0170] In one embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I) as described herein, particularly a pharmaceutically acceptable salt selected from hydrochloride, fumarate, lactate (particularly derived from L-(+)-lactic acid), tartrate (particularly derived from L-(+)-tartaric acid) and trifluoroacetate. In a further particular embodiment, the present invention provides a compound according to formula (I) as described herein (i.e., as the “free base” or “free acid” respectively).

[0171] In some embodiments, the compound of formula (I) is isotopically labeled by replacing one or more atoms therein with atoms having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, for example, but not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18F, 36 Cl, 123 I, and 125 I are included. Some isotopically labeled compounds of formula (I), for example, those incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. Radioisotopes such as tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and simple means of detection. For example, the compounds of formula (I) can be enriched to 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0172] Substitution with a heavier isotope such as deuterium, i.e., 2 H, can result in certain therapeutic advantages arising from higher metabolic stability, such as an extended in vivo half-life or a reduced required dosage.

[0173] 11 C, 18 F, 15 O and 13 substitution with a positron emitting isotope such as N can be useful in positron emission tomography (PET) 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 using an appropriate isotopically labeled reagent in place of the previously used unlabeled reagent, or by a method similar to that described in the examples below.

[0174] Method of Manufacture The preparation of the compounds of formula (I) of the present invention can be carried out by a continuous or convergent synthetic route. The synthesis of the compounds of the present invention is shown in the following scheme. The skills necessary to carry out the reactions and the purification of the resulting products are known to those skilled in the art. The substituents and indicators used in the following description of the method have the significance described above in this specification unless otherwise stated. More specifically, the compounds of formula (I) can be prepared by the methods described hereinafter, by the methods described in the examples, or by analogous methods. The appropriate reaction conditions for the individual reaction steps are known to those skilled in the art. Also, for the reaction conditions described in the literature that affect the reactions described, see, for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 2018). The inventors have found it convenient to carry out the reactions in the presence or absence of a solvent. There are no specific restrictions on the nature of the solvent used as long as there is no harmful effect on the reaction or the reagents used and the reagents can be dissolved to at least some extent. The reactions described can occur over a wide range of temperatures and the exact reaction temperature is not critical to the present invention. It is convenient to carry out the reactions described in the temperature range between -78 °C and the reflux temperature. The time required for the reaction can also vary very widely depending on many factors, especially the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually be sufficient to obtain the intermediates and compounds described. The order of the reactions is not limited to that shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities. The starting materials can be commercially available or can be prepared by methods similar to those described hereinafter, by the methods described in the references cited in this description or in the examples, or by methods known in the art.

[0175] Substituted aniline carboxylic acid derivative 2 (e.g., R 3=Me, Cl, Et) are commercially available. For simplicity, in the presence of a base (such as DIPEA, triethylamine, etc.), in the presence of a solvent (such as DMF, dioxane, THF, etc.), in the presence of a coupling reagent (such as HATU, TBTU, etc.), it can react with amine 1 to obtain amide derivative 3. Then aniline can react with imidazole carboxylic acid 4 in the presence of a base (such as DIPEA, triethylamine, etc.), in the presence of a solvent (such as DMF, dioxane, THF, etc.), in the presence of a coupling reagent (such as HATU, TBTU, etc.) to obtain amide derivative 5. Then, bromoimidazole, or alternatively other halide-like iodine or chloro derivatives, in the presence of a base (such as Na2CO3, Cs2CO3, K2CO3, Et3N, DIPEA, etc.), in a solvent (such as dioxane, THF, DMF, water, etc.), under a transition metal catalyst (such as a typical metal source Pd, etc.), can react with a boronate such as boronic acid 6 or a boronic acid ester such as pinacol ester in a Suzuki reaction to obtain imidazole derivative 11. Then, pyrazole can be alkylated with an alkylating reagent 8 (X = a suitable leaving group, such as a halide (e.g., Br, I, Cl) or a sulfonate), and after an optional deprotection step, the desired target compound of general structure I can be obtained. Alternatively, the boronate already substituted on the nitrogen atom is commercially available or can be prepared by methods well known in the art. Using alternative methods for R 5Substituents can be attached. For example, the Chan-Lam coupling reaction is carried out in the presence of oxygen, in a solvent (such as dioxane, THF, DMF, water, etc.), in the presence of copper(II) species and an amine such as pyridine, DMAP, Et3N, etc., using an appropriate boronate derivative. The order of the steps can be changed. For example, first, the ester aniline derivative 9 is reacted with the imidazole carboxylic acid 4 in the presence of a base (such as DIPEA, triethylamine, etc.) in the presence of a solvent (such as DMF, dioxane, THF, etc.) in the presence of a coupling reagent (such as HATU, TBTU, etc.) to obtain the amide derivative 10, which is then reacted with a boronate such as boronic acid 6 or a boronic acid ester such as pinacol ester in the presence of a base (such as Na2CO3, Cs2CO3, K2CO3, Et3N, DIPEA, etc.) in a solvent (such as dioxane, THF, DMF, water, etc.) under a transition metal catalyst (such as a typical metal source Pd, etc.) in a Suzuki reaction to obtain the imidazole derivative 11. Then the ester can be hydrolyzed to the corresponding acid derivative using a standard method using a base (such as LiOH or NaOH, etc.) in the presence of water and optionally an organic solvent mixture. Some esters such as tert-butyl ester can be cleaved to the corresponding acid derivative using an acid such as TFA in an organic solvent (such as dichloromethane, etc.) under acidic conditions. Then the intermediate carboxylic acid is reacted with the amine 1 in the presence of a base (such as DIPEA, triethylamine, etc.) in the presence of a solvent (such as DMF, dioxane, THF, etc.) in the presence of a coupling reagent (such as HATU, TBTU, etc.) to obtain the amide derivative 7, which is then converted to the target molecule of structure I as described above.

[0176] Alternatively, the intermediate 11 can be, for example, alkylated as described above with R 5Connect to the substituent, convert the ester to the corresponding carboxylic acid, and then react with amine 1 as described above to obtain the target molecule I. Other variations described herein include converting the ester of intermediate 10 to the corresponding carboxylic acid, followed by obtaining intermediate halide 5 by amide coupling with 1, which is then converted by a Suzuki reaction to obtain the target molecule of general structure I after optional deprotection. Scheme 1:

Chem.

[0177] Scheme 1b:

Chem.

[0178] Scheme 2:

Chemical formula

[0179] In one aspect, the present invention provides a method for producing a compound of formula (I) described herein, and this method is: (i) Heteroaryl bromide 5 or 15

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0180] 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 method described herein.

[0181] Use of the compounds of the present invention As shown in the experimental section, the compounds of formula (I) and their pharmaceutically acceptable salts have valuable pharmacological properties for the treatment or prevention of infectious diseases and diseases resulting therefrom, caused by pathogens, in particular by bacteria, more particularly by Acinetobacter species, and most particularly by Acinetobacter baumannii, in particular septicemia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0182] The compounds of formula (I) and their pharmaceutically acceptable salts exhibit activity as antibiotics, in particular as antibiotics against Acinetobacter species, more particularly as antibiotics against Acinetobacter baumannii, and most particularly as pathogen-specific antibiotics against Acinetobacter baumannii.

[0183] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as antibacterial pharmaceutical components suitable for the treatment and prevention of bacterial infections, in particular for the treatment and prevention of bacterial infections caused by Acinetobacter species, more particularly for the treatment and prevention of bacterial infections caused by Acinetobacter baumannii, i.e., as antibiotics.

[0184] The compounds of the present invention can be used alone or in combination with other drugs for the treatment or prevention of infectious diseases and diseases resulting therefrom, caused by pathogens, in particular by bacteria, more particularly by Acinetobacter species, and most particularly by Acinetobacter baumannii, in particular septicemia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0185] In one aspect, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for use as a therapeutic active substance.

[0186] In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for use as an antibiotic. [[ID=2I]]

[0187] 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 diseases caused thereby.

[0188] In certain embodiments, the nosocomial infections and diseases caused thereby are selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, or combinations thereof.

[0189] 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 caused by Gram-negative bacteria and diseases caused thereby.

[0190] In certain embodiments, the infections caused by Gram-negative bacteria and diseases caused thereby are selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, or combinations thereof.

[0191] 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 caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, and diseases caused thereby.

[0192] In a further aspect, the present invention provides a method for the treatment or prevention of infections caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, and diseases caused thereby, the method comprising administering to a mammal a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0193] 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.

[0194] 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 an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, and a disease resulting therefrom.

[0195] 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 a medicament useful for the treatment or prevention of an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, and a disease resulting therefrom.

[0196] In certain embodiments, the infectious disease and the disease resulting therefrom caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection, or a combination thereof.

[0197] In a further aspect, the present invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for the treatment or prevention of an infectious disease and a disease resulting therefrom, in particular bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by a pathogen, in particular a bacterium, more particularly an Acinetobacter species, and most particularly Acinetobacter baumannii.

[0198] In a further aspect, the present invention provides a method for the treatment or prevention of an infectious disease and a disease resulting therefrom, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by a pathogen, particularly a bacterium, more particularly an Acinetobacter species, and most particularly Acinetobacter baumannii, the method comprising administering to a mammal a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0199] In a further aspect, the present invention provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for the treatment or prevention of an infectious disease and a disease resulting therefrom, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by a pathogen, particularly a bacterium, more particularly an Acinetobacter species, and most particularly Acinetobacter baumannii.

[0200] In a further aspect, the present invention provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of an infectious disease and a disease resulting therefrom, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by a pathogen, particularly a bacterium, more particularly an Acinetobacter species, and most particularly Acinetobacter baumannii. Such a medicament comprises a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0201] Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable additives. Exemplary pharmaceutical compositions are described in Examples 163, 164, 165, and 166.

[0202] In a further aspect, the present invention provides a pharmaceutical composition for the treatment or prevention of infectious diseases and diseases caused thereby, in particular bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, caused by pathogens, in particular bacteria, more particularly by Acinetobacter species, and most particularly by Acinetobacter baumannii, comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable additives.

[0203] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as a medicament (for example in the form of a pharmaceutical preparation). The pharmaceutical preparation can be administered internally, for example orally (for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), intranasally (for example in the form of nasal sprays) or rectally (for example in the form of suppositories). However, administration can also be carried out parenterally, for example intramuscularly or intravenously (for example in the form of injection solutions or infusions).

[0204] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic additives for the manufacture of tablets, coated tablets, dragees, and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, as such additives for tablets, dragees and hard gelatin capsules.

[0205] Additives suitable for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0206] Additives suitable for the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0207] Suitable additives for injection solutions are, for example, water, alcohol, polyols, glycerol, vegetable oils, etc.

[0208] Additives suitable for suppositories are, for example, natural oils or hardened oils, waxes, fats, semi-solid or liquid polyols, and the like.

[0209] Furthermore, the pharmaceutical preparation can contain preservatives, solubilizers, thickening substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparation can further contain other therapeutically active substances.

[0210] The dosage can be varied within wide limits and, of course, will be adjusted to the individual requirements in each particular case. Generally, in the case of oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (for example, about 300 mg per person), which can preferably consist of the same amount and is preferably divided into 1 to 3 individual doses, will be appropriate. However, the upper limit described herein may be exceeded when indicated.

[0211] Co - administration of the compound of formula (I) with other drugs The compound of formula (I) or a salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof can be used for treatment alone or in combination with other drugs. For example, the second drug of the combination pharmaceutical preparation or dosing regimen can have complementary activity with respect to the compound of formula (I) so as not to have an adverse effect on each other. The compounds can be administered together or separately within one pharmaceutical composition. In one embodiment, the compound or pharmaceutically acceptable salt can be co - administered with an antibiotic, in particular, for the treatment or prevention of infectious diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, and diseases resulting therefrom.

[0212] The term "co-administering" refers to the simultaneous administration, or separate sequential administration in any manner, of one or more additional pharmaceutical active ingredients, including a compound of formula (I) or a salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an antibiotic formulation. If the administrations are not simultaneous, the compounds are administered in close temporal proximity to each other. Further, it is not important whether the compounds are administered in the same dosage form, for example, one compound may be administered intravenously and another compound may be administered orally.

[0213] Typically, agents having antibacterial activity can be co-administered. Specific examples of such agents are carbapenem (meropenem), fluoroquinolone (ciprofloxacin), aminoglycoside (amikacin), tetracycline (tigecycline), colistin, sulbactam, sulbactam + dulobactam, cefiderocol (fetroja), macrolide peptide, and macrolide (erythromycin), as exemplified, for example, in WO 2017 / 072062, WO 2019 / 185572, and WO 2019 / 206853.

[0214] In one aspect, the present invention provides a pharmaceutical composition described herein further comprising an additional therapeutic agent.

[0215] In one aspect, the present invention provides a pharmaceutical combination comprising a compound of formula (I) described herein and an additional therapeutic agent.

[0216] In one embodiment, the additional therapeutic agent is an antibiotic formulation.

[0217] In one embodiment, the additional therapeutic agent is an antibiotic formulation useful for the treatment or prevention of an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, and a disease resulting therefrom.

[0218] In one embodiment, the additional therapeutic agent is an antibiotic preparation selected from carbapenem (meropenem), fluoroquinolone (ciprofloxacin), aminoglycoside (amikacin), tetracycline (tigecycline), colistin, sulbactam, sulbactam + dulbactam, cefiderocol (fetroja), macrocyclic peptide, and macrolide (erythromycin), as exemplified in WO 2017 / 072062, WO 2019 / 185572, and WO 2019 / 206853.

Examples

[0219] The present invention will be more fully understood by reference to the following examples. However, the claims should not be construed as limited to the scope of the examples.

[0220] When a preparation example is obtained as a mixture of enantiomers, the pure enantiomers can be separated by the methods described herein or methods known to those skilled in the art, for example, by chiral chromatography (e.g., chiral SFC) or crystallization.

[0221] All reaction examples and intermediates were prepared under an argon atmosphere unless otherwise noted. The following abbreviations are used herein: (R)-BINAP = (R)-2,2′-bis(diphenylphosphino)-1,1’-binaphthyl, ACN = acetonitrile, aq. = aqueous, Boc = tert-butyloxycarbonyl, Boc-Glu-OtBu = Boc-L-glutamic acid 1-tert-butyl ester, Boc-Glu(OtBu)-OH = N-α-t.-Boc-L-glutamic acid γ-t.-butyl ester, Boc-Orn(Z)-OH = Nα-Boc-Nδ-Cbz-L-ornithine, Nα-Boc-Nδ-Z-L-ornithine, Nδ-Z-Nα-Boc-L-ornithine, BrettPhos-Pd-G3 = [(2-Di-cyclohexylphosphino-3,6-dimethoxy 2′,4′,6′-triisopropyl 1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate methanesulfonate, CAS = Chemical Abstracts Registry Number, Cs2CO3 = cesium carbonate, DCM = dichloromethane, DIAD = diisopropyl azodicarboxylate, DIPEA = ethyldiisopropylamine, DMA = N,N-dimethylacetamide, DMAP = 4-(dimethylamino)-pyridine, DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide, DMSO-d6 = deuterated dimethyl sulfoxide, EA = ethyl acetate, EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, EI = electron impact, ESI = electrospray ionization, ESI+ = electrospray ionization positive (mode), ESP = electrospray ionization positive (mode), Et2O = diethyl ether, Et3N = triethylamine, EtOAc = ethyl acetate, EtOH = ethanol, FA = formic acid, Fmoc-Agp(Boc)2-OH = N-α-Fmoc-N,NA-γ-di-t.-Butoxycarbonyl-L-diaminobutanoic acid, Fmoc-Arg(Boc)2-OH = N-α-Fmoc-N-ω,N-ωA-bis-t-butoxycarbonyl-L-arginine, H2 = hydrogen, time = time, HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HCl = hydrochloric acid, HFIP = 1,1,1,3,3,3-hexafluoroisopropanol, H2O = water, HOBt = 1-hydroxy-1H-benzotriazole, HPLC = high performance liquid chromatography, HV = high vacuum, ISN = ion spray negative (mode), K2CO3 = potassium carbonate, KI = potassium iodide, KOH = potassium hydroxide, K3PO4 = tripotassium phosphate, LC-MS = liquid chromatography mass spectrometry, LiOH = lithium hydroxide, MeOH = methanol, MgSO4 = magnesium sulfate, min = minute, mL = milliliter, MS = mass spectrometry, MTBE = tert.-butyl methyl ether, N2 = nitrogen, Na2CO3 = sodium carbonate, Na2SO3 = sodium sulfite, Na2SO4 = sodium sulfate, Na2S2O3 = sodium thiosulfate, NEt3 = triethylamine, NaHCO3 = sodium bicarbonate, NaOH = sodium hydroxide, NH4Cl = ammonium chloride, NiCl2.6H2O = nickel(II) chloride hexahydrate, NMO = N-methylmorpholine N-oxide, NMP = N-methyl-2-pyrrolidone, Pd / C = palladium on activated carbon, Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0), PdCl2(PPh3)2 = bis(triphenylphosphine)palladium(II) dichloride, Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), PdCl2(dppf)-CH2Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, PE = petroleum ether, PhI(OAc)2 = (diacetoxyiodo)benzene, PPA = polyphosphoric acid, pTsOH = p-toluenesulfonic acid, Rf = retention factor, RM = reaction mixture, RT = room temperature, SOCl2 = thionyl chloride, SFC = supercritical fluid chromatography, TBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate, T3P = propylphosphonic anhydride, t-Bu-X-phos = 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, TEA = triethylamine, TEMPO = (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, TFA = trifluoroacetic acid, THF = tetrahydrofuran, prep-TLC = preparative thin layer chromatography, UV = ultraviolet light.

[0222] Example 1 N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide hydrochloride

Chemical formula

[0223] Step 1) tert-butyl 4-(4-amino-2-chloro-benzoyl)piperazine-1-carboxylate 4-Amino-2-chlorobenzoic acid (1.5 g, 8.74 mmol, Eq: 1), tert-butyl piperazine-1-carboxylate (2.44 g, 13.1 mmol, Eq: 1.50), and DIPEA (3.39 g, 4.58 ml, 26.2 mmol, Eq: 3.00) were combined with DMF (8.7 ml) to obtain a brown solution. HATU (4.99 g, 13.1 mmol, Eq: 1.50) was added, and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with EtOAc. After drying over Na2SO4, filtering, and evaporation of the volatiles, the product was used in the next step without further purification. MS (ESI, m / z): 340.2 [M+H] +

[0224] Step 2) (4-Amino-2-chlorophenyl)(piperazin-1-yl)methanone dihydrochloride tert-Butyl 4-(4-amino-2-chlorobenzoyl)piperazine-1-carboxylate (2.97 g, 8.74 mmol, Eq: 1) was combined with DCM (15 ml) to obtain a brown solution. 4M HCl in dioxane (10.9 ml, 43.7 mmol, Eq: 5.00) was added (exothermic reaction, controlled with a cooling bath), and the reaction mixture was stirred at RT overnight. Ether was added to the reaction mixture, the solid was filtered off, and dried under HV to obtain the desired product (5.47 g) as a light brown solid. MS (ESI, m / z): 240.1 [M+H] +

[0225] Step 3) tert-Butyl 4-(4-(4-amino-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (4-Amino-2-chlorophenyl)(piperazin-1-yl)methanone dihydrochloride (2.7 g, 8.64 mmol, Eq: 1), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.18 g, 9.5 mmol, Eq: 1.10) and DIPEA (4.47 g, 6.03 ml, 34.5 mmol, Eq: 4.00) were combined with DMF (10 ml) to obtain a brown solution. HATU (4.93 g, 13 mmol, Eq: 1.50) was added and the reaction was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with EtOAc. After drying over Na2SO4, filtering and evaporation of the volatiles, the crude product was dried and used in the next step without further purification. MS (ESI, m / z): 351.2 [M - Boc + H] +

[0226] Step 4) tert-Butyl 4-(4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate tert-Butyl 4-(4-(4-amino-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (3.8 g, 8.43 mmol, Eq: 1), 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid (CAS 1520621-24-2: 1.81 g, 8.85 mmol, Eq: 1.05) and DIPEA (4.36 g, 5.89 ml, 33.7 mmol, Eq: 4.00) were combined with DMF (10 ml) to obtain a brown solution. HATU (4.81 g, 12.6 mmol, Eq: 1.50) was added and the reaction was stirred at RT. Water was added to the reaction mixture and the mixture was extracted with AcOEt. After drying over Na2SO4, filtering and evaporation of the volatiles, the product was purified by flash chromatography (silica gel, 80 g, 0% - 50% MeOH in DCM) to give the title compound (4.41 g) as a light brown foam.

[0227] Step 5) tert-Butyl 4-(4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate tert-Butyl 4-(4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (750 mg, 1.18 mmol, Eq: 1), (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (317 mg, 1.76 mmol, Eq: 1.50), Na2CO3 (249 mg, 2.35 mmol, Eq: 2.00) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (96 mg, 118 μmol, Eq: 0.10) were combined with dioxane (15 ml) and water (1.5 ml) to obtain an orange suspension. The reaction mixture was stirred at 100 °C overnight. Additional (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (211 mg, 1.18 mmol, Eq: 1) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (96 mg, 118 μmol, Eq: 0.10) were added and the reaction mixture was heated again at 100 °C overnight. Again, (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (211 mg, 1.18 mmol, Eq: 1) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (96 mg, 118 μmol, Eq: 0.10) were added and the reaction was stirred at 100 °C overnight. After cooling to RT, the reaction mixture was adsorbed onto Isolute-HM-N and purified by flash chromatography (silica gel, 40 g, 0% - 50% MeOH in DCM) to give the title compound (235 mg) as a brown solid. MS (ESI, m / z): 691.6 [M-H] -

[0228] Project 6) N-(3-Chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide dihydrochloride tert-Butyl 4-(4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (28 mg, 40.4 μmol, Eq: 1) was combined with DCM (50 μl) to obtain a light brown solution. 4M HCl in dioxane (50.5 μl, 202 μmol, Eq: 5.00) was added and the reaction mixture was stirred at RT for 1.5 h. After removal of the volatiles, the product was lyophilized to give the title compound (25 mg) as a light brown solid. MS (ESI, m / z): 593.2 [M+H]+

[0229] Example 2 N-(3-Chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide hydrochloride [Chemical Structure]

[0230] Step 1) tert-Butyl 4-[4-[2-chloro-4-[[1-methyl-5-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate tert-Butyl 4-(4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (50 mg, 72.1 μmol, Eq: 1) and K2CO3 (19.9 mg, 144 μmol, Eq: 2.00) were combined with DMF (500 μl) to give a brown suspension. 2-Bromo-1,1,1-trifluoroethane (14 mg, 86.6 μmol, Eq: 1.20) was added and the reaction mixture was heated to 40 °C and stirred overnight. Stirring was continued at 80 °C for 1 h and then at 50 °C overnight. H2O was added to the mixture and the mixture was extracted with EtOAc. The combined organic layers were concentrated and the residue was purified by preparative HPLC to give the title product (21 mg). MS (ESI, m / z): 776.6 [M+H] +

[0231] [[ID=~4]] Step 2) N-(3-Chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide hydrochloride 4 M HCl in dioxane (37.5 μl, 150 μmol, Eq: 5) was added to a solution of tert-butyl 4-[4-[2-chloro-4-[[1-methyl-5-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (21 mg) in DCM (100 μl). The mixture was stirred overnight, additional 4 M HCl in dioxane (7 uL) was added and the mixture was stirred again overnight. The mixture was concentrated and dried by lyophilization to give the title compound (17 mg). MS (ESI, m / z): 673.6 [M-H] -

[0232] In the same manner as the above procedure, the following examples were obtained:

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

[0233] Example 29 1-Methyl-N-(3-methyl-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide dihydrochloride

Chemical formula

[0234] Step 1) tert-Butyl 4-(4-(2-methyl-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate From 4-amino-2-methyl-benzoic acid, in the same manner as in Example 1, Steps 1-5, the title compound (370 mg) was obtained as a brown solid. MS (ESI, m / z): 671.6 [M-H] -

[0235] Step 2) 1-Methyl-N-(3-methyl-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide dihydrochloride From tert-butyl 4-(4-(2-methyl-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate, in the same manner as in Example 1, Step 6, the title compound (28.8 mg) was obtained as a light brown solid. MS (ESI, m / z): 573.3 [M+H]+

[0236] Example 30 5-(1-(Cyanomethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-N-(3-methyl-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1H-imidazole-2-carboxamide

Chemical Structure

[0237] Example 31 (R)-N-(3-chloro-4-((pyrrolidin-3-ylmethyl)carbamoyl)phenyl)-1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide hydrochloride[[ID=A]] [[ID=B]]

Chemical formula

[0238] Step 1) Methyl 4-(5-bromo-1-methyl-1H-imidazole-2-carboxamide)-2-chlorobenzoate 5-Bromo-1-methyl-1H-imidazole-2-carboxylic acid (CAS 1520621-24-2, 2.8 g, 13.7 mmol, Eq: 1), methyl 4-amino-2-chlorobenzoate (2.53 g, 13.7 mmol, Eq: ½), HATU (6.23 g, 16.4 mmol, Eq: 1.2) were dissolved in DMF (20 ml) and cooled to 0 °C. DIPEA (7.06 g, 9.54 ml, 54.6 mmol, Eq: 4) was added and the reaction mixture was stirred at r.t. for 3 h. The mixture was cooled to 0 °C and water was added. The mixture was filtered to obtain the desired product (4.35 g) as an off-white solid. MS (ESI, m / z): 372.2 [M+H] +

[0239] Step 2) Methyl 2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoate Methyl 4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoate (3.3 g, 8.86 mmol, Eq: 1), (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (1.59 g, 8.86 mmol, Eq: 1) and Na2CO3 (2.16 g, 20.4 mmol, Eq: 2.30) were dissolved in dioxane (20 ml) and water (2 ml). 1,1'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (577 mg, 886 μmol, Eq: 0.1) was added. The solution was divided into three 25 ml microwave shield tubes and each was heated with microwave at 100 °C for 30 min. Additional (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (797 mg, 4.43 mmol, Eq: 0.5) and 1,1'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (289 mg, 443 μmol, Eq: 0.05) were added to the three vials individually. The reaction mixtures were combined, filtered through celite and washed with MeOH. The product was purified by chromatography (silica gel, 120 g, 0% - 10% MeOH in DCM) to give the title compound (2.85 g) as a brown solid. MS(ESI, m / z): 428.2[M+H] +

[0240] Step 3) Intermediate 2 2-Chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoic acid Methyl 2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoate (2.8 g, 6.55 mmol, Eq: 1) and lithium hydroxide hydrate (549 mg, 13.1 mmol, Eq: 2) were dissolved in THF (20 ml) and water (10 ml). The mixture was stirred overnight at RT. The organic solvent was evaporated in vacuo. HCl (1.0 M aq) (13.1 ml, 13.1 mmol, Eq: 2) was added to adjust the pH to 3. The desired product (2.5 g), which precipitated as a light brown solid, was filtered and washed with diethyl ether. MS (ESI, m / z): 414.2 [M+H] +

[0241] The following intermediates were prepared similarly:

Table 2

[0242] Step 4) tert-Butyl (S)-3-((2-chloro-4-(1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzamide)methyl)pyrrolidine-1-carboxylate In a 5 mL sealed tube, 2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoic acid (50 mg, 121 μmol, Eq: 1) and DIPEA (46.9 mg, 63.3 μl, 363 μmol, Eq: 3.00) were combined with DMF (500 μl) to obtain a brown suspension. HATU (59.7 mg, 157 μmol, Eq: 1.30) was added, and after stirring for 10 min, tert-butyl (S)-3-(aminomethyl)pyrrolidine-1-carboxylate (29 mg) was added. The reaction mixture was stirred at RT for 2 h. Then water was added, and the product was extracted with DCM. After removal of the volatile substances, the intermediate was used in the next step without further purification.

[0243] (R)-N-(3-chloro-4-((pyrrolidin-3-ylmethyl)carbamoyl)phenyl)-1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide hydrochloride From tert-butyl (S)-3-((2-chloro-4-(1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzamide)methyl)pyrrolidine-1-carboxylate, in the same manner as in Example 3, the title compound (8 mg) was obtained. MS (ESI, m / z): 532.4 [M-H] -

[0244] The following examples were obtained in the same manner:

Table 3-1

Table 3-2

Table 3-3

[0245] Example 36 N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide hydrochloride

Chemical formula

[0246] Step 1) N-(3-Chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide 2,2,2-trifluoroacetate tert-Butyl 4-(2-chloro-4-(1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzoyl)piperazine-1-carboxylate (Example 34, 1.15 g, 1.85 mmol, Eq: 1) was dissolved in DCM (12 ml). TFA (2.11 g, 1.43 ml, 18.5 mmol, Eq: 10) was added. The reaction mixture was stirred overnight at RT. The organic solvent was removed in vacuo. The residue was triturated with diethyl ether. The precipitate was filtered off to afford the crude title compound (1.16 g) as an off-white solid. MS (ESI, m / z): 520.3 [M+H] +

[0247] Step 2) tert-Butyl (2S,4R)-2-(4-(2-chloro-4-(1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate HATU (43.9 mg, 115 μmol, Eq: 2) was added to a mixture of N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide 2,2,2-trifluoroacetate (30 mg), DIPEA (37.3 mg, 50.4 μl, 289 μmol, Eq: 5) and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (13 mg) in DMF (400 uL). The mixture was stirred overnight and purified by preparative HPLC to afford the title compound (14 mg).

[0248] Step 3) N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; hydrochloride tert-Butyl tert-butyl (2S,4R)-2-(4-(2-chloro-4-(1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate (12 mg, 16.4 μmol, Eq: 1) was combined with DCM (0.4 ml). 4 M HCl in dioxane (20.5 μl, 81.8 μmol, Eq: 5) was added. The reaction mixture was stirred at RT for 4 h. After removal of volatiles, the product was redissolved in water / ACN and then lyophilized to give the title compound (9.1 mg) as a white solid. MS (ESI, m / z): 633.4 [M+H] +

[0249] The following examples were obtained similarly:

Table 4-1

Table 4-2

Table 4-3

[0250] Example 41 N-(4-carbamoyl-3-chlorophenyl)-1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide

Chemical Structure

[0251] Step 1) tert-Butyl 2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoate From tert-butyl 4-amino-2-chlorobenzoate, in the same manner as in Example 31, Step 1-2, the title compound was obtained as an orange solid. MS (ESI, m / z): 470.4 [M+H] +

[0252] Step 2) tert-Butyl 2-chloro-4-(1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoate tert-Butyl 2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoate (470 mg, 1 mmol, Eq: 1) and K2CO3 (276 mg, 2 mmol, Eq: 2.00) were combined with DMF (5 ml) to obtain a white suspension. 3-Bromoprop-1-yne (119 mg, 89.1 μl, 1 mmol, Eq: 1) was added, and the reaction mixture was stirred at RT for 6 h. Additional 3-bromoprop-1-yne (23.8 mg, 17.8 μl, 200 μmol, Eq: 0.2) was added and stirred for 20 min. The reaction mixture was poured into 25 mL of H2O and extracted with EtOAc (3×25 mL), and then extracted with 25 ml of saturated NaCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% - 100% DCM : (DCM / MeOH 9 / 1)) to obtain the title compound (382.1 mg) as an off-white solid. MS (ESI, m / z): 508.3 [M+H] +

[0253] Step 3) Intermediate 3 2-Chloro-4-(1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoic acid trifluoroacetate tert-Butyl 2-chloro-4-(1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoate (330 mg, 650 μmol, Eq: 1) was dissolved in DCM (4 ml). TFA (741 mg, 501 μl, 6.5 mmol, Eq: 10) was added. The reaction mixture was stirred overnight at RT. The organic solvent was removed in vacuo. The residue was triturated in diethyl ether. The precipitate was filtered off to afford the crude title compound (260.2 mg) as an off-white solid. MS (ESI, m / z): 450.3 [M+H] +

[0254] Step 4) N-(4-Carbamoyl-3-chlorophenyl)-1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide HATU (40 mg) was added to a mixture of 2-chloro-4-(1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoic acid trifluoroacetate (30 mg), DIPEA (50 uL) and 25% aq NH3 (10 uL) in DMF (400 uL). The mixture was stirred for 4.5 h and then purified by preparative HPLC to afford the title compound (6 mg) as a white solid. MS (ESI, m / z): 451.2 [M+H] +

[0255] The following examples were obtained in the same manner:

Table 5-1

Table 5-2

Table 5-3

Table 5-4

Table 5-5

Table 5-6

[0256] Example 51 N-(Azetidin-3-yl)-4-(2-chloro-4-(1-methyl-5-(1-(prop-2-yn-1-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamide hydrochloride

Chemical formula

[0257] The following examples were obtained in the same manner:

Table 6-1

Table 6-2

[0258] Example 54 N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-5-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide hydrochloride

Chemical formula

[0259] Example 55 N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide

Chemical Structure

[0260] Step 1) Methyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate 5-Bromo-1-methyl-1H-imidazole-2-carboxylic acid (CAS 1520621-24-2: 800 mg, 3.9 mmol, Eq: 1), methyl 4-amino-2-chlorobenzoate (724 mg, 3.9 mmol, Eq: 1), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (1.63 g, 4.29 mmol, Eq: 1.1), and DIPEA (1.51 g, 2.04 mL, 11.7 mmol, Eq: 3) in DMF (25 mL) were stirred at room temperature for 1 h. The mixture was then poured into water. The aqueous phase was extracted with DCM (3 × 25 mL). The combined organic phases were washed with water, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography to afford the title compound as a yellow solid (0.75 g). MS (ESI, m / z): 371.8 [M+H] +

[0261] Step 2) 4-[(5-Bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoic acid Methyl 4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoate (5 g, 13.4 mmol, Eq: 1) and lithium hydroxide monohydrate (1.69 g, 40.3 mmol, Eq: 3) in MeOH (30 mL), THF (15 mL), and water (10 mL) were stirred at room temperature overnight. The mixture was then acidified with 1 N HCl. The white precipitate was collected, washed with water, and dried in vacuo to afford the title compound as a white solid (4.5 g). MS (ESI, m / z): 357.7 [M+H]+

[0262] Step 3) tert-Butyl 4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carboxylate At room temperature, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2,4,6-trioxide (887 mg, 2.79 mmol, Eq: 2) was added to a mixture of 4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoic acid (500 mg, 1.39 mmol, Eq: 1), tert-butyl piperazine-1-carboxylate (312 mg, 1.67 mmol, Eq: 1.2) and DIPEA (541 mg, 731 μl, 4.18 mmol, Eq: 3) in DMF (5 ml). After stirring for 2 h, the reaction mixture was poured into water. The aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as an oil (500 mg). MS (ESI, m / z): 526.2 [M+H]+

[0263] Step 4) 5-Bromo-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-imidazole-2-carboxamide At room temperature, a solution of tert-butyl 4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxylate (750 mg, 1.42 mmol, Eq: 1) in TFA (10 mL) and CH2Cl2 (10 mL) was stirred for 2 h. The mixture was then concentrated and water (10 mL) was added. The mixture was basified to pH 8 - 9 with K2CO3. The aqueous phase was extracted with DCM (3 × 10 mL). The combined organic phases were washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (500 mg) as a yellow oil. MS (ESI, m / z): 426.2 [M+H]+

[0264] Step 5) tert-Butyl (2S,4R)-2-[4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-4-hydroxy-pyrrolidine-1-carboxylate At room temperature, a mixture of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (325 mg, 1.41 mmol, Eq: 1.2), 5-bromo-N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-1H-imidazole-2-carboxamide (500 mg, 1.17 mmol, Eq: 1), HATU (490 mg, 1.29 mmol, Eq: 1.1) and DIPEA (454 mg, 614 μl, 3.52 mmol, Eq: 3) in DMF (5 ml) was stirred for 1 h. Then the mixture was poured into water. The aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (650 mg). The crude product was used in the next step reaction without further purification. MS (ESI, m / z): 639.3 [M+H]+

[0265] Step 6)[[ID='5']] tert-butyl (2S,4R)-2-[4-[2-chloro-4-[[1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-hydroxy-pyrrolidine-1-carboxylate tert-Butyl (2S,4R)-2-(4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate (300 mg, 469 μmol, Eq: 1), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (90.9 mg, 469 μmol, Eq: 1), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (30.6 mg, 46.9 μmol, Eq: 0.1) and Na2CO3 (149 mg, 1.41 mmol, Eq: 3) in 1,4-dioxane (4 ml) and water (0.4 ml) were sonicated under microwave at 100 °C for 1 h. The solution was then filtered and concentrated. The residue was dissolved in DCM. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (300 mg). The crude product was used in the next step reaction without further purification. MS (ESI, m / z): 709.6 [M+H]+

[0266] Step 7) N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-[-4-yl]imidazole-2-carboxamide 6N HCl (3 mL), then 12N HCl (6 mL) were added to a solution of tert-butyl (2S,4R)-2-(4-(2-chloro-4-(1-methyl-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate (300 mg, 423 μmol, Eq: 1) in THF (5 ml) and stirred at room temperature for 20 min. Then under ice-cooling, the pH was neutralized using aqueous ammonia solution. The aqueous layer was extracted with a mixture of iPrOH and DCM (1:6). The organic layer was concentrated and the residue was purified by preparative HPLC to give the title compound (90 mg). MS (ESI, m / z): 609.43 [M+H]+

[0267] Example 56 N-[3-Chloro-4-[4-(4-Hydroxy-piperidine-4-carbonyl)-piperazine-1-carbonyl]-phenyl]-1-methyl-5-[1-methyl-3-(trifluoromethyl)-pyrazol-4-yl]-imidazole-2-carboxamide 2,2,2-trifluoroacetate

Chemical formula

[0268] Step 1) tert-Butyl 4-[4-[4-[(5-Bromo-1-methyl-imidazole-2-carbonyl)-amino]-2-chloro-benzoyl]-piperazine-1-carbonyl]-4-hydroxy-piperidine-1-carboxylate At room temperature, a mixture of 5-bromo-N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-1H-imidazole-2-carboxamide (300 mg, 703 μmol, Eq: 1), 1-(tert-butoxycarbonyl)-4-hydroxy-piperidine-4-carboxylic acid (259 mg, 1.05 mmol, Eq: 1.5), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (401 mg, 1.05 mmol, Eq: 1.5) and DIPEA (454 mg, 614 μl, 3.52 mmol, Eq: 5) in DMF (5 ml) was stirred overnight. The mixture was then poured into water. The aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product (300 mg), which was used in the next step reaction without further purification. MS(ESI, m / z): 653.4[M+H]+

[0269] Step 2) tert-Butyl 4-[4-[2-chloro-4-[[1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-hydroxy-piperidine-1-carboxylate A mixture of tert-butyl 4-(4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbonyl)-4-hydroxypiperidine-1-carboxylate (200 mg, 306 μmol, Eq: 1), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (89 mg, 459 μmol, Eq: 1.5), Na2CO3 (97.2 mg, 917 μmol, Eq: 3) and palladium(II) dichloride complex with 1,1'-bis(di-tert-butylphosphino)ferrocene (19.9 mg, 30.6 μmol, Eq: 0.1) in 1,4-dioxane (4 ml) and water (0.4 ml) was irradiated under microwave at 100 °C for 1 h. Then the solution was filtered and concentrated. The residue was dissolved in DCM. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product (200 mg) which was used in the next step reaction without further purification. MS (ESI, m / z): 723.6 [M+H]+

[0270] Step 3) N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide 2,2,2-trifluoroacetate At room temperature, a solution of tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)-4-hydroxypiperidine-1-carboxylate (200 mg, 277 μmol, Eq: 1) in DCM (5 ml) and TFA (5 ml) was stirred for 1 h. Then the solution was poured into water, and the aqueous phase was basified with aqueous ammonia. The aqueous layer was extracted with a mixture of DCM and iPrOH (6:1). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC to obtain the title compound (34 mg). MS (ESI, m / z): 623.4 [M+H]+

[0271] Example 57 N-(4-((2-(2-Aminoethoxy)ethyl)carbamoyl)-3-ethylphenyl)-1-methyl-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide hydrochloride

Chemical formula

[0272] Step 1) Methyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-ethyl-benzoate A white suspension of 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid (commercially available) (935 mg, 4.56 mmol, Eq: 1) in DMF (10 mL) at room temperature was treated with HATU (1.91 g, 5.02 mmol, Eq: 1.1) and 1.6 mL of DIPEA (2 eq). Methyl 4-amino-2-ethylbenzoate (826 mg, 4.61 mmol, Eq: 1.01) and 800 μL of DIPEA (1 eq) were added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine / water 1:1 (3 × 80 mL) and dried over Na2SO4. The crude material was absorbed onto Isolute HM-N and purified by flash chromatography on silica eluting with a gradient formed from heptane and ethyl acetate. After evaporation of the fractions containing the product, the title compound (1.057 g, 63%) was obtained as a white solid. (ESI, m / z): 366.1 [M+H] + .

[0273] Step 2) Methyl 2-ethyl-4-[[1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoate Methyl 4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-ethylbenzoate (50 mg, 137 μmol, Eq: 1), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (49 mg, 177 μmol, Eq: 1.3), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.99 mg, 13.7 μmol, Eq: 0.1) and Na2CO3 (28.9 mg, 273 μmol, Eq: 2) in a mixture of dioxane (1 mL) and water (0.1 mL) was stirred at 100 °C overnight. The crude mixture was absorbed on Isolute HM-N and purified by flash column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate. The fractions containing the product were evaporated to give the title compound (50.8 mg, 85%) as a waxy brown solid. (ESI, m / z): 436.3 [M+H] + .

[0274] Step 3) 2-Ethyl-4-[[1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoic acid To a clear solution of methyl 2-ethyl-4-(1-methyl-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoate (45.8 mg, 105 μmol, Eq: 1) in THF (600 μL), water (300 μL) and MeOH (30 μL) was added NaOH (10.0 mg, 250 μmol, Eq: 2.38) and the mixture was stirred at 70 °C for 24 h. The organic solvent was removed, the residue was diluted with water (3 mL) and 0.1 M HCl(aq) was added dropwise to pH 5 - 6. The mixture was extracted with ethyl acetate (2 × 25 mL), the organic layer was washed with water (2 × 20 mL), dried over Na2SO4, filtered off and evaporated to give the title compound (41.2 mg, 93%) as off-white crystals. (ESI, m / z): 422.2 [M+H] + .

[0275] Step 4 tert-Butyl N-[2-[2-[[2-Ethyl-4-[[1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]ethoxy]ethyl]carbamate To a solution of 2-ethyl-4-(1-methyl-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzoic acid (20 mg, 47.5 μmol, Eq: 1) in DMF (1 mL) and NEt3 (24 mg, 33.1 μl, 237 μmol, Eq: 5) at room temperature was added TBTU (17.5 mg, 54.6 μmol, Eq: 1.15), and the mixture was shaken for 30 min. tert-Butyl (2-(2-aminoethoxy)ethyl)carbamate (10.7 mg, 52.2 μmol, Eq: 1.1) was added, and the pale brown transparent mixture was shaken overnight. The mixture was acidified with formic acid (50 uL) and purified by reverse-phase preparative HPLC eluting with a gradient formed from acetonitrile, water and formic acid. The fractions containing the product were evaporated to give the title compound (23.4 mg, 81%) as a colorless solid. (ESI, m / z): 608.4 [M+H] + .

[0276] Step 5 To a solution of tert-butyl (2-(2-(2-ethyl-4-(1-methyl-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzamide)ethoxy)ethyl)carbamate (23 mg, 37.9 μmol, Eq: 1) in DCM (2 mL) was added HCl (4 M) in dioxane (57 μl, 228 μmol, Eq: 6.02), and the mixture was stirred for 16 h, evaporated and dried to give the title compound (20.2 mg, 98%) as a pale brown solid. (ESI, m / z): 508.3 [M+H] + .

[0277] Example 58 N-(3-Chloro-4-((4-(dimethylglycyl)piperazin-1-yl)sulfonyl)phenyl)-1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide

Chem.

[0278] Step 1) tert-Butyl 4-(2-chloro-4-nitro-phenyl)sulfonylpiperazine-1-carboxylate To a solution of tert-butyl piperazine-1-carboxylate (2.37 g, 12.7 mmol, Eq: 1.05) and N-ethyl-N-isopropylpropan-2-amine (3.14 g, 4.24 mL, 24.3 mmol, Eq: 2) in DMF (120 mL), 2-chloro-4-nitrobenzenesulfonyl chloride (3.109 g, 12.1 mmol, Eq: 1) in DCM (10 mL) was slowly added and stirred overnight at room temperature. The mixture was diluted with 10% Na2CO3 (150 mL) and water (150 mL). The mixture was extracted with DCM (2 × 150 mL), the organic layer was dried over MgSO4, filtered, and evaporated. The residue was absorbed on Isolute HM-N, dried, and purified by flash chromatography on silica eluting with a gradient formed from heptane and ethyl acetate. The product-containing fractions were evaporated to give the title compound (4.27 g, 87%) as an orange solid. (ESI, m / z): 306.1 [M+H, -Boc] + .

[0279] Step 2) tert-Butyl 4-(4-amino-2-chloro-phenyl)sulfonylpiperazine-1-carboxylate A solution of tert-butyl 4-((2-chloro-4-nitrophenyl)sulfonyl)piperazine-1-carboxylate (2.51 g, 6.18 mmol, Eq: 1) in ethanol (49.2 mL) and water (16.4 mL) was heated to 80 °C, ammonium chloride (1.06 g, 19.8 mmol, Eq: 3.2) and iron (4.28 g, 76.7 mmol, Eq: 12.4) were added, and the mixture was stirred at 80 °C overnight. The hot reaction mixture was filtered (through Dicalite), and the filter was washed with ethanol (3 × 50 mL). The filtrate was evaporated to dryness, adsorbed onto Isolute HM-N, dried, and purified by flash chromatography on silica eluting with a gradient formed from heptane and ethyl acetate. The product-containing fractions were evaporated to give the title compound (2.3 g, 93%) as an orange solid. (ESI, m / z): 276.2 [M+H, -Boc] + .

[0280] Step 3) tert-butyl 4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-phenyl]sulfonylpiperazine-1-carboxylate A mixture of tert-butyl 4-((4-amino-2-chlorophenyl)sulfonyl)piperazine-1-carboxylate (1.2 g, 3.19 mmol, Eq: 1) and triethylamine (1.62 g, 2.22 ml, 16 mmol, Eq: 5) in DCM (20 mL) was treated with 5-bromo-1-methyl-1H-imidazole-2-carbonyl chloride (1.1 g, 3.69 mmol, Eq: 1.16) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was adsorbed onto Isolute HM-N, dried, and purified by flash chromatography on silica eluting with a gradient formed from heptane / ethyl acetate. The product-containing fractions were evaporated to give the title compound (530 mg, 819 μmol, 26%) as an orange solid. (ESI, m / z): 560.3 [M-H] - .

[0281] Step 4) tert-Butyl 4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]phenyl]sulfonylpiperazine-1-carboxylate A mixture of tert-butyl 4-((4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorophenyl)sulfonyl)piperazine-1-carboxylate (200 mg, 355 μmol, Eq: 1), (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (89.5 mg, 497 μmol, Eq: 1.4), Na2CO3 (75.3 mg, 711 μmol, Eq: 2.00) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (29 mg, 35.5 μmol, Eq: 0.10) in dioxane (3 mL) and water (300 μL) was heated at 100 °C overnight. (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (63.9 mg, 355 μmol, Eq: 1.0) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (29 mg, 35.5 μmol, Eq: 0.10) were added, and the reaction mixture was stirred for 5 h. In dioxane (3 mL) and water (300 μL), (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (63.9 mg, 355 μmol, Eq: 1.0) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (29 mg, 35.5 μmol, Eq: 0.10) were added and heated at 100 °C overnight again. The reaction mixture was evaporated, absorbed on Isolute HM-N, dried and purified by flash chromatography on silica eluting with a gradient formed from heptane / ethyl acetate. The product containing fractions were evaporated to give the title compound (144 mg, 207 μmol, 58%) as an orange solid. (ESI, m / z): 618.4 [M+H] + .

[0282] Step 5) N-(3-chloro-4-piperazin-1-ylsulfonyl-phenyl)-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide A solution of tert-butyl 4-((2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)phenyl)sulfonyl)piperazine-1-carboxylate (144 mg, 233 μmol, Eq: 1) in DCM (4.0 mL) and TFA (266 mg, 180 μL, 2.33 mmol, Eq: 10) was stirred at room temperature for 3 h. TFA (118 mg, 80 μL, 1.04 mmol, Eq: 5) was added and the reaction mixture was stirred for 5 h. The mixture was basified by the addition of aq Na2CO3 and then extracted with DCM (3 × 25 mL). The combined organic layers were washed with 10% aq Na2CO3 (2 × 25 mL) and brine (25 mL). The combined aqueous layers were extracted with ethyl acetate (3 × 25 mL) and the organic layers were washed with 10% aq Na2CO3 (2 × 25 mL) and brine (25 mL). The combined organic layers were dried over MgSO4, filtered, evaporated, and the title compound (57 mg, 103 μmol, 44%) was obtained as an orange solid. (ESI, m / z): 516.4 [M+H] + .

[0283] Step 6) N-(3-chloro-4-((4-(dimethylglycyl)piperazin-1-yl)sulfonyl)phenyl)-1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide Dimethylglycine (6.14 mg, 59.5 μmol, Eq: 1.1), (N-(3-chloro-4-(piperazine-1-ylsulfonyl)phenyl)-1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide (28 mg, 54.1 μmol, Eq: 1)), DIPEA (22.2 mg, 30 μl, 172 μmol, Eq: 3.18) and TBTU (19.1 mg, 59.5 μmol, Eq: 1.1) in DMF (1.5 mL) were reacted overnight at room temperature. The mixture was subjected to purification by reverse-phase preparative HPLC eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated and the title compound (5.4 mg, 99%) was obtained. (ESI, m / z): 603.3 [M+H] + .

[0284] Example 59 N-(3-chloro-4-((4-((2S,4R)-4-hydroxypyrrolidine-2-carbonyl)piperazin-1-yl)sulfonyl)phenyl)-1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide hydrochloride

Chemical Structure

[0285] Intermediate 4 tert-Butyl (1-(2-aminoethoxy)-2-methylpropan-2-yl) carbamate

[0286] Step 1: Allyl tert-butyl carbonate To a solution of allyl alcohol (79.84 g, 1375 mmol, 3 eq) and di-tert-butyl dicarbonate (100.0 g, 458.19 mmol, 1 eq), 4-dimethylaminopyridine (11.2 g, 91.64 mmol, 0.200 eq) was slowly added. The mixture was stirred at 25 °C for 2 h. The mixture was diluted with MTBE (1000 mL), washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with petroleum ether to give allyl tert-butyl carbonate (67 g) as a colorless oil. 1 1H NMR (400 MHz, chloroform-d) δ = 6.01 - 5.87 (m, 1H), 5.34 (qd, J = 1.5, 17.2 Hz, 1H), 5.25 (qd, J = 1.5, 10.4 Hz, 1H), 4.56 (td, J = 1.3, 5.9 Hz, 2H), 1.49 (s, 9H) ppm.

[0287] Step 2: tert-Butyl N-(2-allyloxy-1,1-dimethyl-ethyl) carbamate To a mixture of tert-butyl (1-hydroxy-2-methylpropan-2-yl) carbamate (9.0 g, 47.56 mmol, 1 eq) and allyl tert-butyl carbonate (15.05 g, 95.11 mmol, 2 eq) in THF (135 mL), tetrakis(triphenylphosphine)palladium(0) (2.75 g, 2.38 mmol, 0.050 eq) was added. The resulting mixture was stirred at 8°0 C for 16 h under a nitrogen atmosphere. The mixture was concentrated and the residue was purified by silica gel chromatography eluting with petroleum ether:EtOAc = 30:1 to give tert-butyl N-(2-allyloxy-1,1-dimethyl-ethyl) carbamate (8.6 g) as a pale yellow oil. 11H NMR (400 MHz, chloroform-d) δ = 5.83 (tdd, J = 5.5, 10.6, 17.2 Hz, 1H), 5.20 (qd, J = 1.6, 17.2 Hz, 1H), 5.14 - 5.08 (m, 1H), 4.68 (br s, 1H), 3.93 (td, J = 1.4, 5.5 Hz, 2H), 3.30 (s, 2H), 1.36 (s, 9H), 1.23 (s, 6H) ppm.

[0288] Step 3: tert-Butyl N-[2-(2-hydroxyethoxy)-1,1-dimethyl-ethyl]carbamate Ozone was bubbled into a solution of tert-butyl N-(2-allyloxy-1,1-dimethyl-ethyl)carbamate (14.5 g, 63.23 mmol, 1 eq) in pre-cooled DCM (200 mL) at -70 °C until the mixture turned blue. The mixture was warmed to 0 °C, methanol (40 mL) was added, followed by sodium borohydride (4.78 g, 126.46 mmol, 2 eq). The mixture was stirred at 0 °C for 2 h. The mixture was quenched with saturated aqueous solution. NH4Cl, and then the organic phase was separated. The mixture was dried over sodium sulfate and concentrated to give a residue of the crude product. The residue was purified by silica gel chromatography eluting with petroleum ether:EtOAc = 20:1 to 2:1 to give tert-butyl N-[2-(2-hydroxyethoxy)-1,1-dimethyl-ethyl]carbamate (7.5 g) as a colorless oil.

[0289] Step 4: tert-Butyl N-[2-(2-azidoethoxy)-1,1-dimethyl-ethyl]carbamate A solution of tert-butyl N-[2-(2-hydroxyethoxy)-1,1-dimethylethyl]carbamate (7.5 g, 32.15 mmol, 1 eq) and triethylamine (6.72 mL, 48.22 mmol, 1.5 eq) in DCM (90 mL) was treated with methanesulfonyl chloride (3.23 mL, 41.79 mmol, 1.3 eq). The resulting mixture was stirred at 5 °C for 1 h. The mixture was washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. To a solution of the residue (10.0 g, 32.11 mmol, 1 eq) in DMF (75 mL) was added sodium azide (6.26 g, 96.34 mmol, 3 eq). The resulting mixture was stirred at 50 °C for 2.5 h. The mixture was diluted with water (320 mL) and extracted with EtOAc (200 mL * 2), washed with brine (150 mL), dried over sodium sulfate, concentrated, and tert-butyl N-[2-(2-azidoethoxy)-1,1-dimethylethyl]carbamate (6 g) was obtained as a colorless oil and used directly as the crude product.

[0290] Step 5: tert-butyl N-[2-(2-aminoethoxy)-1,1-dimethylethyl]carbamate To a solution of tert-butyl N-[2-(2-azidoethoxy)-1,1-dimethylethyl]carbamate (6.0 g, 23.23 mmol, 1 eq) in EtOAc (65 mL) was added 10% palladium on carbon (494.36 mg, 4.65 mmol, 0.200 eq). The resulting mixture was hydrogenated at 30 °C for 16 h under 760 mm Hg. The catalyst was removed by filtration. The filtrate was concentrated and tert-butyl N-[2-(2-aminoethoxy)-1,1-dimethylethyl]carbamate (4.02 g) was obtained as a colorless oil. 11H NMR (400 MHz, chloroform-d) δ = 5.00 - 4.55 (m, 1H), 3.54 - 3.48 (m, 1H), 3.42 (t, J = 5.2 Hz, 1H), 3.32 (d, J = 6.0 Hz, 2H), 2.79 (t, J = 5.2 Hz, 1H), 2.75 (t, J = 5.3 Hz, 1H), 1.36 (s, 9H), 1.22 (d, J = 4.3 Hz, 6H) ppm.

[0291] Intermediate 5 tert-Butyl N-[(1S)-2-(2-aminoethoxy)-1-methyl-ethyl]carbamate

[0292] Step 1: tert-Butyl N-[(1S)-2-allyloxy-1-methyl-ethyl]carbamate The title compound was obtained in the same manner as in Step 2 of Intermediate 4 using N-Boc-L-alaninol.

[0293] Step 2: tert-Butyl N-[(1S)-2-(2-hydroxyethoxy)-1-methyl-ethyl]carbamate The title compound was obtained in the same manner as in Step 3 of Intermediate 4 using tert-Butyl N-[(1S)-2-allyloxy-1-methyl-ethyl]carbamate.

[0294] Step 3: tert-Butyl N-[(1S)-2-(2-azidoethoxy)-1-methyl-ethyl]carbamate The title compound was obtained in the same manner as in Step 4 of Intermediate 4 using tert-Butyl N-[(1S)-2-(2-hydroxyethoxy)-1-methyl-ethyl]carbamate.

[0295] Step 4: tert-Butyl N-[(1S)-2-(2-aminoethoxy)-1-methyl-ethyl]carbamate The title compound was obtained in the same manner as in Step 5 of Intermediate 4 using tert-Butyl N-[(1S)-2-(2-azidoethoxy)-1-methyl-ethyl]carbamate. 11H NMR (400 MHz, chloroform-d) δ = 4.68 (br s, 1H), 3.76 (br s, 1H), 3.54 - 3.37 (m, 2H), 3.37 - 3.28 (m, 2H), 2.82 - 2.70 (m, 2H), 1.38 (s, 9H), 1.13 - 1.05 (m, 3H) ppm.

[0296] Intermediate 6 tert-Butyl N-[(1R)-2-(2-aminoethoxy)-1-methyl-ethyl]carbamate

[0297] Step 1: tert-Butyl N-[(1R)-2-allyloxy-1-methyl-ethyl]carbamate The title compound was obtained in the same manner as in Step 2 of Intermediate 4 using N-Boc-D-alaninol.

[0298] Step 2: tert-Butyl N-[(1R)-2-(2-hydroxyethoxy)-1-methyl-ethyl]carbamate The title compound was obtained in the same manner as in Step 3 of Intermediate 4 using tert-Butyl N-[(1R)-2-allyloxy-1-methyl-ethyl]carbamate.

[0299] Step 3: tert-Butyl N-[(1R)-2-(2-azidoethoxy)-1-methyl-ethyl]carbamate The title compound was obtained in the same manner as in Step 4 of Intermediate 4 using tert-Butyl N-[(1R)-2-(2-hydroxyethoxy)-1-methyl-ethyl]carbamate.

[0300] Step 4: tert-Butyl N-[(1R)-2-(2-aminoethoxy)-1-methyl-ethyl]carbamate The title compound was obtained in the same manner as in Step 3 of Intermediate 4 using tert-Butyl N-[(1R)-2-(2-azidoethoxy)-1-methyl-ethyl]carbamate. 11H NMR (400 MHz, chloroform-d) δ = 4.89 - 4.58 (m, 1H), 3.75 (br s, 1H), 3.55 - 3.38 (m, 2H), 3.37 - 3.28 (m, 2H), 2.83 - 2.70 (m, 2H), 1.37 (s, 9H), 1.15 - 1.05 (m, 3H) ppm.

[0301] Example 60 N-[3-Chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; Formic acid

Chemical Structure

[0302] Step 1: tert-Butyl 4-(2-chloro-4-nitro-benzoyl)piperazine-1-carboxylate To a solution of 2-chloro-4-nitrobenzoic acid (2.0 g, 9.92 mmol, 1 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.53 g, 11.91 mmol, 1.2 eq) in DMF (20 mL), triethylamine (1.66 mL, 11.91 mmol, 1.2 eq) was added and the mixture was stirred for 5 min. Then 1-Boc-piperazine (2.22 g, 11.91 mmol, 1.2 eq) was added. The resulting mixture was stirred at 15 °C for 15 h. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over sodium sulfate, concentrated, and tert-butyl 4-(2-chloro-4-nitro-benzoyl)piperazine-1-carboxylate (2.5 g, 6.76 mmol, yield 68.13%) was obtained. This crude product was used directly in the next step without further purification. MS (ESI, m / z): 270.1 [M + H - 100] +

[0303] Step 2: (2-Chloro-4-nitro-phenyl)-piperazin-1-yl-methanone To a solution of tert-butyl 4-(2-chloro-4-nitro-benzoyl)piperazine-1-carboxylate (2.5 g, 6.76 mmol, 1 eq) in methanol (10 mL) was added 4N HCl in MeOH (10 mL). The resulting mixture was stirred at 20 °C for 1 h. The mixture was concentrated to dryness, and the residue was triturated with MTBE to give (2-chloro-4-nitro-phenyl)-piperazin-1-yl-methanone (1.6 g), which was used directly in the next step without further purification. White solid. MS (ESI, m / z): 270.0 [M+H] +

[0304] Step 3: tert-Butyl 4-(4-(2-chloro-4-nitrobenzoyl)piperazine-1-carbonyl)-4-hydroxypiperidine-1-carboxylate To a solution of 1-tert-butoxycarbonyl-4-hydroxy-piperidine-4-carboxylic acid (0.6 g, 2.45 mmol, 1 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1116.18 mg, 2.94 mmol, 1.2 eq) in DMF (10 mL) was added triethylamine (0.68 mL, 4.89 mmol, 2 eq). After stirring for 5 min, (2-chloro-4-nitro-phenyl)-piperazin-1-yl-methanone hydrochloride (0.82 g, 2.69 mmol, 1.1 eq) was added. The resulting mixture was stirred at 20 °C for 15 h. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography eluting with PE:EA = 1:1 to give tert-butyl 4-[4-(2-chloro-4-nitro-benzoyl)piperazine-1-carbonyl]-4-hydroxy-piperidine-1-carboxylate (800 mg, 1.61 mmol, 65.81% yield) as a yellow solid. MS (ESI, m / z): 519.2 [M+Na] +

[0305] Step 4: tert-Butyl 4-(4-(4-amino-2-chlorobenzoyl)piperazine-1-carbonyl)-4-hydroxypiperidine-1-carboxylate To a solution of nickel(II) chloride hexahydrate (143.49 mg, 0.600 mmol, 0.500 eq) and sodium borohydride (50 mg, 0.94 mmol, 0.5 eq) in THF (6.45 mL) and methanol (1.29 mL), tert-butyl 4-[4-(2-chloro-4-nitro-benzoyl)piperazine-1-carbonyl]-4-hydroxy-piperidine-1-carboxylate (600.0 mg, 1.21 mmol, 1 eq) in THF (2 mL) was added, and then sodium borohydride (170 mg, 2.3 mmol, 2.5 eq) was added. The mixture was stirred at 0 °C for 2 h. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over sodium sulfate, concentrated, and tert-butyl 4-[4-(4-amino-2-chloro-benzoyl)piperazine-1-carbonyl]-4-hydroxy-piperidine-1-carboxylate (400 mg, 0.860 mmol, yield 70.95%) was obtained as a yellow oil and used directly in the next step.

[0306] Step 5: 5-Bromo-1-methyl-imidazole-2-carboxylic acid To a solution of methyl 5-bromo-1-methyl-imidazole-2-carboxylate (1.0 g, 4.57 mmol, 1 eq) in THF (20 mL) and water (1 mL), lithium hydroxide monohydrate (aq., 0.15 mL, 9.13 mmol, 2 eq) was added. The resulting mixture was stirred at 25 °C for 2 h. The mixture was acidified with 1 N HCl, extracted with EtOAc, washed with brine, dried over sodium sulfate, concentrated, and 5-bromo-1-methyl-imidazole-2-carboxylic acid (600 mg) was obtained as a white solid. MS (ESI, m / z): 204.9 [M+H] +

[0307] Step 6: tert-Butyl 4-(4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carbonyl)-4-hydroxypiperidine-1-carboxylate To a solution of 5-bromo-1-methyl-imidazole-2-carboxylic acid (150.0 mg, 0.730 mmol, 1 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (417.31 mg, 1.1 mmol, 1.5 eq) in DMF (5 mL) was added triethylamine (0.15 mL, 1.1 mmol, 1.5 eq). After stirring for 5 min, tert-butyl 4-[4-(4-amino-2-chloro-benzoyl)piperazine-1-carbonyl]-4-hydroxy-piperidine-1-carboxylate (341.66 mg, 0.730 mmol, 1 eq) was added. The resulting mixture was stirred at 25 °C for 15 h. The mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography to give tert-butyl 4-[4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-4-hydroxy-piperidine-1-carboxylate (200 mg) as a white solid. MS (ESI, m / z): 539.2 [M+H-100-17] +

[0308] Step 7: 2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]acetonitrile 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (0.8 g, 3.05 mmol, 1 eq), bromoacetonitrile (0.44 g, 3.66 mmol, 1.2 eq), and potassium carbonate (843.8 mg, 6.11 mmol, 2 eq) in ACN (10 mL) were stirred at 25 °C for 16 h. The mixture was filtered, concentrated to give the crude product, which was further purified by column chromatography (PE / EA = 100:1 to 20:1) to afford 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]acetonitrile (950 mg) as a colorless oil. MS (ESI, m / z): 301.9 [M+H] +

[0309] Step 8: tert-Butyl 4-[4-[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-hydroxy-piperidine-1-carboxylate tert-Butyl 4-[4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carbonyl]-4-hydroxy-piperidine-1-carboxylate (200.0 mg, 0.310 mmol, 1 eq), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]acetonitrile (184.15 mg, 0.610 mmol, 2 eq), sodium carbonate (64.83 mg, 0.610 mmol, 2 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.38 mg, 0.030 mmol, 0.100 eq) in 1,4-dioxane (6 mL) / water (0.600 mL) were stirred at 85 °C for 16 h. The mixture was filtered and purified by preparative TLC (DCM / MeOH = 10:1) to give tert-butyl 4-[4-[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-hydroxy-piperidine-1-carboxylate (135 mg) as a pale yellow oil. MS (ESI, m / z): 748.2 [M+H] +

[0310] Step 9: N-[3-Chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide formate A solution of tert-butyl 4-[4-[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-hydroxy-piperidine-1-carboxylate (135.0 mg, 0.180 mmol, 1 eq) in DCM (16.51 mL) was added trifluoroacetic acid (5.0 mL, 64.9 mmol, 359.67 eq), and the mixture was stirred at 25 °C for 16 h. The mixture was concentrated and purified by preparative HPLC (FA) to give N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide as the formate salt (18.9 mg). MS (ESI, m / z): 648.3 [M+H] +

[0311] Example 61 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide formate [Chemical formula]

[0312] Step 1: tert-butyl 4-[4-(2-chloro-4-nitro-benzoyl)piperazine-1-carbonyl]piperidine-1-carboxylate The title compound was obtained in the same manner as in Step 3 of Example 60, using N-Boc-isonipecotic acid as the starting material. MS (ESI, m / z): 503.0 [M+Na] +

[0313] Step 2: tert-butyl 4-[4-(4-amino-2-chloro-benzoyl)piperazine-1-carbonyl]piperidine-1-carboxylate The title compound was obtained in the same manner as in Example 60, Step 4 by using tert-butyl 4-[4-(2-chloro-4-nitro-benzoyl)piperazine-1-carbonyl]piperidine-1-carboxylate as the starting material. MS(ESI, m / z): 473.1 [M+Na] +

[0314] Step 3: tert-butyl 4-[4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate The title compound was obtained in the same manner as in Example 60, Step 6 by using tert-butyl 4-[4-(4-amino-2-chloro-benzoyl)piperazine-1-carbonyl]piperidine-1-carboxylate as the starting material. MS(ESI, m / z): 539.2 [M+H-100] +

[0315] Step 4: tert-butyl 4-[4-[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-ill]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate The title compound was obtained in the same manner as in Example 60, Step 8 by using tert-butyl 4-[4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate as the starting material. MS(ESI, m / z): 732.2 [M+H] +

[0316] Step 5: N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide formate The title compound was obtained in the same manner as in Example 60, Step 9 by using tert-butyl 4-[4-[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate as the starting material. MS(ESI, m / z): 632.1[M+H] +

[0317] Example 62 tert-butyl (S)-(1-(4-(2-chloro-4-(1-methyl-5-(1-(pyridin-3-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate

Chemical formula

[0318] Step 1) tert-butyl 4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxylate 5-Bromo-1-methyl-1H-imidazole-2-carboxylic acid (3.96 g, 19.3 mmol, Eq: 1), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HATU) (11 g, 29 mmol, Eq: 1.5), and 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid (2 g, 9.71 mmol, Eq: 1) were dissolved in DMF (100 ml) and cooled to 0 °C. N-Ethyl-N-isopropylpropan-2-amine (DIPEA) (7.49 g, 10.3 ml, 57.9 mmol, Eq: 3) was added to obtain a brown solution, and the reaction mixture was stirred at room temperature over the weekend. Water was added to the mixture. The resulting precipitate was collected by filtration and dried under HV to obtain the desired product as a beige solid (4.96 g). MS (ESI, m / z): 528.2 [M+H] +

[0319] Step 2) tert-Butyl 4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate In a 250 mL three-necked flask, tert-butyl 4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxylate (4.96 g, 9.42 mmol, Eq: 1), (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (2.54 g, 14.1 mmol, Eq: 1.5), Na2CO3 (2 g, 18.8 mmol, Eq: 2.00), and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (dtbpf) (614 mg, 942 μmol, Eq: 0.10) were combined with dioxane (40 mL) and water (4 ml) to obtain a brown suspension. After bubbling Ar through the reaction mixture for 15 min using Ar, it was stirred at 85 °C overnight. (3-(Trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (847 mg, 4.71 mmol, Eq: 0.5) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (dtbpf) (614 mg, 942 μmol, Eq: 0.10) were added. The RM was stirred again at 85 °C overnight. 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (dtbpf) (307 mg, 471 μmol, Eq: 0.05) and (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (847 mg, 4.71 mmol, Eq: 0.5) were added. The RM was stirred again at 85 °C overnight. 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (dtbpf) (307 mg, 471 μmol, Eq: 0.05) and (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (847 mg, 4.71 mmol, Eq: 0.5) were added two more times. After filtration through Celite, the volatiles were evaporated and the crude was purified by flash chromatography in two batches (silica gel, 40 g, 0% - 100% EtOAc / EtOH 3 / 1 in heptane). The fractions containing the product were combined to give the title compound (2.255 g) as an off-white solid. MS (ESI, m / z): 582.3 [M+H] +

[0320] Step 3) tert-Butyl 4-(2-chloro-4-(1-methyl-5-(1-(pyridin-3-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate Under Ar, tert-butyl 4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (1 g, 1.72 mmol, Eq: 1) was dissolved in DMF (10 ml). Sodium bicarbonate (433 mg, 5.15 mmol, Eq: 3) and 3-(chloromethyl)pyridine hydrochloride (388 mg, 2.37 mmol, Eq: 1.38) were added, and the light brown reaction mixture was stirred with microwave at 120 °C for 2 h. The RM was filtered, and the filtrate was washed 3x with saturated NaHCO3 solution. The organic layers were combined and evaporated to give 1.02 g of a dark brown sticky solid as the crude product. The crude material was purified by flash chromatography (silica gel, 40 g, 0% - 40% EtOAc / EtOH (3 / 1) in heptane). The fraction-containing products were combined and evaporated to give 580 mg of a light brown solid as the desired product. MS (ESI, m / z): 673.4 [M+H] +

[0321] Step 4) N-(3-Chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(pyridin-3-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide trihydrochloride tert-Butyl 4-(2-chloro-4-(1-methyl-5-(1-(pyridin-3-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (580 mg, 862 μmol, Eq: 1) was stirred with 4 M HCl in dioxane (4.31 mL, 17.2 mmol, Eq: 20) in dioxane (5 mL) at room temperature (Rxn molar concentration: 172 mM, reaction time: overnight). Diethyl ether (3 mL) was added and the mixture was stirred at 30 min RT. The resulting suspension was filtered off and the solid was evaporated to dryness, giving 480 mg of an off-white solid as the desired product. MS (ESI, m / z): 573.3 [M+H] +

[0322] Step 5) tert-Butyl (S)-(1-(4-(2-chloro-4-(1-methyl-5-(1-(pyridin-3-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate In a 25 mL pear-shaped flask, N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(pyridin-3-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide trihydrochloride (30 mg, 44 μmol, Eq: 1), and rac-(tert-butoxycarbonyl)-D-alanine (12.5 mg, 65.9 μmol, Eq: 1.5) were combined with DMF (1 mL) to obtain a brown solution. DIEA (8.52 mg, 11.5 μL, 65.9 μmol, Eq: 1.5) was added dropwise at room temperature. The reaction mixture was stirred at room temperature over the weekend. LC / MS indicated the desired product and no starting material remained. The mixture was poured into water and partitioned with ethyl acetate. The organic phase was washed with water (3x), brine (2x), dried over magnesium sulfate, and concentrated. The resulting residue was purified by flash chromatography (0 - 100% EtOAc / EtOH 3 / 1 in heptane) to obtain the desired product as an off-white waxy solid (28 mg). MS (ESI, m / z): 744.7[M+H] +

[0323] Step 6) N-[4-[4-[(2S)-2-aminopropanoyl]piperazine-1-carbonyl]-3-chlorophenyl]-1-methyl-5-[1-(pyridin-3-ylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide trihydrochloride tert-butyl (S)-(1-(4-(2-chloro-4-(1-methyl-5-(1-(pyridin-3-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzoyl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate (28 mg, 37.6 μmol, Eq: 1) was stirred in dioxane (2 mL) at room temperature with 4 M HCl in dioxane (188 μL, 753 μmol, Eq: 20) (Rxn molar concentration: 18.8 mM, reaction time: 2 hours). Diethyl ether (2 mL) was added and the RM was stirred at 30 min RT. The resulting suspension was filtered off, the solid was evaporated to dryness, and a yellow wax-like solid was obtained as the desired product (24 mg). MS (ESI, m / z): 644.3 [M+H] +

[0324] The following examples were obtained in the same manner:

Table 7-1

Table 7-2

Table 7-3

[0325] Example 65 N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-1,2-dienyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; hydrochloride

Chemical formula

[0326] The following additional examples were prepared by the method described above:

Table 8-1

Table 8-2

Table 8-3

Table 8-4

Table 8-5

Table 8-6

Table 8-7

Table 8-8

Table 8-9

Table 8-10

Table 8-11

Table 8-12

Table 8-13

Table 8-14

Table 8-15

Table 8-16

Table 8-17

Table 8-18

Table 8-19

Table 8-20

Table 8-21

Table 8-22

Table 8-23

Table 8-24

Table 8-25

Table 8-26

Table 8-27

Table 8-28

Table 8-29

Table 8-30

Table 8-31

Table 8-32

Table 8-33

[0327] Example 167 N-[3-chloro-4-[4-[rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carboxamide; hydrochloride

Chemical Structure

[0328] Step 1) tert-Butyl 4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzoyl)piperazine-1-carboxylate 2-Chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzoic acid (Intermediate 2, 4.19 g, 8.3 mmol, Eq: 1) and tert-butyl piperazine-1-carboxylate (2.32 g, 12.5 mmol, Eq: 1.5) were combined with DMF (15 ml) to obtain a brown solution. DIPEA (3.22 g, 4.35 ml, 24.9 mmol, Eq: 3.0) and HATU (4.74 g, 12.5 mmol, Eq: 1.5) were added, and the reaction mixture was stirred at RT. Water was added to the reaction mixture, which was then extracted with EtOAc. The organic layer was washed with 5% aqueous LiCl and saturated aqueous NaCl. After drying over Na2SO4, filtration, and evaporation to dryness, the crude material was purified by flash chromatography (silica gel, 80 g, 0% - 100% DCM:MeOH in DCM; 9:1) to give the title compound (2.29 g) as a brown foam. MS (ESI, m / z): 582.2 [M+H] +

[0329] Step 2 tert-Butyl 4-(2-chloro-4-(5-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate Cu(OAc)2 (125 mg) and 4-DMAP (252 mg) were added to tert-butyl 4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (400 mg, 687 μmol, Eq: 1) in dioxane (4 mL) and pyridine (67 μL). The reaction mixture was heated to 100 °C and stirred overnight under air. The crude reaction mixture was concentrated in vacuo. The residue was taken up in 50 mL of EtOAc and extracted with 1 M HCl (3 × 25 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% - 10% MeOH in DCM) to afford the title compound (233 mg, 363 μmol, 52.9% yield) as a yellow solid. MS (ESI, m / z): 622.3 [M+H] +

[0330] Step 3 N-(3-Chloro-4-(piperazine-1-carbonyl)phenyl)-5-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide hydrochloride tert-Butyl 4-(2-chloro-4-(5-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (965 mg, 1.55 mmol, Eq: 1) was dissolved in MeOH (9 mL). HCl (4 M in dioxane) (3.6 g, 3 mL, 12 mmol, Eq: 7.74) was added and stirred for 2.5 h. The crude reaction mixture was concentrated in vacuo to afford the title compound (948 mg) as an orange solid. MS (ESI, m / z): 522.2 [M+H] +

[0331] Project 4 N-[3-Chloro-4-[4-[rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carboxamide; Hydrochloride rac-(1R,5S,6r)-3-(tert-Butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (8.14 mg, 35.8 μmol, Eq: 1) was combined with DMF (0.5 ml) to obtain a brown solution. DIPEA (23.1 mg, 31.3 μl, 179 μmol, Eq: 5) and HATU (27.2 mg, 71.6 μmol, Eq: 2) were added. The reaction mixture was stirred for 15 min. N-(3-Chloro-4-(piperazine-1-carbonyl)phenyl)-5-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide hydrochloride (20 mg, 35.8 μmol, Eq: 1) was added. The mixture was stirred overnight. The crude intermediate was purified by preparative HPLC and then dissolved in MeOH (400 μl). TFA (296 mg, 200 μl, 2.6 mmol, Eq: 72.5) was added and the mixture was stirred for 4 h. The reaction mixture was concentrated and lyophilized to obtain the title compound (12.7 mg, 19 μmol, 53.1% yield) as a pale yellow solid. MS (ESI, m / z): 631.3 [M+H] +

[0332] Example 168 rac-N-((1s,3s)-3-Aminocyclobutyl)-4-(2-chloro-4-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide)benzoyl)piperazine-1-carboxamide hydrochloride

Chemical Structure

[0333] Project 1 rac-tert-butyl ((1s,3s)-3-(4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxamido)cyclobutyl)carbamate 5-Bromo-N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-1H-imidazole-2-carboxamide hydrochloride (Example 55, Step 4, 1000 mg, 2.16 mmol, Eq: 1) was combined with DCM (10 ml) to obtain a light brown suspension. DIPEA (1.4 g, 1.89 ml, 10.8 mmol, Eq: 5.00) was added, followed by triphosgene (256 mg, 864 μmol, Eq: 0.40). After stirring for 30 min, rac-tert-butyl ((1s,3s)-3-aminocyclobutyl)carbamate (1.21 g, 6.48 mmol, Eq: 3.00) was added. The reaction mixture was concentrated and purified by flash chromatography (silica gel, 40 g, 0% - 100% DCM:MeOH:NH4OH (100:10:1) in DCM) to obtain the title compound (1 g) as an off-white foam. MS (ESI, m / z): 638.1 [M+H] +

[0334] Project 2 rac-tert-butyl ((1s,3s)-3-(4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamido)cyclobutyl)carbamate rac-tert-butyl ((1s,3s)-3-(4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxamido)cyclobutyl)carbamate (600 mg, 939 μmol, Eq: 1), (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (203 mg, 1.13 mmol, Eq: 1.20), Na2CO3 (199 mg, 1.88 mmol, Eq: 2.00) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (61.2 mg, 93.9 μmol, Eq: 0.10) in a mixture of dioxane (2.5 ml) and water (250 μl) was heated at 90 °C in a microwave for 2 h. The reaction mixture was diluted with AcOEt and filtered through celite. The product was purified by flash chromatography (silica gel, 40 g, 0% - 80% DCM:MeOH:NH3 in DCM; 100:10:1) to give the title compound (652 mg) as a brown viscous oil. MS (ESI, m / z): 694.2 [M+H] +

[0335] Step 3 rac-N-((1s,3s)-3-aminocyclobutyl)-4-(2-chloro-4-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamide hydrochloride Iodoethane (11 mg, 70 μmol, Eq: 2) was added to a mixture of rac-tert-butyl ((1s,3s)-3-(4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamido)cyclobutyl)carbamate (24.3 mg, 35 μmol, Eq: 1) and K2CO3 (19.3 mg, 140 μmol, Eq: 4) in DMF (500 μl). The mixture was stirred overnight, filtered and then purified by preparative HPLC. Intermediate MS (ESI, m / z): 722.4 [M+H]+ The intermediate was combined with DCM (350 μl), and then HCl (65.6 μl, 262 μmol, Eq: 7.5) was added. The reaction mixture was stirred at room temperature for 4 h and then stored in the refrigerator at 4 °C overnight. After removal of the volatile substances, the product was lyophilized. MS (ESI, m / z): 622.2 [M+H] +

[0336] Example 169 rac-N-((1s,3s)-3-Aminocyclobutyl)-4-(2-chloro-4-(5-(1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamide hydrochloride

Chemical formula

[0337] Example 170 N-(4-((2-(2-Amino-2-methylpropoxy)ethyl)carbamoyl)-3-ethylphenyl)-5-(1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide

Chemical formula

[0338] Step 1: tert-Butyl N-[2-[2-[(4-amino-2-ethyl-benzoyl)amino]ethoxy]-1,1-dimethyl-ethyl]carbamate A mixture of 4-amino-2-ethyl-benzoic acid (175.0 mg, 1.06 mmol, 1 eq), N,N-diisopropylethylamine (0.37 mL, 2.12 mmol, 2 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (483.37 mg, 1.27 mmol, 1.2 eq) in DMF (7 mL) was stirred at 10 °C for 0.5 h, and then tert-butyl N-[2-(2-aminoethoxy)-1,1-dimethyl-ethyl]carbamate (Intermediate 4, 270.73 mg, 1.17 mmol, 1.1 eq) was added. The mixture was stirred at 15 °C for 16 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product, which was purified by preparative HPLC to give the title compound (100 mg, 0.260 mmol, 25% yield) as a pale yellow solid. MS (ESI, m / z): 402.2 [M+Na] +

[0339] Step 2: tert-Butyl N-[2-[2-[[2-Ethyl-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]ethoxy]-1,1-dimethyl-ethyl]carbamate 1-Methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxylic acid (57.59 mg, 0.220 mmol, 1.2 eq), N,N-diisopropylethylamine (0.06 mL, 0.370 mmol, 2 eq), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (84.16 mg, 0.220 mmol, 1.2 eq) in DMF (3 mL) were stirred at 10 °C for 0.5 h, then tert-butyl N-[2-[2-[(4-amino-2-ethyl-benzoyl)amino]ethoxy]-1,1-dimethyl-ethyl]carbamate (70.0 mg, 0.180 mmol, 1 eq) was added. The mixture was stirred at 10 °C for 2 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2x20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative TLC (EtOAc) to give the title compound (112 mg, 0.180 mmol, 97.67% yield) as a pale yellow oil. MS (ESI, m / z): 622.4 [M+H] +

[0340] Step 3: N-[2-[2-[[4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]ethoxy]-1,1-dimethyl-ethyl]carbamate tert-Butyl N-[2-[2-[[2-Ethyl-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]ethoxy]-1,1-dimethyl-ethyl]carbamate (85.0 mg, 0.140 mmol, 1 eq) and potassium carbonate (37.79 mg, 0.270 mmol, 2 eq) in DMF (3 mL) were added bromoacetonitrile (24.6 mg, 0.210 mmol, 1.5 eq) at 10 °C, and then the solution was stirred at 10 °C for 18 h. The solution was poured into water and extracted with EtOAc (50 mL * 2). The combined organic layers were washed with brine (50 mL), concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH = 10 / 1) to give tert-butyl N-[2-[2-[[4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]ethoxy]-1,1-dimethyl-ethyl]carbamate (90 mg, 0.140 mmol, 99% yield) as a pale yellow oil. MS (ESI, m / z): 661.4 [M+H] +

[0341] Step 4: N-(4-((2-(2-Amino-2-methylpropoxy)ethyl)carbamoyl)-3-ethylphenyl)-5-(1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide To a solution of tert-butyl N-[2-[2-[[4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]ethoxy]-1,1-dimethyl-ethyl]carbamate (100.0 mg, 0.150 mmol, 1 eq) in DCM (5 mL) was added trifluoroacetic acid (0.5 mL, 6.49 mmol, 42.88 eq) at 10 °C, and the mixture was stirred at 10 °C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (formic acid) to give the product N-[4-[2-(2-amino-2-methyl-propoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide (36.3 mg, 0.060 mmol, yield 39.54%, formate salt) as a pale yellow solid. MS (ESI, m / z): 561.2 [M+H] +

[0342] Example 171 N-(azetidin-3-yl)-4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1-vinyl-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamide [Chemical Structure]

[0343] Step 1: tert-butyl 3-(4-(2-chloro-4-nitrobenzoyl)piperazine-1-carboxamido)azetidine-1-carboxylate A solution of (2-chloro-4-nitro-phenyl)-piperazin-1-yl-methanone (500.0 mg, 1.3 mmol, 1 eq, TFA salt) (Organic Preparations and Procedures International, 1976, vol. 8, p. 85) in DMF (5 mL) was treated with N,N'-carbonyldiimidazole (211.29 mg, 1.3 mmol, 1 eq) and triethylamine (0.36 mL, 2.61 mmol, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min, then 1-Boc-3-(amino)azetidine (0.09 mL, 1.3 mmol, 1 eq) was added at 0 °C. The mixture was warmed to 20 °C and stirred for an additional 2 h. The mixture was quenched with 10 mL of water and extracted with EtOAc (20 ml * 3). The combined organic layers were washed with saturated aqueous NH4Cl (20 mL * 3) and brine (20 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel (PE / EA = 10 / 1) to afford the title compound (450 mg, 0.960 mmol, 73.81% yield) as a light yellow solid. MS (ESI, m / z): 468.3 [M+H] +

[0344] Step 2: tert-Butyl 3-(4-(4-amino-2-chlorobenzoyl)piperazine-1-carboxamido)azetidine-1-carboxylate A mixture solution of NiCl2·6H2O (0.11 g, 0.480 mmol, 0.500 eq) and sodium borohydride (0.11 g, 2.89 mmol, 3 eq) in methanol (4.63 mL) was stirred at 0 °C for 30 min. Then, a solution of tert-butyl 3-[[4-(2-chloro-4-nitro-benzoyl)piperazine-1-carbonyl]amino]azetidine-1-carboxylate (0.45 g, 0.960 mmol, 1 eq) and sodium borohydride (0.11 g, 2.89 mmol, 3 eq) in THF (4.63 mL) was added at 0 °C, and the mixture was stirred at 0 °C for an additional 1.5 h. The mixture was filtered and concentrated to obtain the crude product tert-butyl 3-[[4-(4-amino-2-chloro-benzoyl)piperazine-1-carbonyl]amino]azetidine-1-carboxylate (240 mg, 0.550 mmol, yield 56.98%) as a white solid, which was used directly without purification. MS (ESI, m / z): 438.1 [M+H] +

[0345] Step 3: 4-Iodo-3-(trifluoromethyl)-1-trityl-1H-pyrazole To a solution of 4-iodo-3-(trifluoromethyl)-1H-pyrazole (222.0 g, 847.43 mmol, 1 eq) in THF (2220 mL) was added sodium hydride (60% in oil, 37.28 g, 932.17 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then trityl chloride (259.87 g, 932.17 mmol, 1.1 eq) was added. The mixture was warmed to 10 °C and stirred for 16 h. The mixture was quenched with saturated NH4Cl (500 mL), extracted with EtOAc (300 mL × 2), washed with brine (700 mL), dried over sodium sulfate, filtered, concentrated in vacuo to obtain the crude product, which was purified by silica gel column chromatography (eluent petroleum ether / EtOAc = 100 / 1) to give 4-iodo-3-(trifluoromethyl)-1-trityl-pyrazole (284 g, 563.17 mmol, yield 66.46%) as a white solid. 11H NMR (400 MHz, chloroform-d) δ = 7.42 (s, 1H), 7.34 - 7.37 (m, 9H), 7.09 - 7.12 (m, 6H) ppm.

[0346] Step 4: (3-(Trifluoromethyl)-1-trityl-1H-pyrazol-4-yl)boronic acid To a solution of 4-iodo-3-(trifluoromethyl)-1-trityl-pyrazole (284.0 g, 563.17 mmol, 1 eq) in THF (2000 mL), butyllithium solution (270.32 mL, 675.8 mmol, 1.2 eq) was added dropwise at -70 °C under N2 protection. The mixture was stirred at -70 °C for 0.5 h, then triisopropyl borate (194.94 mL, 844.75 mmol, 1.5 eq) was added dropwise to the mixture, and the mixture was stirred at -70 °C for 1 h. TLC (petroleum ether / EtOAc = 5 / 1, R f = 0.2) indicated that the reaction was complete. Then the mixture was diluted with 300 mL of saturated NH4Cl, extracted with EtOAc (300 mL × 2), the combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and the crude desired intermediate (290 g, 686.86 mmol, yield 73.18%) was obtained as a pale yellow oil, which was used for the next step without purification. MS (ESI, m / z): 445.2 [M+23] + .

[0347] Step 5: Ethyl 1-methyl-5-(3-(trifluoromethyl)-1-trityl-1H-pyrazol-4-yl)-1H-imidazole-2-carboxylate [3-(Trifluoromethyl)-1-trityl-pyrazol-4-yl]boronic acid (543.48 mg, 1.29 mmol, 1.5 eq), ethyl 5-bromo-1-methyl-imidazole-2-carboxylate (200.0 mg, 0.860 mmol, 1 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (62.79 mg, 0.090 mmol, 0.100 eq) and sodium carbonate (181.91 mg, 1.72 mmol, 2 eq) in 1,4-dioxane (5.4 mL) were stirred at 85 °C for 16 h under N2 protection. LCMS indicated that the reaction was complete. The mixture was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (petroleum ether / EtOAc = 3 / 1) to give the title compound (330 mg, 0.620 mmol, 72.48% yield) as a light yellow oil. MS (ESI, m / z): 531.1 [M+H] +

[0348] Step 6: Ethyl 1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxylate A solution of ethyl 1-methyl-5-[3-(trifluoromethyl)-1-trityl-pyrazol-4-yl]imidazole-2-carboxylate (220.0 g, 331.74 mmol, 1 eq) in HCl / 1,4-dioxane (4N, 1000.0 mL, 4000 mmol, 12.06 eq) was stirred at 10 °C for 24 h. The solution was concentrated, and the residue was triturated with MTBE (500 mL) to give the title compound (38.3 g, 117.96 mmol, 35.56% yield) as a white solid. MS (ESI, m / z): 289.1 [M+H]+.

[0349] Step 7: 1-Methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxylic acid A solution of ethyl 1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxylate hydrochloride (38.3 g, 117.96 mmol, 1 eq) and lithium hydroxide hydrate (14.85 g, 353.88 mmol, 3 eq) in a mixed solvent of THF (100 mL) and methanol (50 mL) and water (100 mL) was stirred at 5 °C for 16 h. The mixture was concentrated to remove THF and MeOH, and then acidified to pH = 7 using 1N HCl solution. A large amount of white solid was formed, the mixture was filtered, the filter cake was washed with water (100 mL), dried, and the title compound (25 g, 96.09 mmol, 81% yield) was obtained as a white solid. MS(ESI, m / z): 261.0 [M+H] +

[0350] Step 8: tert-Butyl 3-(4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamido)azetidine-1-carboxylate A mixture of 1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxylic acid (0.7 g, 2.29 mmol, 1 eq, formate), tert-butyl 3-[[4-(4-amino-2-chlorobenzoyl)piperazine-1-carbonyl]amino]azetidine-1-carboxylate (1.0 g, 2.29 mmol, 1 eq), and N,N-diisopropylethylamine (1.19 mL, 6.86 mmol, 3 eq) in DMF (5.95 mL) was added to O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.3 g, 3.43 mmol, 1.5 eq) at 0 °C. Then the solution was warmed to 30 °C and stirred for 16 h. The mixture was diluted with aqueous HCl (1 L, 0.5 N), extracted with EtOAc (300 ml * 3), washed with brine (500 mL * 3), dried over Na2SO4, concentrated, and purified by silica (PE / EA / MeOH = 1 / 1 / 0.04) to give the title compound (950 mg, 1.4 mmol, 61.1% yield) as a white solid. MS (ESI, m / z): 680.1 [M+H]+

[0351] Step 9: tert-Butyl 3-(4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamido)azetidine-1-carboxylate To a mixture of 1,2-dichloroethane (4 mL) and 50% sodium hydroxide solution (58.81 mg, 0.740 mmol, 5 eq), tert-butyl 3-[[4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]amino]azetidine-1-carboxylate (100.0 mg, 0.150 mmol, 1 eq) and benzyltriethylammonium chloride (3.35 mg, 0.010 mmol, 0.100 eq) were added. Subsequently, the resulting mixture was heated at 80 °C for 4 h. The mixture was diluted with DCM (20 mL), dried over sodium sulfate, filtered, concentrated in vacuo to afford the crude product, which was purified by preparative TLC (DCM / MeOH = 10 / |) to give the title compound (50 mg, 0.070 mmol, 48.16% yield) as an off-white solid. MS (ESI, m / z): 706.3 [M+H] +

[0352] Step 10: N-(azetidin-3-yl)-4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamide A mixture of tert-butyl 3-[[4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]amino]azetidine-1-carboxylate (50.0 mg, 0.070 mmol, 1 eq) and trifluoroacetic acid (0.01 mL, 0.070 mmol, 1 eq) in DCM (1.93 mL) was stirred at 20 °C for 4 h. The mixture was concentrated in vacuo to afford the crude product, which was purified by preparative HPLC to give the title compound (11.28 mg, 0.020 mmol, 27% yield, formate) as a white solid. MS (ESI, m / z): 606.5 [M+H]+

[0353] Example 172 N-(3-chloro-4-(((1R,5S,6s)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamoyl)phenyl)-5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide formate

Chemical formula

[0354] Step 1) tert-butyl (1R,5S,6s)-6-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzamide)-3-azabicyclo[3.1.0]hexane-3-carboxylate 2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzoic acid hydrochloride (Intermediate 2, 978 mg, 2.09 mmol, Eq: 1), tert-butyl (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (517 mg, 2.61 mmol, Eq: 1.25) and HATU (952 mg, 2.5 mmol, Eq: 1.2) were combined in DMF (15 ml) to obtain a light brown suspension. DIPEA (1.35 g, 1.82 ml, 10.4 mmol, Eq: 5.00) was added and the reaction mixture was stirred at room temperature overnight. Brine was added to the reaction mixture and extracted with EtOAc. After drying over Na2SO4, filtration and evaporation of the volatile substances, the product was purified by flash chromatography (silica gel, 50 g, 10% - 100% EtOAc in heptane) to obtain the title compound (984 mg) as a yellow oil. MS (ESI, m / z): 594.1 [M+H] + Step 2)

[0355] Intermediate 7 N-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamoyl)-3-chlorophenyl)-1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide hydrochloride tert-Butyl (1R,5S,6s)-6-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate (766 mg, 1.29 mmol, Eq: 1) was dissolved in DCM (20 ml) and treated with excess 4 M HCl in dioxane (6.45 ml, 25.8 mmol, Eq: 20.00). The reaction mixture was stirred overnight at RT. Ether was added to the reaction mixture, the solid was filtered off and dried under HV to give the desired product (680 mg) as a white powder. MS (ESI, m / z): 494.1 [M+H] +

[0356] Step 3) tert-Butyl 4-((1R,5S,6s)-6-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzamido)-3-azabicyclo[3.1.0]hexane-3-carbonyl)piperidine-1-carboxylate N-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamoyl)-3-chlorophenyl)-1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide hydrochloride (200 mg, 0.377 mmol, Eq: 1), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (CAS 84358-13-4: 112 mg, 0.49 mmol, Eq: 1.30), and TBTU (CAS 125700-67-9: 150 mg, 0.453 mmol, Eq: 1.20) were combined in DMF (10 ml). TEA (191 mg, 0.263 ml, 1.89 mmol, Eq: 5.00) was added and the reaction was stirred overnight at room temperature. Brine was added to the reaction mixture and the mixture was extracted with EtOAc. After drying over Na2SO4, filtering, and evaporation of the volatiles, the product was purified by flash chromatography (silica gel, 20 g, 0% - 30% MeOH in EtOAc) to give the title compound (223 mg) as a white solid. MS (ESI, m / z): 705.2 [M+H] +

[0357] Step 4) tert-butyl 4-((1R,5S,6s)-6-(2-chloro-4-(5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide)benzamide)-3-azabicyclo[3.1.0]hexane-3-carbonyl)piperidine-1-carboxylate tert-Butyl 4-((1R,5S,6s)-6-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzamido)-3-azabicyclo[3.1.0]hexane-3-carbonyl)piperidine-1-carboxylate (20 mg, 0.029 mmol, Eq: 1) dissolved in 2 ml of DMF was treated with potassium carbonate (14 mg, 0.102 mmol, Eq: 3.50) and 2-bromo-1,1-difluorocyclopropane (CAS 51326-64-8: 11.4 mg, 0.0725 mmol, Eq: (2.5). The reaction mixture was stirred at room temperature overnight. After filtration of potassium carbonate and evaporation of the volatiles, the product was used in the next step without further purification. MS (ESI, m / z): 781.3 [M+H]+

[0358] Step 5) N-(3-chloro-4-(((1R,5S,6s)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamoyl)phenyl)-5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide formate tert-Butyl 4-((1R,5S,6s)-6-(2-chloro-4-(5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide)benzamido)-3-azabicyclo[3.1.0]hexane-3-carbonyl)piperidine-1-carboxylate (23 mg, 0.029 mmol, Eq: 1) dissolved in DCM was treated with excess TFA (103 mg, 0.069 ml, 0.9 mmol, Eq: (30). The reaction mixture was stirred at room temperature overnight. After evaporation of the volatiles, the residue was purified by preparative HPLC to give the title product (14 mg). MS (ESI, m / z): 681.4 [M+H]+

[0359] The following examples were obtained similarly:

Table 9-1

Table 9-2

[0360] Example 175 (1R,5S,6s)-6-(2-chloro-4-(5-(1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzamide)-N-(trans-4-hydroxypyrrolidin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxamide formate

Chemical formula

[0361] Step 1) tert-butyl trans-3-((1R,5S,6s)-6-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzamide)-3-azabicyclo[3.1.0]hexane-3-carboxamide)-4-hydroxypyrrolidine-1-carboxylate In 5 ml of DMF, the title compound was prepared from intermediate 7 N-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamoyl)-3-chlorophenyl)-1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide hydrochloride (180 mg, 0.339 mmol, Eq: 1) by combining with a pre-stirred mixture of tert-butyl trans-3-amino-4-hydroxypyrrolidine-1-carboxylate (103 mg, 0.509 mmol, Eq: 1.50), CDI (CAS 530-62-1: 77.1 mg, 0.475 mmol, Eq: 1.40) and TEA (103 mg, 0.142 ml, 1.02 mmol, Eq: 3.00) for 30 min. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extracted with EtOAc. After drying over Na2SO4, filtering and evaporation of the volatiles, the product was used in the next step without further purification. MS (ESI, m / z): 722.5 [M+H] +

[0362] Step 2) tert-butyl trans-3-((1R,5S,6s)-6-(2-chloro-4-(5-(1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide)benzamide)-3-azabicyclo[3.1.0]hexane-3-carboxamide)-4-hydroxypyrrolidine-1-carboxylate tert-Butyl trans-3-((1R,5S,6s)-6-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzamido)-3-azabicyclo[3.1.0]hexane-3-carboxamido)-4-hydroxypyrrolidine-1-carboxylate (30 mg, 0.0415 mmol, Eq: 1) was dissolved in 1 ml of AcCN, and potassium carbonate (11.5 mg, 0.125 mmol, Eq: 2.0) and 2-bromoacetonitrile (15 mg, 0.0725 mmol, Eq: 2.5) were added. The reaction mixture was stirred at 60 °C overnight. Water was added to the reaction mixture, and the mixture was extracted with EtOAc. After drying over Na2SO4, filtering, and evaporation of the volatile substances, the product was used in the next step without further purification. MS (ESI, m / z): 761.5 [M+H]+

[0363] Step 3) tert-Butyl trans-3-((1R,5S,6s)-6-(2-chloro-4-(5-(1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzamido)-3-azabicyclo[3.1.0]hexane-3-carboxamido)-4-hydroxypyrrolidine-1-carboxylate tert-Butyl 4-((1R,5S,6s)-6-(2-chloro-4-(5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzamido)-3-azabicyclo[3.1.0]hexane-3-carbonyl)piperidine-1-carboxylate (30.4 mg, 0.040 mmol, Eq: 1) dissolved in 2 ml of DCM was treated with excess TFA (912 mg, 0.616 ml, 8 mmol, Eq: (200). The reaction mixture was stirred at room temperature overnight. After evaporation of the volatile substances, the residue was purified by preparative HPLC to give the title product (3.7 mg). MS (ESI, m / z): 661.4 [M+H]+

[0364] Example 176 (1R,5S,6s)-6-(2-chloro-4-(5-(1-(2-fluoroallyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzamido)-N-(trans-4-hydroxypyrrolidin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxamide formate

Chemical Structure

[0365] Example 177 (1R,5S,6s)-N-(cis-3-aminocyclobutyl)-6-(2-chloro-4-(5-(1-(2,2-difluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzamido)-3-azabicyclo[3.1.0]hexane-3-carboxamide

Chemical Structure

[0366] Step 1) Methyl 2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoate To a mixture of 15 mL of AcCN and 8 mL of DMF dissolved methyl 2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide) benzoate intermediate (954 mg, 2.23 mmol, Eq: 1), potassium carbonate (616 mg, 4.46 mmol, Eq: 2.00) and 1,1-difluoro-2-iodoethane (642 mg, 3.35 mmol, Eq: (1.5) were added. The reaction was stirred at 60 °C overnight. After filtration of potassium carbonate and evaporation of volatiles, the product was purified by flash chromatography (silica gel, 40 g, 10% - 100% EtOAc in heptane) to give the title compound (748 mg) as a white powder. MS (ESI, m / z): 492.0 [M+H] +

[0367] Step 2) 2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoic acid hydrochloride A mixture of methyl 2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoate (744 mg, 1.51 mmol, Eq: 1) and lithium hydroxide monohydrate (318 mg, 7.56 mmol, Eq: 5) in MeOH (10 mL), THF (25 mL) and water (10 mL) was stirred at room temperature overnight. The mixture was then acidified with 1 N HCl. The white precipitate was collected, washed with water and dried in vacuo to give the title compound as a white powder (587 mg). MS (ESI, m / z): 478.1 [M+H]+

[0368] Step 3) tert-Butyl (1R,5S,6s)-6-(2-chloro-4-(5-(1-(2,2-difluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate 2-Chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoic acid hydrochloride (56.6 mg, 0.110 mmol, Eq: 1), tert-butyl (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (32.7 mg, 0.165 mmol, Eq: 1.50), and TBTU (CAS 125700-67-9: 47.3 mg, 0.143 mmol, Eq: 1.30) were combined in DMF (25 ml). TEA (55.7 mg, 0.0767 ml, 0.550 mmol, Eq: 5.00) was added and the reaction was stirred overnight at room temperature. 1N KHSO4 solution was added to the reaction mixture and the mixture was extracted with EtOAc. After drying over Na2SO4, filtering, and evaporation of the volatiles, the product was used in the next step without further purification. MS (ESI, m / z): 658.4 [M+H] +

[0369] Step 4) N-(4-(((1R,5S,6s)-3-Azabicyclo[3.1.0]hexan-6-yl)carbamoyl)-3-chlorophenyl)-5-(1-(2,2-difluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide formate tert-Butyl (1R,5S,6s)-6-(2-chloro-4-(5-(1-(2,2-difluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate (72.3 mg, 0.110 mmol, Eq: 1) was treated with excess TFA (376 mg, 0.254 ml, 3.3 mmol, Eq: (30)). The reaction mixture was stirred overnight at room temperature. The mixture was quenched with TEA. After evaporation of the volatiles, the residue was purified by preparative HPLC to give the title product (41.1 mg). MS (ESI, m / z): 558.2 [M+H]+

[0370] Step 5) tert-Butyl (cis-3-((1R,5S,6s)-6-(2-chloro-4-(5-(1-(2,2-difluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzamido)-3-azabicyclo[3.1.0]hexane-3-carboxamido)cyclobutyl)carbamate To a solution of N-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamoyl)-3-chlorophenyl)-5-(1-(2,2-difluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide formate (33.4 mg, 60 μmol, Eq: 1) in DCM was added a solution of triphosgene (CAS 32315-10-9: 7.12 mg, 24 μmol, Eq: 0.40), followed by cis tert-butyl (-3-aminocyclobutyl)carbamate (27.9 mg, 150 μmol, Eq: 2.5) and TEA (30.4 mg, 41.8 μl, 300 μmol, Eq: 5). The mixture was stirred overnight at room temperature. 1N KHSO4 solution was added to the reaction mixture and extracted with EtOAc. After drying over Na2SO4, filtering and evaporation of the volatiles, the product was used in the next step without further purification.

[0371] Step 6) (1R,5S,6s)-N-(cis-3-Aminocyclobutyl)-6-(2-chloro-4-(5-(1-(2,2-difluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzamide)-3-azabicyclo[3.1.0]hexane-3-carboxamide tert-Butyl (cis-3-((1R,5S,6s)-6-(2-chloro-4-(5-(1-(2,2-difluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzamide)-3-azabicyclo[3.1.0]hexane-3-carboxamide)cyclobutyl)carbamate (23.1 mg, 30 μmol, Eq: 1) dissolved in DCM was treated with excess TFA (103 mg, 69 μl, 0.9 mmol, Eq: 30). The reaction mixture was stirred overnight at room temperature. The mixture was quenched with TEA. After evaporation of the volatiles, the residue was purified by preparative HPLC to give the title product (3.4 mg). MS (ESI, m / z): 670.3 [M+H]+

[0372] Example 178 N-(4-(((1-Aminocyclopropyl)methyl)carbamoyl)-3-chlorophenyl)-5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide formate

Chemical formula

[0373] Step 1) Using 2-bromo-1,1-difluorocyclopropane instead of 1,1-difluoro-2-iodoethane, 2-chloro-4-(5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide)benzoic acid was prepared in the same manner as in Step 1 of Example 177. MS(ESI, m / z): 490.3 [M+H] +

[0374] Step 2) tert-Butyl (1-((2-chloro-4-(5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide)benzamide)methyl)cyclopropyl)carbamate 2-Chloro-4-(5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide)benzoic acid (29.4 mg, 0.060 mmol, Eq: 1), tert-butyl (1-(aminomethyl)cyclopropyl)carbamate (17.3 mg, 0.090 mmol, Eq: 1.50) and TBTU (CAS 125700-67-9: 26.8 mg, 0.081 mmol, Eq: 1.35) were combined with DMF (2.5 ml). TEA (30.4 mg, 42 μl, 0.300 mmol, Eq: 5.00) was added and the reaction mixture was stirred at room temperature overnight. The residue was purified by preparative HPLC to give the title product (37 mg). MS(ESI, m / z): 602.4 [M-tBu+H]+

[0375] Step 3) N-(4-(((1-aminocyclopropyl)methyl)carbamoyl)-3-chlorophenyl)-5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide formate tert-Butyl (1-((2-chloro-4-(5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzamido)methyl)cyclopropyl)carbamate (29.6 mg, 45 μmol, Eq: 1) was treated with excess TFA (128 mg, 87 μl, 1.13 mmol, Eq: (25)). The reaction mixture was stirred at room temperature overnight. The mixture was quenched with TEA. After evaporation of the volatiles, the residue was purified by preparative HPLC to afford the title product (10.1 mg). MS (ESI, m / z): 558.3 [M+H]+

[0376] Example 179 N-(3-chloro-4-(4-fluoro-4-((3-(trans-4-hydroxypyrrolidin-3-yl)ureido)methyl)piperidine-1-carbonyl)phenyl)-5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide formate

Chemical formula

[0377] Step 1) Using tert-butyl 3-(aminomethyl)piperidine-1-carboxylate instead of tert-butyl (1-(aminomethyl)cyclopropyl)carbamate, N-[4-[4-(aminomethyl)-4-fluoro-piperidine-1-carbonyl]-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide was prepared in the same manner as in Step 1 of Example 178. MS (ESI, m / z): 604.3 [M+H] +

[0378] Step 2) N-(3-chloro-4-(4-fluoro-4-((3-(trans-4-hydroxypyrrolidin-3-yl)ureido)methyl)piperidine-1-carbonyl)phenyl)-5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide formate tert-Butyl trans-3-amino-4-hydroxypyrrolidine-1-carboxylate (12.6 mg, 62.5 μmol, Eq: 2.50), CDI (CAS 530-62-1: 8.9 mg, 55 μmol, Eq: 2.20) and TEA (12.6 mg, 18 μl, 0.125 mmol, Eq: 5.00) were mixed in DMF at room temperature for 20 min. N-[4-[4-(aminomethyl)-4-fluoro-piperidine-1-carbonyl]-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide (16.2 mg, 25 μmol, Eq: 1.00) was then added. The reaction mixture was stirred at room temperature overnight. After evaporation of the volatiles, the product dissolved in DCM was treated with excess TFA (85 mg, 60 μl, 0.75 mmol, Eq: 30). The reaction mixture was stirred at room temperature overnight. The mixture was quenched with TEA. After evaporation of the volatiles, the residue was purified by preparative HPLC to give the title product (1.5 mg). MS (ESI, m / z): 688.4 [M+H]+

[0379] Example 167 N-(3-aminocyclobutyl)-4-(2-chloro-4-(1-methyl-5-(1-(2-methylallyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide)benzoyl)piperazine-1-carboxamide hydrochloride

Chemical formula

[0380] Step 1) tert-Butyl 4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate (3-(Trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (512 mg, 2.85 mmol, Eq: 1.5), tert-butyl 4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxylate (1 g, 1.9 mmol, Eq: 1), chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (127 mg, 190 μmol, Eq: 0.1), and potassium carbonate (525 mg, 3.8 mmol, Eq: 2) in a mixture of 1,4-dioxane (17.3 ml) and water (1.73 ml) were evacuated and backfilled with argon. The mixture was then heated at 130 °C by microwave for 30 min. LC / MS indicated ~30% progress. Additional (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (341 mg, 1.9 mmol, Eq: 1) was added and the mixture was heated at 130 °C for an additional 30 min. LC / MS indicated ~70% progress. It was heated again at 130 °C by microwave for 30 min. Little change was observed. Additional (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (520 mg, 2.89 mmol, Eq: 1.52) was added and the mixture was heated at 130 °C for 30 min again. LC / MS indicated complete consumption of the starting material. The mixture was diluted with ethyl acetate. The organic layer was washed with saturated NaHCO3 (2x), brine, then dried over magnesium sulfate and concentrated. The resulting residue was purified by flash chromatography (0 - 100% in heptane (75:25 EtOAc:EtOH), 80 g of SiO2) to give the title compound (740 mg, 1.27 mmol, 67% yield) as a yellow solid. MS (ESI, m / z): 582.3 [M+H]+

[0381] Process 2) tert-Butyl 4-[2-chloro-4-[[1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate A mixture of tert-butyl 4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (0.3 g, 515 μmol, Eq: 1), potassium carbonate (92.6 mg, 670 μmol, Eq: 1.3), and 3-bromo-2-methylprop-1-ene (83.5 mg, 56.7 μl, 619 μmol, Eq: 1.2) was stirred at room temperature for 90 min. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, then dried over magnesium sulfate, concentrated, and the crude title compound (319 mg, 486 μmol, yield 94.4%) was obtained as a yellow sticky solid. It was used as such in the next step. MS (ESI, m / z): 636.3 [M+H]+

[0382] Process 3) N-[3-Chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; hydrochloride A mixture of 4 M HCl in dioxane (2.51 ml, 10 mmol, Eq: 20) and tert-butyl 4-(2-chloro-4-(1-methyl-5-(1-(2-methylallyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (0.319 g, 502 μmol, Eq: 1) in dioxane (3 ml) was stirred at room temperature overnight. Diethyl ether was added. The white solid was collected by filtration, washed with diethyl ether (2x), and dried under reduced pressure to give the title compound (0.26 g, 445 μmol, yield 88.8%) as a white solid. MS (ESI, m / z): 536.2

[0383] Step 4) tert-Butyl (1R,5S,6r)-6-(4-(2-chloro-4-(1-methyl-5-(1-(2-methylallyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1R,5S,6r)-3-(tert-Butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (11.9 mg, 52.4 μmol, Eq: 1.2), N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(2-methylallyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide hydrochloride (0.025 g, 43.7 μmol, Eq: 1), HATU (19.9 mg, 52.4 μmol, Eq: 1.2) and DIEA (14.1 mg, 19.1 μl, 109 μmol, Eq: 2.5) in dry DMF (1 ml) were stirred at room temperature for 90 min (Rxn molar concentration: 43.7 mM). The mixture was diluted in ethyl acetate, washed with saturated NaHCO3 (4x), and then concentrated. The resulting residue was purified by flash chromatography to give the title compound (21 mg, 27.6 μmol, 63.2% yield) as a white powder. MS (ESI, m / z): 745.4

[0384] Step 5) N-(4-(4-((1R,5S,6r)-3-Azabicyclo[3.1.0]hexane-6-carbonyl)piperazine-1-carbonyl)-3-chlorophenyl)-1-methyl-5-(1-(2-methylallyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide hydrochloride tert-Butyl (1R,5S,6r)-6-(4-(2-chloro-4-(1-methyl-5-(1-(2-methylallyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.021 g, 28.2 μmol, Eq: 1) and 4 M HCl in dioxane (141 μl, 564 μmol, Eq: 20) in dioxane (0.5 ml) were stirred at room temperature overnight. Diethyl ether was added. The mixture was stirred for 30 min and then concentrated. The resulting residue was further washed with diethyl ether and then dried in vacuo to give the title compound (14 mg, 20.3 μmol, 72.2% yield) as a white solid. MS (ESI, m / z): 645.4

[0385] Step 6) tert-Butyl (3-(4-(2-chloro-4-(1-methyl-5-(1-(2-methylallyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamido)cyclobutyl)carbamate N-(3-Chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(2-methylallyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide hydrochloride (25 mg, 43.7 μmol, Eq: 1) was dissolved in DCM (625 μl). DIPEA (28.2 mg, 38.1 μl, 218 μmol, Eq: 5) and triphosgene (5.18 mg, 17.5 μmol, Eq: 0.4) were added successively. After 5 min, tert-butyl (cyclobutyl-3-yl)carbamate (24.4 mg, 131 μmol, Eq: 3) was added. The reaction mixture was stirred at room temperature for 2.5 h. The mixture was quenched with saturated NaHCO3 and extracted with DCM. The organic matter was dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography to give the title compound (17 mg, 22.3 μmol, 51% yield) as a white solid. MS (ESI, m / z): 748.4

[0386] Step 7) N-(3-Aminocyclobutyl)-4-(2-chloro-4-(1-methyl-5-(1-(2-methylallyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamide hydrochloride A mixture of 4M HCl in dioxane (107 μl, 428 μmol, Eq: 20) and tert-butyl (3-(4-(2-chloro-4-(1-methyl-5-(1-(2-methylallyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamido)cyclobutyl)carbamate (0.016 g, 21.4 μmol, Eq: 1) in dioxane was stirred overnight at room temperature. Diethyl ether was added to the mixture. The resulting white solid was washed twice with diethyl ether and then dried in vacuo to give the title compound (10 mg, 14.6 μmol, 68.3% yield) as a white solid. MS (ESI, m / z): 648.3

[0387] Example 180 N-[3-Chloro-4-[4-(3-Hydroxy-1-piperidinecarbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carboxamide; trihydrochloride

Chemical Structure

[0388] Step 1) tert-Butyl 4-[2-chloro-4-[[5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate Under argon, tert-butyl 4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (Example 167, Step 1) (0.6 g, 1.03 mmol, Eq: 1) was dissolved in DMF (6 mL). Sodium bicarbonate (433 mg, 5.15 mmol, Eq: 5) and 1-bromo-2-fluoroethane (262 mg, 154 μL, 2.06 mmol, Eq: 2) were added, and the dark brown reaction mixture was stirred with microwave at 120 °C for 2 h. The reaction mixture was filtered, and the filtrate was washed three times with saturated NaHCO3 solution. The organic layers were combined and evaporated. The crude material was purified by flash chromatography to give the title compound (200 mg, 31%) as an off-white solid. MS (ESI, m / z): 628.4

[0389] Step 2) N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; hydrochloride tert-butyl 4-(2-chloro-4-(5-(1-(2-fluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (200.4 mg, 319 μmol, Eq: 1) was stirred with 4 M HCl in dioxane (1.6 mL, 6.38 mmol, Eq: 20) in dioxane (2 mL) at room temperature for 5 h. Diethyl ether (3 mL) was added, and the reaction mixture was stirred at room temperature for 30 min. The resulting suspension was filtered off, and the solid was evaporated to dryness to give the title compound (142 mg) as off-white crystals. MS (ESI, m / z): 528.3

[0390] Step 3) tert-Butyl 3-[4-[2-chloro-4-[[5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-3-hydroxy-piperidine-1-carboxylate N-(3-Chloro-4-(piperazine-1-carbonyl)phenyl)-5-(1-(2-fluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide hydrochloride (24 mg, Eq: 1), 1-(tert-butoxycarbonyl)-3-hydroxypiperidine-3-carboxylic acid (28 mg, 57 μmol, Eq: 1.35), and HATU (17.3 mg, 45.6 μmol, Eq: 1.25 eq) were combined in DMF to obtain a yellow solution. DIEA (7.37 mg, 9.96 μl, 57 μmol, Eq: 1.5) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to obtain the title compound (15 mg) as a white solid.

[0391] Step 4) N-[3-Chloro-4-[4-(3-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methylimidazole-2-carboxamide; hydrochloride tert-Butyl 3-(4-(2-chloro-4-(5-(1-(2-fluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)-3-hydroxypiperidine-1-carboxylate (15 mg, 20.1 μmol, Eq: 1) was stirred overnight in dioxane (0.5 ml) at room temperature with 4 M HCl in dioxane (100 μl, 401 μmol, Eq: 20). Diethyl ether (2 mL) was added and the reaction mixture was stirred for 30 min at RT. The resulting suspension was filtered off and the obtained solid was dried to obtain the title compound (12 mg, 53%) as a white waxy solid. MS (ESI, m / z): 655.3

[0392] Intermediates A and B Methyl (R)-2-chloro-4-(5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide) benzoate (A)

Chem.

Chem.

[0393] Step 1) Methyl 2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino] benzoate To a solution of methyl 2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazole-2-carboxamide) benzoate (1.5 g, 3.51 mmol, Eq: 1) in DMF (10 ml) were added potassium carbonate (727 mg, 5.26 mmol, Eq: 1.5) and 2-bromo-1,1-difluorocyclopropane (771 mg, 431 μl, 4.91 mmol, Eq: 1.4). The mixture was stirred at 75 °C overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed three times with 5% LiCl. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. -> 1.5115 g of a light brown solid. The residue was purified by flash chromatography to give the title compound (1.0335 g, 2.01 mmol, 57.3% yield) as a white solid. MS (ESI, m / z): 504.3

[0394] Process 2) Methyl (R)-2-chloro-4-(5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide) benzoate (A) and methyl (S)-2-chloro-4-(5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide) benzoate (B) Methyl 2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoate was separated by chiral SFC to obtain enantiomer A MS (ESI, m / z): 504.1 and B MS (ESI, m / z): 504.1.

[0395] Example 181 (1S,5R)-6-[[2-chloro-4-[[5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; hydrochloride [Chemical formula]

[0396] Process 1) 2-chloro-4-[[5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoic acid Methyl (R)-2-chloro-4-(5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide) benzoate (Intermediate A) was dissolved in 2-methyl-THF and MeOH. Lithium hydroxide was added. The reaction mixture was stirred at room temperature overnight. The solvent was removed. 1.5 ml of water was added. The solution was acidified with 1 M aqueous HCl. The aqueous phase was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated. The residue was purified by reverse-phase preparative HPLC to give the title compound (80 mg, 89.8 μmol, 76.7% yield) as a white solid. MS (ESI, m / z): 490.3

[0397] Step 2) tert-Butyl (1S,5R)-6-[[2-chloro-4-[[5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (R)-2-Chloro-4-(5-(1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide) benzoic acid (30 mg, 61.3 μmol, Eq: 1), HATU (23.3 mg, 61.3 μmol, Eq: 1) and DIEA (23.7 mg, 32.1 μl, 184 μmol, Eq: 3) were dissolved in DMF (613 μl). After 10 minutes, tert-butyl (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (14.6 mg, 73.5 μmol, Eq: 1.2) was added. The resulting yellow solution was stirred at room temperature for 2 hours. 10 mL of ethyl acetate was added. The organic solution was washed 4 times, dried, concentrated, and the title compound (33 mg, 80%) was obtained as a white solid. It was used as such. MS (ESI, m / z): 670.4

[0398] Process 3) N-[4-[[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]-3-chloro-phenyl]-5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide tert-Butyl (1R,5S,6s)-6-(2-chloro-4-(5-(1-((R)-2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide)benzamide)-3-azabicyclo[3.1.0]hexane-3-carboxylate (33 mg, 49.3 μmol, Eq: 1) was dissolved in dioxane (246 μL), then 4 M hydrochloric acid in dioxane (246 μl, 985 μmol, Eq: 20) was added. The reaction mixture was stirred at room temperature for 3 h. 1 mL of diethyl ether was added. Then the mixture was concentrated to give the title compound as an orange wax-like solid (37 mg, purity 80%, quantitative). It was used as such. MS (ESI, m / z): 570.3

[0399] Process 4) tert-Butyl (3R,4R)-3-[[(1S,5R)-6-[[2-chloro-4-[[5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylate It should be noted that there seems to be an error in the original text in item . It says "stirred at room temperature for 30min" which might be a typo as the following text seems to imply 3 hours of stirring. The translation has been adjusted according to the corrected content.A solution of CDI (5.14 mg, 31.7 μmol, Eq: 1.3) and tert-butyl (3R,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate (6.42 mg, 31.7 μmol, Eq: 1.3) in DMF (0.5 ml) was stirred for 80 min. N-(4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamoyl)-3-chlorophenyl)-5-(1-((R)-2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H-imidazole-2-carboxamide hydrochloride (18.5 mg, 24.4 μmol, Eq: 1) in 250 ul of DMF was added to the reaction. The resulting mixture was stirred overnight. 5 mL of ethyl acetate was added. The organic phase was washed 4 times with water, dried over magnesium sulfa...

Claims

1. Formula (I) 【Chemical Formula 1】 [wherein: R Ａ is C １ -C ６ -alkyl or group [Chemical 2] is; and here: (i) R １ and R ２ together with the nitrogen atom to which they are attached may be substituted with one or more (1-2) R ８ optionally substituted C ２ -C ９ -heterocyclic ring; or (ii) R １ is hydrogen, C １ -C ６ -alkyl, amino-C １ -C ６ -alkyl-, amino-C １ -C ６ -alkyl-O-C １ -C ６ -alkyl-, C １ -C ６ -alkoxycarbonyl-NH-C １ -C ６ -alkyl-, C １ -C ６ -alkoxycarbonyl-C １ -C ６ -alkyl-NH-C １ -C ６ -alkyl- or a group [Chemical Formula 3] is; and R ２ is hydrogen or C １ -C ６ alkyl; R ３ and R ７ each independently is hydrogen, halogen or C １ -C ６ -alkyl; R ４ is halo-C １ -C ６ -alkyl or C ６ -C １４ -aryl; R ５ is C substituted with hydrogen, CF ３ R １１ and R １２ and is C １ -C ６ -alkyl, C ２ -C ６ -alkenyl, halo-C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, amino-C ２ -C ６ -alkynyl-, C １ -C ６ -alkoxy, halo-C １ -C ６ -alkoxy-C １ -C ６ -alkyl, C １ -C ６ -alkoxy-C ２ -C ６ -alkynyl-, hydroxy-C ２ -C ６ -alkynyl-, or a group 【Chemical 4】 is; R ６ is C １ -C ６ alkyl; R ８ is C １ -C ６ -alkoxycarbonyl, amino-C １ -C ６ -alkyl, C １ -C ６ -alkyl-NH-, amino-C １ -C ６ -alkyl-C(O)-, amino-C １ -C ６ -alkyl-NH-C(O)-C １ -C ６ -alkyl-, amino-C １ -C ６ -alkyl-CH(OH)-, amino-C １ -C ６ -alkyl-CH(NH ２ )-C(O)-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-N(C １ -C ６ -alkyl)-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-C(O)-, C １ -C ６ -alkyl-NH-C １ -C ６ -alkyl-C(O)-, C １ -C ６ -alkyl-NH-C １ -C ６ -alkyl-NH-C(O)-, oxo, amino, halogen, or group [Chemical Formula 5] is; R ９ and R １０ each independently represents hydrogen, hydroxy, amino, C １ -C ６ -alkyl, C １ -C ６ -alkoxy, amino-C １ -C ６ -alkyl-C(O)-NH-, amino-C １ -C ６ -alkyl-CH(halo-C １ -C ６ -alkyl)-NH-C(O)-, amino-C ３ -C １２ -cycloalkyl-C(O)-NH- or a group 【Chemical Formula 6】 is; R １１ and R １２ each independently is hydrogen, halogen, hydroxy, cyano, CF ３ , carbamoyl, halo-C １ -C ６ -alkoxy-, (C １ -C ６ -alkyl) ２ N-C(O)-, C １ -C ６ -alkyl-NH-C(O)-, C １ -C ６ -alkoxy-, or C １ -C ６ -alkoxy-C １ -C ６ -alkoxy; R １３ 、 R １４ 、 and R １５ each independently is hydrogen, oxo, amino, hydroxy, C １ -C ６ -alkyl-NH-, (C １ -C ６ -alkyl) ２ N-, halogen, C ３ -C １２ -cycloalkyl, C １ -C ６ -alkyl, halo-C １ -C ６ -alkyl or hydroxy-C １ -C ６ -alkyl; R １６ 、R １７ 、and R １８ each independently is hydrogen, halogen, amino, hydroxy, amino-C １ -C ６ -alkyl, C １ -C ６ -alkyl-NH- or C １ -C ６ -alkyl; R １９ and R ２０ each independently is hydrogen, amino, hydroxy, C １ -C ６ -alkyl, amino-C １ -C ６ -alkyl-, or HO-S(O) ２ -C １ -C ６ -alkyl; A, B, C, and D are each independently C ６ -C １４ -aryl, C １ -C １３ -heteroaryl, C ３ -C １２ -cycloalkyl, or C ２ -C ９ -heterocyclyl; and X １ 、 X ２ 、 X ３ 、 X ４ 、 and X ５ each independently is a covalent bond, carbonyl, C １ -C ６ -alkyl, -C １ -C ６ -alkyl-C(O)-, -NH-C(O)-, -C(O)-NH-, -NH-C(O)-NH-, -NH-C(O)-NH-C １ -C ６ -alkyl-, -NH-C(O)-N(C １ -C ６ -alkyl)-C １ -C ６ -alkyl-, -C １ -C ６ -alkyl-NH-C(O)-NH-C １ -C ６ -alkyl-, -C １ -C ６ -alkyl-NH-C(O)-, -S-, -SO-, -SO ２ - or a group [Chemical Formula 7] is] a compound, or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) is a compound of formula (I-II) 【Chemical Formula 8】 [wherein: (i) R １ and R ２ together with the nitrogen atom to which they are attached, may form a C ８ -C ２ -C ９ -heterocyclic ring; or (ii) R １ is hydrogen, C １ -C ６ -alkyl, amino-C １ -C ６ -alkyl-, amino-C １ -C ６ -alkyl-O-C １ -C ６ -alkyl-, or a group 【Chemical Formula 9】 is; and R ２ is hydrogen or C １ -C ６ -alkyl; R ３ and R ７ each independently is hydrogen, halogen or C １ -C ６ -alkyl; R ４ is halo-C １ -C ６ -alkyl or C ６ -C １４ -aryl; R ５ is hydrogen, CF ３ , R １１ and R １２ substituted C １ -C ６ -alkyl, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, amino-C ２ -C ６ -alkynyl-, C １ -C ６ -alkoxy-C ２ -C ６ -alkynyl-, hydroxy-C ２ -C ６ -alkynyl-, or group 【Chemical 10】 is; R ６ is C １ -C ６ alkyl; R ８ is C １ -C ６ -alkoxycarbonyl, amino-C １ -C ６ -alkyl-C(O)-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-C(O)-, C １ -C ６ -alkyl-NH-C １ -C ６ -alkyl-C(O)-, C １ -C ６ -alkyl-NH-C １ -C ６ -alkyl-NH-C(O)-, or a group 【Chemical 11】 is; R ９ and R １０ each independently is hydrogen, hydroxy, amino, amino-C １ -C ６ -alkyl-C(O)-NH-, or amino-C ３ -C １２ -cycloalkyl-C(O)-NH-; R １１ and R １２ each independently is hydrogen, halogen, hydroxy, cyano, CF ３ , carbamoyl, halo-C １ -C ６ -alkoxy-, (C １ -C ６ -alkyl) ２ N-C(O)-, C １ -C ６ -alkyl-NH-C(O)-, C １ -C ６ -alkoxy-, or C １ -C ６ -alkoxy-C １ -C ６ -alkoxy; R １３ 、 R １４ 、 and R １５ each independently is hydrogen, oxo, halogen, C ３ -C １２ -cycloalkyl, C １ -C ６ -alkyl, or hydroxy-C １ -C ６ -alkyl; R １６ and R １７ each independently is hydrogen, amino, hydroxy, amino-C １ -C ６ -alkyl, or C １ -C ６ -alkyl; A, B, and C are each independently C ６ -C １４ -aryl, C １ -C １３ -heteroaryl, C ３ -C １２ -cycloalkyl, or C ２ -C ９ -heterocyclyl; and X １ , X ２ , X ３ , and X ４ is, each independently, a shared bond, carbonyl, C １ -C ６ -alkyl, -NH-C(O)-, -C(O)-NH-, -C １ -C ６ -alkyl-NH-C(O)-, or -SO ２ -]] The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) is a compound of formula (I-A): 【Chemical 12】 [wherein, X １ , R １ ~R ３ , and R ５ ~R ７ are as defined in claim 1 or 2] The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. The compound of formula (I) is a compound of formula (I-B): 【Chemical Formula 13】 [wherein, X １ , R １ ~R ３ , R ５ , and R ７ are as defined in claim 1] The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

5. The compound of formula (I) is a compound of formula (I-C): 【Chemical Formula 14】 [wherein, R ３ , R ５ , R ７ , R ８ and X １ are as defined in claim 1, and Y is CH or N] The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

6. The compound of formula (I) is a compound of formula (I-D): 【Chemical Formula 15】 [wherein, R ３ , R ５ , R ７ , R ８ and X １ are as defined in claim 1] The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

7. (i) R １ and R ２ together with the nitrogen atom to which they are attached form a piperazinyl or piperidyl ring which may be substituted with one or two R ８ groups; or (ii) R １ is 2-(2-amino-2-methyl-propoxy)ethyl or a group 【Chemical 16】 and R ２ is hydrogen, The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

8. R ３ is halogen or C １ -C ６ -alkyl, a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. R ４ is halo-C １ -C ６ -alkyl, a compound of formula (I) according to any one of claims 1, 2, 7 and 8, or a pharmaceutically acceptable salt thereof.

10. R ５ where R １１ and R １２ substitute for C １ -C ６ -alkyl, C ２ -C ６ -alkenyl, halo-C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, or the group 【Chemical 17】 is, the compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. R ６ The compound of formula (I) according to any one of claims 1 to 3 and 7 to 10, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

12. R ７ The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or halogen.

13. R ８ is halogen or a group 【Chemical 18】 is, the compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. R ９ is hydrogen, amino, hydroxy, alkyl, alkoxy, amino-C １ -C ６ -alkyl-C(O)-NH- or a group 【Chemical Formula 19】 is, the compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. R １０ is hydrogen, C １ -C ６ -alkyl or C １ -C ６ -alkoxy, a compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. R １１ is hydrogen, cyano, CF ３ , or halogen, a compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

17. R １２ The compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or halogen.

18. R １３ is hydrogen, oxo, halogen, C ３ -C １２ -cycloalkyl, C １ -C ６ -alkyl, halo-C １ -C ６ -alkyl or hydroxy-C １ -C ６ -alkyl, a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

19. R １４ is hydrogen, oxo, halogen, or C １ -C ６ -alkyl, a compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

20. R １５ The compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or halogen.

21. R １６ The compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, amino, or hydroxy.

22. R １７ is hydrogen, amino or C １ -C ６ -alkyl, a compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof.

23. R １８ The compound of formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or amino.

24. R １９ The compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, amino or hydroxy.

25. R ２０ The compound of formula (I) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or hydroxy.

26. A is cyclobutyl, cyclopropyl or 3-azabicyclo[3.1.0]hexan-6-yl, the compound of formula (I) according to any one of claims 1 to 4 and 7 to 25, or a pharmaceutically acceptable salt thereof.

27. B is cyclopropyl, cyclobutyl, or spiro[2.3]hexan-5-yl, the compound of formula (I) according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof.

28. The compound of formula (I) according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein C is cyclobutyl, cyclopentyl, 3-piperidyl, 4-piperidyl, pyrrolidin-3-yl, azetidin-3-yl, 3-azabicyclo[3.1.0]hexan-6-yl, or 2,5-diazabicyclo[2.2.1]heptan-2-yl.

29. The compound of formula (I) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein D is pyrrolidin-3-yl, 4-piperidyl or cyclobutyl.

30. X １ is —S—, a covalent bond, a carbonyl, —SO ２ — or a group 【Chemical 20】 The compound of formula (I) according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein [description of conditions].

31. X ２ is a covalent bond or C １ -C ６ -alkyl, a compound of formula (I) according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof.

32. X ３ is a covalent bond or C １ -C ６ -alkyl, a compound of formula (I) according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof.

33. X ４ is a covalent bond, carbonyl, -NH-C(O)-, -NH-C(O)-NH-, -NH-C(O)-NH-C １ -C ６ -alkyl-, -C １ -C ６ -alkyl-NH-C(O)-, -C １ -C ６ -alkyl-C(O)- or -SO ２ -, a compound of formula (I) according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof.

34. X ５ The compound of formula (I) according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein X is carbonyl, -C(O)-NH-, -NH-C(O)- or -NH-C(O)-NH-.

35. R Ａ is C １ -C ６ -alkyl or a group 【Chemical 21】 [Wherein: (i) R １ and R ２ together with the nitrogen atom to which they are attached form a C ８ -C ２ -C ９ -heterocyclic ring which may be substituted by one or two R (ii) R １ is hydrogen, C １ -C ６ -alkyl, amino-C １ -C ６ -alkyl-, amino-C １ -C ６ -alkyl-O-C １ -C ６ -alkyl-, C １ -C ６ -alkoxycarbonyl-NH-C １ -C ６ -alkyl-, C １ -C ６ -alkoxycarbonyl-C １ -C ６ -alkyl-NH-C １ -C ６ -alkyl- or group 【Chemical formula 22】 [description of condition 1]; and R ２ is hydrogen or C １ -C ６ alkyl]; R ３ is halogen or C １ -C ６ alkyl; R ４ is halo-C １ -C ６ -alkyl or C ６ -C １４ -aryl; R ５ wherein R １１ and R １２ are C １ -C ６ -alkyl, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, halo-C ２ -C ６ -alkenyl, amino-C ２ -C ６ -alkynyl-, halo-C １ -C ６ -alkoxy-C １ -C ６ -alkyl, C １ -C ６ -alkoxy-C ２ -C ６ -alkynyl-, hydroxy-C ２ -C ６ -alkynyl-, or a group 【Chemical 23】 [description of condition 2]; R ６ is C １ -C ６ alkyl; R ７ is hydrogen or halogen; R ８ is C １ -C ６ -alkoxycarbonyl, amino-C １ -C ６ -alkyl, C １ -C ６ -alkyl-NH-, amino-C １ -C ６ -alkyl-C(O)-, amino-C １ -C ６ -alkyl-NH-C(O)-C １ -C ６ -alkyl-, amino-C １ -C ６ -alkyl-CH(OH)-, amino-C １ -C ６ -alkyl-CH(NH ２ )-C(O)-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-N(C １ -C ６ -alkyl)-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-C(O)-, C １ -C ６ -alkyl-NH-C １ -C ６ -alkyl-NH-C(O)-, oxo, amino, halogen, or group 【Chemical 24】 [description of condition 3]; R ９ is hydrogen, amino, hydroxy, alkyl, alkoxy, amino-C １ -C ６ -alkyl-C(O)-NH- or a group 【Chemical 25】 [description of condition 4]; R １０ is hydrogen, C １ -C ６ -alkyl or C １ -C ６ -alkoxy; R １１ is hydrogen, halogen, hydroxy, cyano, CF ３ , carbamoyl, halo-C １ -C ６ -alkoxy-, (C １ -C ６ -alkyl) ２ N-C(O)-, C １ -C ６ -alkyl-NH-C(O)-, or C １ -C ６ -alkoxy-C １ -C ６ -alkoxy; R １２ is hydrogen or halogen; R １３ is hydrogen, oxo, halogen, C ３ -C １２ -cycloalkyl, C １ -C ６ -alkyl, halo-C １ -C ６ -alkyl or hydroxy-C １ -C ６ -alkyl; R １４ is hydrogen, oxo, halogen, or C １ -C ６ -alkyl; R １５ is hydrogen or halogen; R １６ is hydrogen, halogen, amino, hydroxy, amino-C １ -C ６ -alkyl, C １ -C ６ -alkyl-NH- or C １ -C ６ -alkyl; R １７ is hydrogen, amino or C １ -C ６ -alkyl; R １８ is hydrogen or amino; R １９ is hydrogen, amino, hydroxy, C １ -C ６ -alkyl, amino-C １ -C ６ -alkyl or HO-SO ２ -C １ -C ６ -alkyl; R ２０ is hydrogen or hydroxy; A is C ２ -C ９ -heterocyclyl or C ３ -C １２ -cycloalkyl; B is C ６ -C １４ -aryl, C １ -C １３ -heteroaryl, C ３ -C １２ -cycloalkyl, or C ２ -C ９ -heterocyclyl; C is C ３ -C １２ -cycloalkyl or C ２ -C ９ -heterocyclyl; D is C ３ -C １２ -cycloalkyl or C ２ -C ９ -heterocyclyl; X １ is —S—, a covalent bond, a carbonyl, —SO ２ — or a group 【Chemical 26】 [description of condition 5]; X ２ is a covalent bond or C １ -C ６ -alkyl; X ３ is a covalent bond or C １ -C ６ -alkyl; X ４ is a covalent bond, a carbonyl group, -NH-C(O)-, -NH-C(O)-NH-, -NH-C(O)-NH-C １ -C ６ -alkyl-, -C １ -C ６ -alkyl-NH-C(O)-, -C １ -C ６ -alkyl-C(O)- or -SO ２ -; and X ５ is carbonyl, -C(O)-NH-, -NH-C(O)- or -NH-C(O)-NH- The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

36. R Ａ is the base 【Chemical 27】 [Wherein: (i) R １ and R ２ together with the nitrogen atom to which they are attached may form a C ８ -C ２ -C ９ -heterocyclic ring which may be substituted by one or two R (ii) R １ is amino-C １ -C ６ -alkyl-O-C １ -C ６ -alkyl- or a group 【Chemical 28】 [description of condition 1]; and R ２ is hydrogen]; and R ３ is halogen or C １ -C ６ alkyl; R ４ is halo-C １ -C ６ -alkyl; R ５ where R １１ and R １２ are C １ -C ６ -alkyl, C ２ -C ６ -alkenyl, halo-C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, or a group 【Chemical Formula 29】 [description of condition 2]; R ６ is C １ -C ６ alkyl; R ７ 、 R １０ 、 R １５ 、 R １７ 、 R １８ and R ２０ are all hydrogen; R ８ is a halogen or a group 【Chemical 30】 [description of condition 3]; R ９ is an amino or group 【Chemical 31】 [description of condition 4]; R １１ is hydrogen, cyano, CF ３ , or halogen; R １２ 、R １３ 、and R １４ each is independently hydrogen or halogen; R １６ and R １９ each is independently hydrogen, amino, or hydroxy; A, C, and D are each independently C ２ -C ９ -heterocyclyl or C ３ -C １２ -cycloalkyl; B is C ３ -C １２ - is cycloalkyl; X １ is a carbonyl; X ２ and X ３ each independently is a covalent bond or C １ -C ６ -alkyl; X ４ is carbonyl, -NH-C(O)-, -NH-C(O)-NH-C １ -C ６ -alkyl- or -C １ -C ６ -alkyl-NH-C(O)-; and X ５ is carbonyl or -NH-C(O)- The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

37. R Ａ is the base 【Chemical 32】 [Wherein: (i) R １ and R ２ together with the nitrogen atom to which they are attached form a piperazinyl or piperidyl ring which may be substituted with one or two R ８ groups; or (ii) R １ is 2-(2-amino-2-methyl-propoxy)ethyl or a group 【Chemical 33】 [description of condition 1]; and R ２ is hydrogen]; and R ３ is chloro or ethyl; R ４ is CF ３ ; and R ５ wherein R １１ and R １２ are C １ -C ６ -alkyl, allyl, prop-2-ynyl, or a group 【Chemical 34】 and wherein said C １ -C ６ -alkyl is methyl, ethyl, or isopropyl; R ６ is methyl; R ７ 、 R １０ 、 R １５ 、 R １７ 、 R １８ and R ２０ are all hydrogen; R ８ is fluoro or a group 【Chemical 35】 [description of condition 2]; R ９ is an amino or group 【Chemical 36】 [description of condition 3]; R １１ is hydrogen, cyano, CF ３ , or fluoro; R １２ , R １３ , and R １４ each is independently hydrogen or fluoro; R １６ and R １９ each is independently hydrogen, amino, or hydroxy; A is cyclobutyl, cyclopropyl or 3-azabicyclo[3.1.0]hexan-6-yl; B is cyclopropyl, cyclobutyl, or spiro[2.3]hexan-5-yl; C is cyclobutyl, cyclopentyl, 3-piperidyl, 4-piperidyl, pyrrolidin-3-yl, azetidin-3-yl, 3-azabicyclo[3.1.0]hexan-6-yl, or 2,5-diazabicyclo[2.2.1]heptan-2-yl; D is pyrrolidin-3-yl, 4-piperidyl or cyclobutyl; X １ is a carbonyl; X ２ and X ３ each is independently a covalent bond or -CH ２ -; X ４ is carbonyl, -NH-C(O)-, -NH-C(O)-NH-CH ２ -, or -CH ２ -NH-C(O)-; and X ５ is carbonyl or -NH-C(O)- The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

38. The compound of formula (I) is: N-(azetidin-3-yl)-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pent-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 4-[2-Chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S,4S)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-(dimethylcarbamoyl)phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-1,2-dienyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[2-[(2R)-2-aminopropoxy]ethylcarbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[2-(2-amino-2-methyl-propoxy)ethylcarbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2R)-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(1-methylprop-2-ynyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-But-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-Allyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4-methoxybut-2-ynyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-[(2S)-2-aminopropoxy]ethylcarbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-isobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-(methylcarbamoyl)phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[4-(3-aminopropylcarbamoyl)-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(4-aminobut-2-ynyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4-hydroxy-2-butynyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(4-Carbamoyl-3-chloro-phenyl)-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazin-1-yl]sulfonyl-phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(2S)-2-aminopropanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(Cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-N-[3-methyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]imidazole-2-carboxamide; N-[3-Chloro-4-[[(3S)-pyrrolidin-3-yl]methylcarbamoyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[[(3S,4R)-4-hydroxypyrrolidin-3-yl]methylcarbamoyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazin-1-yl]sulfonyl-phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[[(3R)-pyrrolidin-3-yl]methylcarbamoyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[2-(isopropylamino)-2-oxo-ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-cyanoethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; tert-butyl 4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate; 5-[1-(2-amino-1-methyl-2-oxo-ethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(1,1-dioxothietan-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(2-pyrazol-1-ylethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 1-Methyl-N-[3-methyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[2-(methylamino)-2-oxo-ethyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(2-Amino-2-oxo-ethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[2-(dimethylamino)-2-oxo-ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(1-cyclopropyl-2-oxo-pyrrolidin-3-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[2-(2-methoxyethoxy)ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(6-Aminohexylcarbamoyl)-3-methyl-phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(3-Amino-3-oxo-propyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(1S,3R)-3-Aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-(5-Aminopentylcarbamoyl)-3-methyl-phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-propan-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[1-methyl-5-[1-propan-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[4-[(3R)-3-Aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-propan-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[(1S,2R)-2-Aminocyclopentyl]-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,6-diazaspiro[3.3]heptane-6-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(3S)-3-Aminopiperidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[(3-Aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Aminopiperidine-1-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(3,6-diazabicyclo[3.2.0]heptane-3-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(2S)-2-aminopropanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-N-[(rac-(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]piperazine-1-carboxamide; N-[4-[4-[(3aS,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-(3-amino-3-methyl-azetidine-1-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-(2-azaspiro[3.3]heptan-6-yl)-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-N-[2-(methylamino)ethyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-spiro[2.3]hexan-5-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperazine-1-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[(2,2-difluorocyclopropyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[(1S,3S)-3-aminocyclopentyl]-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 4-[4-[[5-[1-allyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-N-(azetidin-3-yl)piperazine-1-carboxamide; 5-[1-allyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[4-[(3-aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[5-[1-cyclobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[(3,3-difluorocyclobutyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[3-(trifluoromethyl)-1-(3,3,3-trifluoropropyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(fluoromethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[3-[[(2R)-2-aminopropanoyl]amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(1-cyanoethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[(3-methylthietan-3-yl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-isopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[2-(difluoromethoxy)ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[(3-aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-5-[1-cyclobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(difluoromethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[[3-[[(1S,3R)-3-aminocyclopentanecarbonyl]amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[4-(aminomethyl)-4,5-dihydrooxazol-2-yl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(3-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[1-methyl-5-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[(3-aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[(3-Aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(Azetidin-3-yl)-4-[2-chloro-4-[[5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 5-[1-[1-(Chloromethyl)-2-hydroxy-ethyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(Cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-[2-(Chloromethyl)-3-hydroxy-2-methyl-propyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Amino-4-methyl-piperidine-1-carbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(2,2-Difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(1S,3R)-3-aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-fluoro-5-methyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-Aminopiperidine-1-carbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(Cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-[rac-(3S,4S)-3-amino-4-methyl-piperidine-1-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-(6-Amino-2-azaspiro[3.3]heptane-2-carbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-(3-phenyl-1H-pyrazol-4-yl)imidazole-2-carboxamide; N-[4-[4-(3-Aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-fluoro-5-methyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(Cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(3-methylpiperazine-1-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(Cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[4-[4-(2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[3-(aminomethyl)pyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[4-(aminomethyl)-4,5-dihydrooxazol-2-yl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(2S)-2-aminopropanoyl]piperazine-1-carbonyl]-3-fluoro-5-methyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-fluoro-5-methyl-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(azetidine-3-carbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(3-hydroxy-3-methyl-butyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(1H-pyrazol-5-ylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-(3-azabicyclo[3.1.0]hexan-6-yl)-4-[4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]piperazine-1-carboxamide; 5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-ethyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[2-(aminomethyl)pyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; 5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-ethyl-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-ethyl-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-ethyl-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 4-[2-ethyl-4-[[1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; N-[3-ethyl-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(3-pyridylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-[[3-chloro-1-(hydroxymethyl)-3-methyl-cyclobutyl]methyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(azetidine-3-carbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(3-aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-[(2-methylthiazol-4-yl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-fluoro-4-[4-(3-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]-5-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(4-aminocyclohexyl)carbamoyl]-3-chloro-phenyl]-1-methyl-5-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazole-2-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[4-[(1-Aminocyclopropyl)methylcarbamoyl]-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; (1R,5S)-6-[[2-Chloro-4-[[5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,5S)-6-[[2-Chloro-4-[[5-[1-[(1S)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1R,5S)-6-[[2-Chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1S,5R)-6-[[2-Chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-Chloro-4-[[rac-(1S,5R)-3-(piperazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[[rac-(1S,5R)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(5-Aminopentylcarbamoyl)-3-chloro-phenyl]-5-[1-(2-fluoroallyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1S,5R)-6-[[2-Chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(1R,2S)-2-aminocyclopentyl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[4-(6-Aminohexylcarbamoyl)-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Chloro-4-piperazin-1-ylsulfonyl-phenyl)-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1S,5R)-6-[[2-Chloro-4-[[5-[1-(2-fluoroallyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1R,5S)-6-[[2-Chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3S)-pyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1S)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[4-[4-aminobutyl(methyl)carbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-aminoethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[rac-(1S,5R)-3-[rac-(3R)-3-aminopyrrolidine-1-carbonyl]-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(6-aminospiro[3.3]heptan-2-yl)carbamoyl]-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-fluoro-4-[[[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamoylamino]methyl]piperidine-1-carbonyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(Cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-fluoro-4-[4-[rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[(3R)-3-(aminomethyl)pyrrolidine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-ylmethylcarbamoyl)-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(azetidin-3-yl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1-vinyl-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-[(2R,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazin-1-yl]sulfonyl-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(4-aminobutylcarbamoyl)-3-chloro-phenyl]-1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-(2-aminoacetyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(Aminomethyl)-4-fluoro-piperidine-1-carbonyl]-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-Aminoacetyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 5-[1-(2,2-Difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-N-[4-(2-oxopyrrolidin-1-yl)phenyl]imidazole-2-carboxamide; N-[4-(5-Aminopentylcarbamoyl)-3-chloro-phenyl]-1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(1R,3R)-3-Aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(Aminomethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(Azetidine-3-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-6-[[2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[4-[4-(2-Aminoacetyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[1-methyl-5-[1-spiro[2.3]hexane-5-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[4-[(1S,3R)-3-Aminocyclopentanecarbonyl]piperazin-1-yl]sulfonyl-3-chloro-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-5-[1-cyclobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-Amino-2-methyl-propoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(6-Amino-3-azabicyclo[3.1.0]hexane-3-carbonyl)-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(2,2-Difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-fluoro-4-[4-[(rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-(Azetidin-3-ylmethyl)-4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 5-[1-Allyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-Aminoazetidine-1-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(3S)-3-(Aminomethyl)pyrrolidine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[4-[[5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-fluoro-benzoyl]piperazine-1-carboxamide; tert-Butyl 2-[5-[[4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]amino]pentylamino]acetate; N-[3-Chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-[(2,2-difluorocyclopropyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(5-Aminopentylcarbamoyl)-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-Amino-2-methyl-propoxy)ethylcarbamoyl]-3-ethyl-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3R)-piperidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(azetidine-3-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 3-[[[2-Chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]methyl]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]piperidine-1-carboxamide; N-[3-Chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-Aminoethyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(1R,3R)-3-Aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Aminocyclohexanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[(1R,3R)-3-Aminocyclopentyl]-4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-(Azetidin-3-yl)-4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[(3-Aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-pyrrolidin-3-yl-piperazine-1-carboxamide; N-(3-Aminocyclobutyl)-4-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]piperidine-1-carboxamide; N-(3-Amino-3-methyl-cyclobutyl)-4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[4-(2-Aminoethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-Benzyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-Aminoethoxy)ethylcarbamoyl]-3-ethyl-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[4-[(1R,2S)-2-Aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-N-(4-piperazin-1-ylsulfonylphenyl)imidazole-2-carboxamide; N-[3-chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3R)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(5-aminopentylcarbamoyl)-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1R,5S)-N-[1-(aminomethyl)-2-chloro-ethyl]-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-chloro-4-(3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2R)-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[5-[1-(2-chloroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[4-(3-aminopropanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[3-[[(3R)-pyrrolidine-3-carbonyl]amino]cyclobutyl]carbamoyl]phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-4-[2-chloro-4-[[5-[1-[(2,2-difluorocyclopropyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-(3-aminopropylcarbamoyl)-3-chloro-phenyl]-1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[3-(methylamino)cyclobutyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S)-2-methylpyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[rac-(1S,5R)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-5-[1-(3-fluorocyclobuta-2-en-1-yl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Fluoro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[6-[(3-Aminocyclobutyl)carbamoylamino]hexylcarbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Bromo-4-[4-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[[rac-(1S,5R)-3-[4-(3-aminopropyl)piperazine-1-carbonyl]-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1R,5S)-N-(3-Aminocyclobutyl)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[(1R,3S)-3-Amino-2,2-dimethyl-cyclobutyl]-4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[3-[(3-aminocyclobutanecarbonyl)amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-Amino-2-hydroxy-propanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[rac-(3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-fluoro-benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-[(2R)-piperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopentyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[3-[[(1R,3S)-3-aminocyclopentyl]carbamoylamino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[3-(aminomethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(2S)-2-aminopropanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]phenyl]sulfonyl-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-Chloro-4-[[rac-(3S,4S)-4-methoxypyrrolidin-3-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[4-(azetidine-2-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-aminoacetyl)piperazin-1-yl]sulfonylphenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[[rac-(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(6-aminohexylcarbamoyl)-3-bromo-phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S)-2,5-diaminopentanoyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(5-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(1R,3R)-3-aminocyclohexanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(3aR,6aS)-2-[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxamide; N-[4-[(4-aminocyclohexyl)methylcarbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-aminoethyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[N-(3-aminopropyl)-S-methyl-sulfonimidoyl]-3-methyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-4-[2-chloro-4-[[5-[1-isobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-(3-aminocyclobutyl)-4-[2-chloro-4-[[5-[1-[(3,3-difluorocyclobutyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-(3-aminocyclobutyl)-4-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-methyl-amino]piperidine-1-carboxamide; N-[3-Chloro-4-[4-(4-methylpiperazine-1-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[6-[[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamoylamino]-3-azabicyclo[3.1.0]hexane-3-carbonyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(2,2-Difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-fluoro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-aminobutanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyclopentylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-4-[2-chloro-4-[[1-methyl-5-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-[[rac-(1S,5R)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(3-Aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-5-[1-(3,3-difluoroallyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-(2,2-Difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-N-(3-methyl-4-methylsulfanyl-phenyl)imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[[[2-Chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]methyl]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxamide; N-[3-Chloro-4-[4-(4-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 5-[1-[(E)-But-2-enyl]-3-(trifluoromethyl)pyrazol-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2R,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; tert-Butyl N-[4-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]butyl]carbamate; N-[4-[[3-[[(3R)-3-aminopyrrolidine-1-carbonyl]amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(6-aminospiro[3.3]heptan-2-yl)carbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxypyrrolidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxypiperidine-3-carbonyl)piperazine- carbonyl]phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(3-azabicyclo[3.2.0]heptan-6-ylcarbamoyl)-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(4-hydroxy-4-piperidyl)methyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[(1S,5R)-3-[(3R)-3-aminopyrrolidine-1-carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-piperidyl)piperidine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[4-[[(2S)-2-aminopropanoyl]amino]cyclohexyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-4-[2-bromo-4-[[5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 3-amino-N-[3-[[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]piperidine-1-carboxamide; N-[4-[[4-[(1S,3R)-3-aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-aminocyclobutyl)-4-[2-chloro-4-[[1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-[[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide; N-[3-Chloro-4-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-Aminoacetyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[methyl-[[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamoyl]amino]butylcarbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[2-(trifluoromethoxy)ethyl]-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-4-methyl-piperidine-1-carboxamide; (1S,5R)-N-[(1R,2S)-2-Aminocyclopentyl]-6-[[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[[2-Chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]piperidine-1-carboxamide; N-[3-Chloro-4-(4-piperazin-1-ylsulfonylpiperazine-1-carbonyl)phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-1-[2-chloro-4-[[5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[4-[4-(3-Aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[(4-hydroxypyrrolidin-3-yl)carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[N-(3-Aminopropyl)-S-methyl-sulfonimidoyl]-3-methyl-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; N-[3-Chloro-4-[(4-methyl-4-piperidyl)carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-(4-Aminobutylcarbamoyl)-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 6-[[2-Chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.2.0]heptane-3-carboxamide; N-[4-[4-[(2R)-azetidine-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[[4-methoxy-1-[[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamoyl]pyrrolidin-3-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[(4-Aminocyclohexyl)carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-cyclopropylethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[N-(3-aminopropyl)-S-methyl-sulfonimidoyl]-3-methyl-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-[[2-chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]cyclobutyl]-3-methyl-piperazine-1-carboxamide; N-[4-(5-aminopentylcarbamoyl)-3-ethyl-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)ethyl-methyl-amino]piperidine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[3-[[3-(aminomethyl)pyrrolidine-1-carbonyl]amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[3-(dimethylamino)-3-methyl-butyl]piperidine-1-carbonyl]phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[3-[[2-(aminomethyl)pyrrolidine-1-carbonyl]amino]cyclobutyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Aminopiperidine-1-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[6-(piperidine-4-carbonyl)-1,6-diazaspiro[3.3]heptane-1-carbonyl]phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(2,2-difluoroethyl)-3-(difluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 6-[[[2-Chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]methyl]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-Chloro-4-[4-(methylamino)piperidine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4S)-4-fluoropyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[methyl(4-piperidyl)carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[(1R,3R)-3-aminocyclopentyl]-4-[2-chloro-4-[[5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(4-hydroxy-1-piperidyl)piperidine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[4-[(3-aminocyclobutanecarbonyl)amino]cyclohexyl]carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[[1-[(3-aminocyclobutyl)carbamoyl]azetidin-3-yl]methylcarbamoyl]-3-chloro-phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-bromo-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(2-aminoethylamino)-2-oxo-ethyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1R,5S)-N-(azetidin-3-yl)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1S,5R)-8-[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxamide; N-[4-[6-(azetidin-3-ylmethylcarbamoyl)amino]hexylcarbamoyl]-3-chloro-phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[3-(trifluoromethyl)-1-[2-(trifluoromethyl)cyclopropyl]pyrazol-4-yl]imidazole-2-carboxamide; (1S,5R)-6-[[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-[(2,2-difluorocyclopropyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; (1S,5R)-6-[[2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; (1S,5R)-6-[[4-[[5-[1-Allyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide or (1S,5R)-6-[[2-Chloro-4-[[5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

39. The compound of formula (I) is: N-(Azetidin-3-yl)-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; 4-[2-Chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[(1S,2R)-2-aminocyclopentyl]-4-[2-chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[4-[(3-Aminocyclobutyl)carbamoyl]-3-chloro-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; 4-[2-Chloro-4-[[1-methyl-5-[1-prop-2-ynyl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]-N-[(rac-(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-spiro[2.3]hexan-5-yl-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[(2,2-difluorocyclopropyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[4-[[5-[1-allyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]-N-(azetidin-3-yl)piperazine-1-carboxamide; N-[3-Chloro-4-(piperazine-1-carbonyl)phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[5-[1-cyclobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; 4-[2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[(3,3-difluorocyclobutyl)methyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-isopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[4-[(1-aminocyclopropyl)methylcarbamoyl]-3-chloro-phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1S)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1R,5S)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-chloro-4-[[rac-(1S,5R)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1S,5R)-6-[[2-chloro-4-[[5-[1-(2-fluoroallyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; rac-(1R,5S)-6-[[2-chloro-4-[[5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,5S)-6-[[2-chloro-4-[[5-[1-[(1S)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-chloro-4-[4-fluoro-4-[[[rac-(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamoylamino]methyl]piperidine-1-carbonyl]phenyl]-5-[1-(2,2-difluorocyclopropyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1-vinyl-pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; ； N-(3-aminocyclobutyl)-6-[[2-chloro-4-[[5-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-[3-Chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-cyclobutyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[4-[2-(2-Amino-2-methyl-propoxy)ethylcarbamoyl]-3-ethyl-phenyl]-5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[5-[1-(cyclopropylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-[[3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]phenyl]-5-[1-(cyclobutylmethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide; rac-(1S,5R)-6-[[2-Chloro-4-[[5-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]amino]-N-[rac-(3R,4R)-4-hydroxypyrrolidin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxamide; N-(3-Aminocyclobutyl)-4-[2-chloro-4-[[5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(3-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-fluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]-1-methyl-imidazole-2-carboxamide or N-(3-aminocyclobutyl)-4-[2-chloro-4-[[1-methyl-5-[1-(2-methylallyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

40. (i) heteroaryl bromide 5 or 15 【Chemical 37】 [wherein, (i) R １ and R ２ together with the nitrogen atom to which they are attached may be substituted with C ８ -C ２ -C ９ -heterocyclic ring (wherein R ８ is as defined in claim 2) to form; or (ii) R １ is hydrogen, C １ -C ６ -alkyl, amino-C １ -C ６ -alkyl-, amino-C １ -C ６ -alkyl-O-C １ -C ６ -alkyl-, or a group 【Chemical Formula 38】 (wherein R ９ , R １０ , A and X2 are as defined in claim 2); and R ２ is hydrogen or C １ -C ６ -alkyl; R ３ and R ７ each independently is hydrogen, halogen or C １ -C ６ -alkyl; and R ６ is C １ -C ６ alkyl], in formula 6b 【Chemical Formula 39】 [wherein, R ４ is halo-C １ -C ６ -alkyl or C ６ -C １４ -aryl; R ５ is C substituted with hydrogen, CF ３ , R １１ and R １２ -C substituted with １ -C ６ -alkyl (wherein R １１ and R １２ are as defined in claim 2), C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, amino-C ２ -C ６ -alkynyl-, C １ -C ６ -alkoxy-C ２ -C ６ -alkynyl-, hydroxy-C ２ -C ６ -alkynyl-, or a group 【Chemical Formula 40】 (wherein R １３ ~R １５ , B and X3 are as defined in claim 2)] with a boronate which is a compound of formula, in the presence of a transition metal catalyst such as 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, to obtain a compound of formula (II-I) according to claim 2, wherein X １ is carbonyl or -SO ２ -; or (ii) carboxylic acid 12a 【Chemical Formula 41】 (wherein R ３ ~R ７ is as defined in claim 2) with amine 1 【Chemical Formula 42】 (wherein R １ and R ２ are as defined in claim 2), and reacting in the presence of a coupling reagent (for example, HATU or TBTU) and a base (for example, DIPEA or triethylamine) to obtain the compound of formula (I-I) according to claim 2, provided that X １ is a carbonyl); or (iii) amine 7 【Chemical 43】 (wherein R １ ~R ４ , R ６ and R ７ are as defined in claim 2) with an alkylating reagent 8 【Chemical 44】 [wherein, X is a leaving group such as a halide (e.g., Br, I, Cl) or a sulfonate, and R ５ is as defined in claim 2] and reacting to obtain a compound of formula (I-I) according to claim 2, provided that X １ is carbonyl); and (iv) Optionally, converting the compound of formula (I-I) into its pharmaceutically acceptable salt A compound of formula (I-I) according to claim 2, comprising (wherein X １ is carbonyl or -SO ２ -), or a pharmaceutically acceptable salt thereof, for use in the synthesis of a method.

41. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

42. The compound of formula (I) according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, for use in the treatment of infections caused by Gram-negative bacteria and bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

43. The pharmaceutical composition according to claim 42, wherein the Gram-negative bacteria are selected from Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli.

44. The pharmaceutical composition according to claim 43, wherein the Gram-negative bacteria are Acinetobacter baumannii.

45. Use of the compound of formula (I) according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful in the treatment of infections caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, and bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

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